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Mendeliome v0.9871 CRYBB2 Zornitza Stark Phenotypes for gene: CRYBB2 were changed from to Cataract 3, multiple types, MIM# 601547
Mendeliome v0.9870 CRYBB2 Zornitza Stark Publications for gene: CRYBB2 were set to
Mendeliome v0.9868 CRYBB2 Zornitza Stark reviewed gene: CRYBB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9158139, 10634616, 11424921, 17234267; Phenotypes: Cataract 3, multiple types, MIM# 601547; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9868 CRYBB1 Zornitza Stark Phenotypes for gene: CRYBB1 were changed from to Cataract 17, multiple types, MIM# 611544
Mendeliome v0.9867 CRYBB1 Zornitza Stark Publications for gene: CRYBB1 were set to
Mendeliome v0.9865 CRYBB1 Zornitza Stark reviewed gene: CRYBB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12360425, 16110300, 17460281, 21972112; Phenotypes: Cataract 17, multiple types, MIM# 611544; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9864 TNFAIP3 Zornitza Stark Publications for gene: TNFAIP3 were set to
Mendeliome v0.9862 TNFAIP3 Zornitza Stark reviewed gene: TNFAIP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26642243, 34030699, 33446651, 32521965, 31299923; Phenotypes: Autoinflammatory syndrome, familial, Behcet-like, MIM# 616744, Inflammatory bowel disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9859 UCP2 Zornitza Stark Publications for gene: UCP2 were set to
Mendeliome v0.9856 UCP2 Zornitza Stark reviewed gene: UCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19065272, 11381268; Phenotypes: {Obesity, susceptibility to, BMIQ4} 607447, Hyperinsulinism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9856 CRYBA4 Zornitza Stark Phenotypes for gene: CRYBA4 were changed from to Cataract 23, MIM# 610425
Mendeliome v0.9855 CRYBA4 Zornitza Stark Publications for gene: CRYBA4 were set to
Mendeliome v0.9853 CRYBA4 Zornitza Stark reviewed gene: CRYBA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 16960806, 16960806, 20577656; Phenotypes: Cataract 23, MIM# 610425; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9853 CRYBA1 Zornitza Stark Phenotypes for gene: CRYBA1 were changed from to Cataract 10, multiple types, MIM# 600881
Mendeliome v0.9852 CRYBA1 Zornitza Stark Publications for gene: CRYBA1 were set to
Mendeliome v0.9850 CRYBA1 Zornitza Stark reviewed gene: CRYBA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9788845, 14598164, 34419537, 33827296, 31488069; Phenotypes: Cataract 10, multiple types, MIM# 600881; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9850 CRYAA Zornitza Stark Phenotypes for gene: CRYAA were changed from to Cataract 9, multiple types, MIM# 604219
Mendeliome v0.9849 CRYAA Zornitza Stark Publications for gene: CRYAA were set to
Mendeliome v0.9847 CRYAA Zornitza Stark reviewed gene: CRYAA: Rating: GREEN; Mode of pathogenicity: None; Publications: 9467006, 11006246, 16735993, 17724170, 23255486; Phenotypes: Cataract 9, multiple types, MIM# 604219; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9846 CALU Ain Roesley reviewed gene: CALU: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.9845 EDNRA Zornitza Stark Publications for gene: EDNRA were set to
Mendeliome v0.9843 EDNRA Zornitza Stark reviewed gene: EDNRA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25772936, 27671791; Phenotypes: Mandibulofacial dysostosis with alopecia, MIM# 616367; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9842 DVL3 Zornitza Stark Publications for gene: DVL3 were set to
Mendeliome v0.9840 DVL3 Zornitza Stark reviewed gene: DVL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26924530; Phenotypes: Robinow syndrome, autosomal dominant 3 MIM#616894; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9839 IRF6 Zornitza Stark Publications for gene: IRF6 were set to 20301581
Mendeliome v0.9837 IRF6 Zornitza Stark Publications for gene: IRF6 were set to
Mendeliome v0.9834 MATN3 Zornitza Stark Publications for gene: MATN3 were set to
Mendeliome v0.9831 INPPL1 Zornitza Stark Publications for gene: INPPL1 were set to
Mendeliome v0.9829 INPPL1 Zornitza Stark reviewed gene: INPPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9828 MAF Zornitza Stark Publications for gene: MAF were set to
Mendeliome v0.9825 LRP4 Zornitza Stark Publications for gene: LRP4 were set to
Mendeliome v0.9824 LRP4 Zornitza Stark reviewed gene: LRP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24234652, 26052878, 24200689, 21471202, 32286743, 28477420, 26751728, 29524275; Phenotypes: Myasthenic syndrome, congenital, 17, MIM# 616304, Sclerosteosis 2, MIM# 614305, Syndactyly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9822 MLC1 Zornitza Stark Publications for gene: MLC1 were set to
Mendeliome v0.9819 MMP13 Zornitza Stark Publications for gene: MMP13 were set to
Mendeliome v0.9817 MBTPS2 Zornitza Stark Publications for gene: MBTPS2 were set to
Mendeliome v0.9813 IHH Zornitza Stark Publications for gene: IHH were set to
Mendeliome v0.9809 KCTD1 Zornitza Stark Publications for gene: KCTD1 were set to
Mendeliome v0.9803 MID1 Zornitza Stark Publications for gene: MID1 were set to
Mendeliome v0.9799 KAT6A Zornitza Stark Publications for gene: KAT6A were set to
Mendeliome v0.9798 MESP2 Zornitza Stark Publications for gene: MESP2 were set to
Mendeliome v0.9795 KAT6A Zornitza Stark reviewed gene: KAT6A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.9793 CRLF1 Zornitza Stark Publications for gene: CRLF1 were set to
Mendeliome v0.9791 CRLF1 Zornitza Stark reviewed gene: CRLF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12509788, 17436251, 17436252; Phenotypes: Cold-induced sweating syndrome 1, MIM#272430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9790 CPT2 Zornitza Stark Publications for gene: CPT2 were set to
Mendeliome v0.9788 CPT2 Zornitza Stark reviewed gene: CPT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11477613, 12410208, 8651281, 12410208, 8358442; Phenotypes: CPT II deficiency, infantile 600649, CPT II deficiency, lethal neonatal 608836, CPT II deficiency, myopathic, stress-induced 255110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9787 COX7B Zornitza Stark Publications for gene: COX7B were set to
Mendeliome v0.9785 COX7B Zornitza Stark reviewed gene: COX7B: Rating: GREEN; Mode of pathogenicity: None; Publications: 23122588; Phenotypes: Linear skin defects with multiple congenital anomalies 2, MIM#300887; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.9785 IRF6 Ain Roesley reviewed gene: IRF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301581; Phenotypes: Popliteal pterygium syndrome 1MIM#119500, van der Woude syndrome MIM#119300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.9785 MATN3 Daniel Flanagan reviewed gene: MATN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31724101, 32025536, 11968079, 14729835; Phenotypes: Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type (MIM#608728), Epiphyseal dysplasia, multiple, 5 (MIM#607078); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9785 INPPL1 Ain Roesley reviewed gene: INPPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23273567, 34529350, 34094554; Phenotypes: Opsismodysplasia MIM#258480; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.9785 MAF Daniel Flanagan reviewed gene: MAF: Rating: GREEN; Mode of pathogenicity: None; Publications: 30160832, 34643041; Phenotypes: Ayme-Gripp syndrome (MIM#601088); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9784 COQ4 Zornitza Stark Publications for gene: COQ4 were set to
Mendeliome v0.9782 COQ4 Zornitza Stark reviewed gene: COQ4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25658047, 26185144, 33704555; Phenotypes: Coenzyme Q10 deficiency, primary, 7, MIM# 616276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9782 LRP4 Daniel Flanagan reviewed gene: LRP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23636941, 23664847, 30041615, 20381006; Phenotypes: Cenani-Lenz syndactyly syndrome (MIM#212780); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9781 COLEC11 Zornitza Stark Publications for gene: COLEC11 were set to
Mendeliome v0.9779 COLEC11 Zornitza Stark reviewed gene: COLEC11: Rating: GREEN; Mode of pathogenicity: None; Publications: 21258343, 26789649, 28301481; Phenotypes: 3MC syndrome 2, MIM# 265050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9779 MLC1 Daniel Flanagan reviewed gene: MLC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11254442, 18757878, 16652334; Phenotypes: Megalencephalic leukoencephalopathy with subcortical cysts (MIM#604004); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9779 MBTPS2 Daniel Flanagan reviewed gene: MBTPS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27380894, 19361614, 21426410; Phenotypes: Osteogenesis imperfecta, type XIX, (MIM301014), IFAP syndrome with or without BRESHECK syndrome (MIM#308205), Keratosis follicularis spinulosa decalvans, X-linked (MIM#308800), ?Olmsted syndrome, X-linked (MIM#300918); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.9779 MMP13 Daniel Flanagan reviewed gene: MMP13: Rating: GREEN; Mode of pathogenicity: Other; Publications: 19615667, 24781753, 24648384; Phenotypes: Metaphyseal anadysplasia 1 (MIM#602111), Metaphyseal dysplasia, Spahr type (MIM#250400), ?Spondyloepimetaphyseal dysplasia, Missouri type (MIM#602111); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9779 IHH Ain Roesley reviewed gene: IHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 34530144, 12632327, 32311039, 29155992; Phenotypes: Acrocapitofemoral dysplasia MIM#607778, Brachydactyly, type A1 MIM#112500; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.9779 KIAA1109 Ain Roesley reviewed gene: KIAA1109: Rating: GREEN; Mode of pathogenicity: None; Publications: 29290337, 30906834; Phenotypes: Alkuraya-Kucinskas syndrome MIM#617822; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.9779 KCTD1 Ain Roesley reviewed gene: KCTD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23541344, 31324836; Phenotypes: Scalp-ear-nipple syndrome MIM#181270; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.9779 KCNJ2 Ain Roesley reviewed gene: KCNJ2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Andersen syndrome MIM#170390, Atrial fibrillation, familial, 9 MIM#613980, Short QT syndrome 3 MIM#609622; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.9779 MID1 Daniel Flanagan reviewed gene: MID1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1103076, 9354791; Phenotypes: Opitz GBBB syndrome, type I (MIM#300000); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9779 KAT6A Ain Roesley reviewed gene: KAT6A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30245513; Phenotypes: Arboleda-Tham syndrome MIM#616268; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.9779 MESP2 Daniel Flanagan reviewed gene: MESP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18485326; Phenotypes: Spondylocostal dysostosis 2, autosomal recessive (MIM#608681); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9779 ZNF365 Ain Roesley reviewed gene: ZNF365: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.9778 COG1 Zornitza Stark Publications for gene: COG1 were set to
Mendeliome v0.9776 COG1 Zornitza Stark reviewed gene: COG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16537452, 19008299, 17904886, 11980916; Phenotypes: Congenital disorder of glycosylation, type IIg, MIM# 611209; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9776 NEBL Bryony Thompson Added comment: Comment on list classification: Limited gene-disease vailidity, Classification - 09/25/2020 by ClinGen Dilated Cardiomyopathy GCEP. Evidence Summary: NEBL was evaluated for autosomal dominant dilated cardiomyopathy (DCM). Human genetic evidence supporting this gene-disease relationship includes case-level data. Arimura and colleagues (2000, PMID: 11140941) analyzed 83 DCM patients and 311 healthy controls, identifying 4 missense variants of unknown significance (VUSs) in 4 DCM cases. High minor allele frequencies (MAFs) and lack of segregation excluded these variants as evidence. Purevjav and colleagues (2010, PMID: 20951326) investigated a total of 260 DCM patients and 300 unrelated ethnic matched controls by direct DNA sequencing. Authors identified 4 missense VUSs. One of these variants (Q128R) was downgraded in level of evidence due to the lack of segregation. The other 3 variants were not scored because of their MAF. Perrot and colleagues (2016, PMID: 27186169) investigated a total of 389 patients with DCM, HCM, or LVNC, 320 Caucasian sex-matched controls and 192 Caucasian sex-matched blood donors and identified 3 missense VUSs in 4 families. One of these variants was also carried by healthy relatives and therefore was excluded, however this may be explained by reduced penetrance. The 2 other variants lacked segregation as well and therefore were also excluded. In addition, this gene-disease association is supported by animal models. Mastronotaro and colleagues (2015, PMID: 25987543) created a NEBL knockout mice that exhibited normal cardiac function up to 9 months of age but after 2 weeks of transaortic constriction (TAC), these mice showed Z-line widening since the age of 5 months and upregulation of cardiac stress genes (basal and after TAC) However, absence of clinical DCM features in KO-NEBL mice as well as Western Blot analysis which contradicted previous findings by showing a similar protein expression between knockout and wild-type mice, excluding it as evidence. Purevjav and colleagues (2010, PMID: 20951326) generated a transgenic mouse overexpressing WT or mutant NEBL under the control of the α-MyHC promoter (4 variants were tested). Mice overexpressing p.K60N or p.Q128R variants died within 1 year because of severe heart enlargement and heart failure. Mice overexpressing p.G202R or p.A592E were born and developed normally but after 6 months displayed reduced stress tolerance, cardiac enlargement due to left ventricle dilation, myocyte disarray, and interstitial cell infiltration. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of NEBL and autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 11, 2019 (SOP Version 7). Gene Clinical Validity Standard Operating Procedures (SOP) - SOP7
Mendeliome v0.9774 SPATA5L1 Zornitza Stark edited their review of gene: SPATA5L1: Added comment: Note some of the affected individuals had isolated deafness, hence two OMIM phenotypes have been associated with this gene. All were of Ashkenazi Jewish origin, and had the p.Ile466Met founder variant, either hmz or compound het with another variant.; Changed publications: 34626583; Changed phenotypes: Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616, Deafness, autosomal recessive 119, MIM# 619615
Mendeliome v0.9774 SPATA5L1 Zornitza Stark reviewed gene: SPATA5L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9773 MEIS2 Zornitza Stark Publications for gene: MEIS2 were set to
Mendeliome v0.9770 LAMA4 Zornitza Stark Publications for gene: LAMA4 were set to
Mendeliome v0.9767 LAMA4 Zornitza Stark reviewed gene: LAMA4: Rating: RED; Mode of pathogenicity: None; Publications: 17646580, 26406308, 27532257; Phenotypes: Cardiomyopathy, dilated, 1JJ (MIM#615235); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9763 NR4A3 Ain Roesley reviewed gene: NR4A3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.9763 PRKG2 Zornitza Stark Publications for gene: PRKG2 were set to 33106379
Mendeliome v0.9762 PRKG2 Zornitza Stark reviewed gene: PRKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34782440; Phenotypes: Acromesomelic dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9762 MED17 Zornitza Stark edited their review of gene: MED17: Changed publications: 30345598, 33756211
Mendeliome v0.9761 CNTNAP2 Zornitza Stark Publications for gene: CNTNAP2 were set to
Mendeliome v0.9759 CNTNAP2 Zornitza Stark reviewed gene: CNTNAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16571880, 19896112, 27439707; Phenotypes: Cortical dysplasia-focal epilepsy syndrome, MIM# 610042; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9758 CKAP2L Zornitza Stark Publications for gene: CKAP2L were set to
Mendeliome v0.9756 CKAP2L Zornitza Stark reviewed gene: CKAP2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439729, 33913579, 29473684; Phenotypes: Filippi syndrome, MIM# 272440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9755 P3H1 Zornitza Stark Publications for gene: P3H1 were set to
Mendeliome v0.9753 P3H1 Dean Phelan reviewed gene: P3H1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 17277775, 19088120, 27864101, 33737016; Phenotypes: Osteogenesis imperfecta; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9753 CHST3 Zornitza Stark Phenotypes for gene: CHST3 were changed from to Spondyloepiphyseal dysplasia with congenital joint dislocations, MIM# 143095
Mendeliome v0.9752 CHST3 Zornitza Stark Publications for gene: CHST3 were set to
Mendeliome v0.9750 CHST3 Zornitza Stark reviewed gene: CHST3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513679; Phenotypes: Spondyloepiphyseal dysplasia with congenital joint dislocations, MIM# 143095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9749 IL1RAPL1 Zornitza Stark Publications for gene: IL1RAPL1 were set to
Mendeliome v0.9746 IFITM5 Zornitza Stark Publications for gene: IFITM5 were set to
Mendeliome v0.9742 CHRND Zornitza Stark Publications for gene: CHRND were set to
Mendeliome v0.9740 CHRND Zornitza Stark reviewed gene: CHRND: Rating: GREEN; Mode of pathogenicity: None; Publications: 16916845, 11435464, 12499478, 18398509, 11782989, 29399782, 18252226; Phenotypes: Myasthenic syndrome, congenital, 3B, fast-channel, MIM#616322, Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency, MIM#616323, Myasthenic syndrome, congenital, 3A, slow-channel, MIM#616321, Multiple pterygium syndrome, lethal type, MIM# 253290, MONDO:0009668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9739 CHRNA1 Zornitza Stark Publications for gene: CHRNA1 were set to
Mendeliome v0.9737 CHRNA1 Zornitza Stark reviewed gene: CHRNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26910802, 10195214, 12588888, 15079006, 18806275, 7619526, 8872460, 9158151, 18252226; Phenotypes: Multiple pterygium syndrome, lethal type, MIM# 253290, MONDO:0009668, Myasthenic syndrome, congenital, 1A, slow-channel, MIM# 601462, Myasthenic syndrome, congenital, 1B, fast-channel , MIM#608930; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9737 IMPAD1 Ain Roesley reviewed gene: IMPAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22887726, 21549340; Phenotypes: Chondrodysplasia with joint dislocations, GPAPP type MIM#614078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.9737 IL1RAPL1 Ain Roesley reviewed gene: IL1RAPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34452636, 27470653, 21484992, 18801879, 18801879; Phenotypes: Intellectual developmental disorder, X-linked 21 MIM#300143; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v0.9736 MAFB Zornitza Stark Publications for gene: MAFB were set to
Mendeliome v0.9735 MAFB Zornitza Stark reviewed gene: MAFB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27181683; Phenotypes: Duane retraction syndrome 3, MIM# 617041; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9733 MAFB Daniel Flanagan reviewed gene: MAFB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23956186, 30208859; Phenotypes: Multicentric carpotarsal osteolysis syndrome (MIM#166300); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9733 IFITM5 Ain Roesley reviewed gene: IFITM5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22863190, 22863195, 32383316, 24519609; Phenotypes: Osteogenesis imperfecta, type V MIM#610967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.9732 CHKB Zornitza Stark Publications for gene: CHKB were set to
Mendeliome v0.9730 CHKB Zornitza Stark reviewed gene: CHKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 21665002, 23692895, 24997086; Phenotypes: Muscular dystrophy, congenital, megaconial type, MIM# 602541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9729 CHAMP1 Zornitza Stark Publications for gene: CHAMP1 were set to
Mendeliome v0.9727 CHAMP1 Zornitza Stark reviewed gene: CHAMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27148580, 26340335; Phenotypes: Mental retardation, autosomal dominant 40 (MIM#616579); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9725 CFTR Zornitza Stark reviewed gene: CFTR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cystic fibrosis, MIM# 219700, Congenital bilateral absence of vas deferens, MIM# 277180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9725 ASIP Ain Roesley reviewed gene: ASIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.9724 ETV6 Zornitza Stark Publications for gene: ETV6 were set to
Mendeliome v0.9722 ETV6 Zornitza Stark reviewed gene: ETV6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25581430, 25807284; Phenotypes: Thrombocytopaenia 5, MIM# 616216; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9719 TPCN2 Zornitza Stark Publications for gene: TPCN2 were set to
Mendeliome v0.9716 MYO9B Zornitza Stark Publications for gene: MYO9B were set to
Mendeliome v0.9714 HKDC1 Zornitza Stark gene: HKDC1 was added
gene: HKDC1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: HKDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HKDC1 were set to 30085091
Phenotypes for gene: HKDC1 were set to Retinitis pigmentosa 92, MIM# 619614
Review for gene: HKDC1 was set to RED
Added comment: Two unrelated Chinese men reported with relatively late-onset RP, and same homozygous missense variant.
Sources: Expert Review
Mendeliome v0.9713 BSG Paul De Fazio reviewed gene: BSG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Blood group, OK] MIM#111380; Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9713 TPCN2 Paul De Fazio reviewed gene: TPCN2: Rating: RED; Mode of pathogenicity: None; Publications: 20197744, 26918892; Phenotypes: [Skin/hair/eye pigmentation 10, blond/brown hair] MIM#612267; Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9713 MYO9B Paul De Fazio reviewed gene: MYO9B: Rating: RED; Mode of pathogenicity: None; Publications: 16720215, 16423886, 16282976; Phenotypes: {Celiac disease, susceptibility to, 4} MIM#609753; Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9712 CENPJ Zornitza Stark Publications for gene: CENPJ were set to
Mendeliome v0.9710 CENPJ Zornitza Stark reviewed gene: CENPJ: Rating: GREEN; Mode of pathogenicity: None; Publications: 20522431, 23166506, 15793586, 20978018, 22775483, 32677750, 32549991; Phenotypes: Microcephaly 6, primary, autosomal recessive, MIM# 608393, MONDO:0012029, Seckel syndrome 4, MIM# 613676, MONDO:0013358; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9709 CDON Zornitza Stark Publications for gene: CDON were set to
Mendeliome v0.9707 CDON Zornitza Stark reviewed gene: CDON: Rating: GREEN; Mode of pathogenicity: None; Publications: 21802063, 26529631, 26728615, 23071453; Phenotypes: Holoprosencephaly 11, MIM# 614226, MONDO:0013642; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9706 CDH3 Zornitza Stark Publications for gene: CDH3 were set to
Mendeliome v0.9704 CDH3 Zornitza Stark reviewed gene: CDH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11544476, 15805154, 28061825, 22140374; Phenotypes: Ectodermal dysplasia, ectrodactyly, and macular dystrophy, MIM# 225280, Hypotrichosis, congenital, with juvenile macular dystrophy, MIM# 601553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9704 EFHC1 Zornitza Stark reviewed gene: EFHC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.9704 EFHC1 Bryony Thompson Added comment: Comment on list classification: ClinGen Epilepsy GCEP gene-disease association curation: Disputed - We have disregarded the very limited functional evidence in light of the complete lack of genetic evidence connecting EFHC1 and epilepsy. In summary, there is convincing evidence disputing the association between EFHC1 and epilepsy. All variants in EFHC1 associated with epilepsy have contradictory evidence for disease association (too common in ExAC/gnomAD, with minor allele frequencies (MAF) of 2.857e-5 to 0.05973). More evidence is needed to either support or refute the role EFHC1 plays in this disease. Classification - 07/27/2018, reviewed Sept 2021
Mendeliome v0.9702 MICAL1 Bryony Thompson gene: MICAL1 was added
gene: MICAL1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MICAL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MICAL1 were set to 29394500; 21638339
Phenotypes for gene: MICAL1 were set to Autosomal dominant epilepsy with auditory features (ADEAF)
Review for gene: MICAL1 was set to AMBER
Added comment: Two families with supporting in vitro functional assays. Assessment of expression pattern of Mical-1 in the temporal neocortex of patients with intractable temporal epilepsy and pilocarpine-induced rat model, suggests Mical-1 may associate with inner pathophysiological modulation in epilepsy.
Sources: Expert list
Mendeliome v0.9701 CPA6 Bryony Thompson Added comment: Comment on list classification: ClinGen Epilepsy GCEP has reviewed both inheritances for gene-disease associations with epilepsy: AR disease is Disputed - There is contradictory case level and experimental data regarding any association between CPA6 and autosomal recessive epilepsy. Classification - 07/29/2021 AD disease is Refuted- There is very limited evidence supporting a gene-disease association. Many of the reported pathogenic variants have been subsequently identified as having a high minor allele frequency in population databases. Classification - 07/29/2021
Mendeliome v0.9700 CNTN2 Bryony Thompson Publications for gene: CNTN2 were set to 23518707
Mendeliome v0.9698 CNTN2 Bryony Thompson reviewed gene: CNTN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 23518707, 34120799, 34691156; Phenotypes: Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9696 ADSSL1 Zornitza Stark Publications for gene: ADSSL1 were set to
Mendeliome v0.9694 ADSSL1 Zornitza Stark reviewed gene: ADSSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26506222; Phenotypes: Myopathy, distal, 5, MIM#617030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9693 BRAT1 Zornitza Stark Publications for gene: BRAT1 were set to
Mendeliome v0.9691 BRAT1 Zornitza Stark edited their review of gene: BRAT1: Changed publications: 26483087, 26494257, 27282546, 22279524, 23035047, 25319849, 25500575, 34747546; Changed phenotypes: Neurodevelopmental disorder with cerebellar atrophy and with or without seizures, MIM#618056, Rigidity and multifocal seizure syndrome, lethal neonatal, MIM# 614498
Mendeliome v0.9687 BMPR1B Zornitza Stark Publications for gene: BMPR1B were set to
Mendeliome v0.9685 BMPR1B Zornitza Stark reviewed gene: BMPR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 15805157, 24129431, 26105076, 25758993, 14523231, 14523231; Phenotypes: Acromesomelic dysplasia, Demirhan type, MIM# 609441, Brachydactyly, type A1, D, MIM# 616849, Brachydactyly, type A2, MIM# 112600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9684 BMPER Zornitza Stark Publications for gene: BMPER were set to
Mendeliome v0.9682 BMPER Zornitza Stark edited their review of gene: BMPER: Changed publications: 20869035, 30006055
Mendeliome v0.9681 BMP4 Zornitza Stark Publications for gene: BMP4 were set to
Mendeliome v0.9679 BMP4 Zornitza Stark reviewed gene: BMP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31053785, 19249007, 31909686, 21340693; Phenotypes: Orofacial cleft 11 600625, Microphthalmia, syndromic 6, MIM# 607932; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9678 BMP2 Zornitza Stark Publications for gene: BMP2 were set to
Mendeliome v0.9676 BMP2 Zornitza Stark reviewed gene: BMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29198724; Phenotypes: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1, MIM# 617877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9675 BMP1 Zornitza Stark Publications for gene: BMP1 were set to
Mendeliome v0.9673 BMP1 Zornitza Stark reviewed gene: BMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25402547, 22052668, 22482805, 25214535; Phenotypes: Osteogenesis imperfecta, type XIII , MIM#614856; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9672 BIN1 Zornitza Stark Publications for gene: BIN1 were set to
Mendeliome v0.9670 BIN1 Zornitza Stark reviewed gene: BIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17676042; Phenotypes: Centronuclear myopathy 2, MIM# 255200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9669 BHLHA9 Zornitza Stark Publications for gene: BHLHA9 were set to
Mendeliome v0.9667 BHLHA9 Zornitza Stark reviewed gene: BHLHA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25466284, 34272776, 31912643, 31152918, 30107244; Phenotypes: Syndactyly, mesoaxial synostotic, with phalangeal reduction, MIM# 609432; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9666 DLL4 Zornitza Stark Publications for gene: DLL4 were set to
Mendeliome v0.9664 DLL4 Zornitza Stark reviewed gene: DLL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26299364, 33899511, 31261205, 29924900; Phenotypes: Adams-Oliver syndrome 6 MIM#616589; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9664 BFSP2 Zornitza Stark Phenotypes for gene: BFSP2 were changed from to Cataract 12, multiple types, MIM# 611597
Mendeliome v0.9663 BFSP2 Zornitza Stark Publications for gene: BFSP2 were set to
Mendeliome v0.9661 BFSP2 Zornitza Stark reviewed gene: BFSP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10729115, 10739768, 15570218, 24654948, 21836522; Phenotypes: Cataract 12, multiple types, MIM# 611597; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9658 HPSE2 Zornitza Stark Publications for gene: HPSE2 were set to
Mendeliome v0.9656 HNRNPK Zornitza Stark Publications for gene: HNRNPK were set to 29904177
Mendeliome v0.9655 HNRNPK Zornitza Stark reviewed gene: HNRNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: 30998304, 26173930, 29904177, 26954065, 28771707; Phenotypes: Au-Kline syndrome MIM#616580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9655 HNRNPK Zornitza Stark Publications for gene: HNRNPK were set to
Mendeliome v0.9651 HES7 Zornitza Stark Publications for gene: HES7 were set to
Mendeliome v0.9648 DIS3L2 Zornitza Stark Publications for gene: DIS3L2 were set to
Mendeliome v0.9646 DIS3L2 Zornitza Stark reviewed gene: DIS3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22306653, 28328139, 29950491; Phenotypes: Perlman syndrome MIM# 267000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9645 DDX3X Zornitza Stark Publications for gene: DDX3X were set to
Mendeliome v0.9643 DDX3X Zornitza Stark reviewed gene: DDX3X: Rating: GREEN; Mode of pathogenicity: None; Publications: 30266093, 26235985, 25533962, 33528536, 30936465, 31274575, 30817323; Phenotypes: Intellectual developmental disorder, X-linked, syndrome, Snijders Blok type MIM# 300958; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.9640 HSD17B3 Zornitza Stark Publications for gene: HSD17B3 were set to
Mendeliome v0.9638 HSD17B3 Zornitza Stark reviewed gene: HSD17B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 8550739, 11158067; Phenotypes: Pseudohermaphroditism, male, with gynecomastia MIM#264300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9638 HR Ain Roesley reviewed gene: HR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alopecia universalis MIM#203655, Atrichia with papular lesions MIM#209500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.9638 HPSE2 Ain Roesley reviewed gene: HPSE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25145936, 23313374, 33558177; Phenotypes: Urofacial syndrome 1 MIM#236730; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.9638 HNRNPK Ain Roesley reviewed gene: HNRNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Au-Kline syndrome MIM#616580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.9638 HES7 Ain Roesley reviewed gene: HES7: Rating: ; Mode of pathogenicity: None; Publications: 29459493, 23897666, 18775957, 20087400; Phenotypes: Spondylocostal dysostosis 4, autosomal recessive MIM#613686; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.9636 C9orf3 Zornitza Stark gene: C9orf3 was added
gene: C9orf3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C9orf3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C9orf3 were set to 34596301
Phenotypes for gene: C9orf3 were set to Dystonia 31, MIM# 619565
Review for gene: C9orf3 was set to GREEN
Added comment: Dystonia-31 (DYT31) is an autosomal recessive progressive neurologic disorder characterized by involuntary muscle twisting movements and postural abnormalities affecting the upper and lower limbs, neck, face, and trunk. Some patients may have orofacial dyskinesia resulting in articulation and swallowing difficulties. The age at onset ranges from childhood to young adulthood. There are usually no additional neurologic symptoms, although late-onset parkinsonism was reported in 1 family.

5 individuals from 4 unrelated families reported.

HGNC approved name is AOPEP.
Sources: Literature
Mendeliome v0.9633 ASXL1 Zornitza Stark Publications for gene: ASXL1 were set to
Mendeliome v0.9631 ASXL1 Zornitza Stark reviewed gene: ASXL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29446906, 21706002; Phenotypes: Bohring-Opitz syndrome , MIM#605039; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9630 ASNS Zornitza Stark Publications for gene: ASNS were set to
Mendeliome v0.9628 ASNS Zornitza Stark edited their review of gene: ASNS: Changed publications: 24139043
Mendeliome v0.9628 SIK3 Krithika Murali gene: SIK3 was added
gene: SIK3 was added to Mendeliome. Sources: Expert list,Literature
Mode of inheritance for gene: SIK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIK3 were set to 30232230; 22318228
Phenotypes for gene: SIK3 were set to ?Spondyloepimetaphyseal dysplasia, Krakow type - #618162
Review for gene: SIK3 was set to AMBER
Added comment: Biallelic SIK3 variants reported in 2 siblings from a consanguineous family with an uncharacterised skeletal dysplasia. Radiographic features included widened/flared metaphyses with irregular ossifications, motheaten long bones, fragmentation of the proximal metacarpals, rounded vertebral bodies, and a distinctive transverse gap seen in the tibias.

In addition to the skeletal phenotype, the siblings manifested significant developmental delay with brain MRI abnormalities, a severe unclassified immunodeficiency, and normal parathyroid hormone concentration with mild hypercalcemia.

One sibling had a more severe phenotype, particularly immunodeficiency, and died of Epstein-Barr virus induced small muscle cancer at 10 years of age.

Mouse models support impaired chondrocyte development with skeletal dysplasia phenotye.
Sources: Expert list, Literature
Mendeliome v0.9627 ANTXR1 Zornitza Stark Publications for gene: ANTXR1 were set to
Mendeliome v0.9625 ANTXR1 Zornitza Stark reviewed gene: ANTXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23602711, 25045128, 31425299, 30575274, 29436111, 28870703; Phenotypes: GAPO syndrome, MIM# 230740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9624 ANOS1 Zornitza Stark Publications for gene: ANOS1 were set to
Mendeliome v0.9622 ANOS1 Zornitza Stark reviewed gene: ANOS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1594017, 8504298, 8989261; Phenotypes: Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), MIM# 308700; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9621 LTBP4 Zornitza Stark Publications for gene: LTBP4 were set to
Mendeliome v0.9619 LTBP4 Zornitza Stark reviewed gene: LTBP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22829427, 19836010, 28684544; Phenotypes: Cutis laxa, autosomal recessive, type IC, MIM# 613177; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9618 EFEMP2 Zornitza Stark Publications for gene: EFEMP2 were set to
Mendeliome v0.9616 EFEMP2 Zornitza Stark reviewed gene: EFEMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30140196, 23532871, 31548410, 19664000; Phenotypes: Autosomal recessive cutis laxa type 1B (ARCL1B), MIM# 614437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9616 MYH10 Krithika Murali gene: MYH10 was added
gene: MYH10 was added to Mendeliome. Sources: Expert list,Literature
Mode of inheritance for gene: MYH10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYH10 were set to 24825879; 24901346; 25356899; 22495309; 25003005
Phenotypes for gene: MYH10 were set to Microcephaly; Intellectual Disability
Review for gene: MYH10 was set to GREEN
Added comment: De novo variants were identified in 5 unrelated individuals with moderate-severe ID and developmental delay.

Other reported phenotypic features include microcephaly (4/5), IUGR/failure to thrive (4/5), cerebral atrophy (3/5), hydrocephalus (2/5), congenital bilateral hip dysplasia (2/5), cerebellar atrophy (1/5), congenital diaphragmatic hernia (1/5), cranial nerve palsy (1/5), nystagmus (1/5), dysplastic kidney (1/5).

Defects in heart development, body wall closure and other birth defects noted in mouse models.
Sources: Expert list, Literature
Mendeliome v0.9615 CSF2RB Zornitza Stark Publications for gene: CSF2RB were set to
Mendeliome v0.9613 CSF2RB Zornitza Stark reviewed gene: CSF2RB: Rating: GREEN; Mode of pathogenicity: None; Publications: 21205713, 27514590, 7568173, 30846703; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 5, MIM#614370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9612 CSF2RA Zornitza Stark Publications for gene: CSF2RA were set to
Mendeliome v0.9610 CSF2RA Zornitza Stark reviewed gene: CSF2RA: Rating: GREEN; Mode of pathogenicity: None; Publications: 20622029, 25425184, 18955570; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 4, MIM# 300770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9609 RNPC3 Zornitza Stark Publications for gene: RNPC3 were set to 29866761; 32462814
Mendeliome v0.9607 RNPC3 Zornitza Stark edited their review of gene: RNPC3: Added comment: PMID 33650182: third individual reported with growth failure and ID.; Changed rating: GREEN; Changed publications: 29866761, 32462814, 33650182; Changed phenotypes: Growth hormone deficiency, Intellectual disability
Mendeliome v0.9606 OTUD7A Zornitza Stark Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Mendeliome v0.9604 OTUD7A Zornitza Stark edited their review of gene: OTUD7A: Added comment: Additional patient reported in PMID 33381903, with hypotonia, ID and seizures. Bi-allelic LoF variants. Some supportive functional data.; Changed rating: AMBER; Changed publications: 31997314, 29395075, 29395074, 33381903
Mendeliome v0.9603 GNAQ Zornitza Stark Publications for gene: GNAQ were set to
Mendeliome v0.9600 GNAQ Zornitza Stark reviewed gene: GNAQ: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30920161; Phenotypes: Sturge-Weber syndrome, somatic, mosaic 185300, Capillary malformations, congenital, 1, somatic, mosaic 163000, Phacomatosis pigmentovascularis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9599 AKR1C2 Zornitza Stark Publications for gene: AKR1C2 were set to
Mendeliome v0.9596 AKR1C2 Zornitza Stark reviewed gene: AKR1C2: Rating: RED; Mode of pathogenicity: None; Publications: 21802064, 25322899, 33675863; Phenotypes: 46XY sex reversal 8, MIM# 614279, Obesity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9595 AMER1 Zornitza Stark Publications for gene: AMER1 were set to
Mendeliome v0.9593 AMER1 Zornitza Stark reviewed gene: AMER1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20209645, 19079258; Phenotypes: Osteopathia striata with cranial sclerosis, MIM# 300373; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.9592 ALG1 Zornitza Stark Publications for gene: ALG1 were set to
Mendeliome v0.9590 ALG1 Zornitza Stark reviewed gene: ALG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26931382; Phenotypes: Congenital disorder of glycosylation, type Ik, MIM# 608540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9590 NUP85 Eleanor Williams reviewed gene: NUP85: Rating: ; Mode of pathogenicity: None; Publications: 34170319; Phenotypes: intellectual disability, Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH–SCKS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9590 GNB2 Eleanor Williams reviewed gene: GNB2: Rating: ; Mode of pathogenicity: None; Publications: 34124757; Phenotypes: Sturge-Weber syndrome, somatic, mosaic, OMIM:185300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.9590 GNAQ Eleanor Williams reviewed gene: GNAQ: Rating: ; Mode of pathogenicity: None; Publications: 34124757; Phenotypes: Sturge-Weber syndrome, somatic, mosaic, OMIM:185300; Mode of inheritance: None
Mendeliome v0.9589 TUB Zornitza Stark Publications for gene: TUB were set to
Mendeliome v0.9586 TUB Zornitza Stark reviewed gene: TUB: Rating: AMBER; Mode of pathogenicity: None; Publications: 24375934, 28852204; Phenotypes: Retinal dystrophy and obesity, MIM# 616188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9586 KSR2 Zornitza Stark gene: KSR2 was added
gene: KSR2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KSR2 was set to Other
Publications for gene: KSR2 were set to 29273807; 24209692
Phenotypes for gene: KSR2 were set to Obesity
Review for gene: KSR2 was set to RED
Added comment: PMID: 24209692 Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. PMID: 29273807 GWAS identified KSR2 (13 genes studied) implicated in extreme obesity.
Sources: Expert Review
Mendeliome v0.9584 SIM1 Zornitza Stark Publications for gene: SIM1 were set to
Mendeliome v0.9581 SIM1 Zornitza Stark edited their review of gene: SIM1: Added comment: At least 20 probands with reduced penetrance reported.

PMID:33434169;
1x missense inherited from normal mother

PMID:30926952;
2x unrelated - 1 missense 1 splice. Family history noted

PMID:23778136;
4 children with clinical features of PWL syndrome, including severe obesity - all missense
1x inherited from normal father

PMID:23778139;
at least 13 families with segregation and reduced penetrance evidence - all missense
In vitro luciferase done to show LoF

NOTE:
Individuals with Prader-Willi-like phenotype may have 6q16.2del instead, which encompasses SIM1; Changed rating: GREEN; Changed publications: 33434169, 30926952, 23778136, 23778139; Changed phenotypes: congenital obesity, Prader-Willi-like syndrome; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9580 POMC Zornitza Stark Publications for gene: POMC were set to
Mendeliome v0.9578 MLIP Zornitza Stark Publications for gene: MLIP were set to
Mendeliome v0.9575 MLIP Michelle Torres edited their review of gene: MLIP: Changed publications: 34581780; Changed phenotypes: MLIP-related myopathy with rhabdomyolysis
Mendeliome v0.9574 CACNA1A Zornitza Stark Publications for gene: CACNA1A were set to
Mendeliome v0.9572 CACNA1A Anna Ritchie reviewed gene: CACNA1A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34267336; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9569 STT3A Zornitza Stark Publications for gene: STT3A were set to
Mendeliome v0.9567 KIAA0391 Lucy Spencer gene: KIAA0391 was added
gene: KIAA0391 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0391 were set to PMID: 34715011
Added comment: Four unrelated families with multisystem disease associated with bi-allelic variants in PRORP. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes.

-1 consanguineous family with homozygous missense in 3 affected sisters, het parents unaffected. Siblings had profound bilateral SNHL in infancy. In teens developed primary amenorrhea/Perrault syndrome, and hypergonadotropic hypogonadism.
-1 unrelated male with compound het missense, each inherited from an unaffected parent. Hearing loss noted at 3, diagnosed at 5.
-1 unrelated male compound het for a missense and a frameshift. appendicular hypertonia in infancy, mild dysmorphism. Severe global dev delay at 20 months. Normal hearing at 18 months, but at 3 years had bilateral SNHL.
-an affected mother and her 2 affected children (son and daughter), homozygous for a missense. Father is heterozygous and unaffected. Son has psychotic disorder, autistic traits. Sister had intrauterine growth retardation, global developmental delay, and seizures in the first years of life. Mother presented with retrobulbar optic neuritis and tonic pupil at 39 years of age, then with asthenia, myalgias, memory loss, and frequent headaches.

All variants are in p.400s.
Sources: Literature
Mendeliome v0.9566 MLIP Michelle Torres gene: MLIP was added
gene: MLIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MLIP were set to 34581780
Review for gene: MLIP was set to GREEN
Added comment: PMID: 34581780: 7 individuals with 6 families with truncating (one splice that also resulted in a frameshift variant) biallelic variants (used NM_1281746).

In 3 patients patients’ skeletal muscle, these variants were shown to cause reduction overall RNA expression levels of the predominant MLIP isoform.

Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels.
Sources: Literature
Mendeliome v0.9565 STT3A Elena Savva reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 34653363, 23842455, 30701557, 28424003; Phenotypes: Congenital disorder of glycosylation, type Iw MIM#615596; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9564 SPATA5L1 Paul De Fazio gene: SPATA5L1 was added
gene: SPATA5L1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Intellectual disability; spastic-dystonic cerebral palsy; epilepsy; hearing loss
Review for gene: SPATA5L1 was set to GREEN
gene: SPATA5L1 was marked as current diagnostic
Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.
Sources: Literature
Mendeliome v0.9563 SPRED2 Dean Phelan gene: SPRED2 was added
gene: SPRED2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to PMID: 34626534
Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Review for gene: SPRED2 was set to GREEN
Added comment: PMID: 34626534
Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome.
Sources: Literature
Mendeliome v0.9563 KPNA3 Ain Roesley gene: KPNA3 was added
gene: KPNA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to 34564892
Phenotypes for gene: KPNA3 were set to infantile onsetHereditary Spastic Paraplegia
Penetrance for gene: KPNA3 were set to Complete
Review for gene: KPNA3 was set to GREEN
gene: KPNA3 was marked as current diagnostic
Added comment: 8 affecteds from 5 families with infantile-onset pure HSP
all missense variants, in vitro functional demonstrated reduced cargo binding
Noted that 1 individual had 2 de novo missense in the gene and though 1 is less deleterious than the other in the functional assays, authors were not able to rule out either one as a VUS
Sources: Literature
Mendeliome v0.9562 POMC Zornitza Stark reviewed gene: POMC: Rating: GREEN; Mode of pathogenicity: None; Publications: 33666293; Phenotypes: Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9561 PHF6 Zornitza Stark Publications for gene: PHF6 were set to
Mendeliome v0.9559 PHF6 Zornitza Stark reviewed gene: PHF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 16912705; Phenotypes: Borjeson-Forssman-Lehmann syndrome, MIM# 301900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9558 PCSK1 Zornitza Stark Publications for gene: PCSK1 were set to
Mendeliome v0.9556 PCSK1 Zornitza Stark reviewed gene: PCSK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30383237; Phenotypes: Obesity with impaired prohormone processing MIM#600955; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9543 EHBP1L1 Krithika Murali gene: EHBP1L1 was added
gene: EHBP1L1 was added to Mendeliome. Sources: Expert list,Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to 34645488; 26833786
Phenotypes for gene: EHBP1L1 were set to Non-immune hydrops fetalis
Review for gene: EHBP1L1 was set to AMBER
Added comment: No OMIM gene disease association.

Biallelic EHBP1L1 variants identified in 2 consanguineous families from Saudi Arabia with non-immune hydrops fetalis resulting in recurrent fetal loss. Supportive mouse models for this phenotype also reported.
Sources: Expert list, Literature
Mendeliome v0.9538 GNPNAT1 Zornitza Stark reviewed gene: GNPNAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Rhizomelic dysplasia, Ain-Naz type, MIM#619598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9537 GRIK2 Zornitza Stark reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9537 CACNA1C Krithika Murali gene: CACNA1C was added
gene: CACNA1C was added to Mendeliome. Sources: Expert list,Literature
Mode of inheritance for gene: CACNA1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CACNA1C were set to Timothy syndrome - MIM# 601005; Neurodevelopmental abnormalities and epilepsy, no OMIM#; Long QT syndrome 8- MIM#618447
Review for gene: CACNA1C was set to GREEN
Added comment: Well-established gene-disease association with Timothy Syndrome

Rodan et al. (2021) reported 25 individuals from 22 families with heterozygous truncating and missense variants in CACNA1C. The individuals presented with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy BUT absence of classic features of Timothy syndrome or long QT syndrome.
Sources: Expert list, Literature
Mendeliome v0.9537 BGN Krithika Murali gene: BGN was added
gene: BGN was added to Mendeliome. Sources: Expert list,Literature
Mode of inheritance for gene: BGN was set to Other
Publications for gene: BGN were set to 27236923; 27632686
Phenotypes for gene: BGN were set to Meester-Loeys syndrome - #300989; Spondyloepimetaphyseal dysplasia, X-linked - #300106
Review for gene: BGN was set to GREEN
Added comment: Well-established gene-disease associated with X-linked spondyloepimetaphyseal dysplasia (SEMD) and Meester-Loeys syndrome (connective tissue disorder with phenotypic features including aortic dissection, aortic aneurysym, dysmorphism, joint hypermobility and mild skeletal dysplasia - with juvenile-onset reported in males)

SEMD - X-linked recessive inheritance
Meester-Loeys syndrome - hemizygous males, monoallelic mutations may cause disease in females (may be less severe, later onset than males)
Sources: Expert list, Literature
Mendeliome v0.9537 ATP13A2 Krithika Murali gene: ATP13A2 was added
gene: ATP13A2 was added to Mendeliome. Sources: Expert list,Literature
Mode of inheritance for gene: ATP13A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP13A2 were set to 1694263
Phenotypes for gene: ATP13A2 were set to Kufor-Rakeb syndrome - MIM#606693
Review for gene: ATP13A2 was set to GREEN
Added comment: Well-established gene-disease association with Kufor-Rakeb syndrome, a form of autosomal recessive hereditary parkinsonism and dementia showing juvenile onset, as well as neuronal ceroid lipofucinosis (NCL) features in some families. Also associated with adult-onset hereditary spastic paraparesis.
Sources: Expert list, Literature
Mendeliome v0.9537 ACTC1 Krithika Murali gene: ACTC1 was added
gene: ACTC1 was added to Mendeliome. Sources: Expert list,Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to 26061005; 17947298; 31430208; 18403758; 30384889
Phenotypes for gene: ACTC1 were set to Atrial septal defect 5, MIM# 612794; Cardiomyopathy, dilated, 1R - MIM# 613424; Cardiomyopathy, hypertrophic, 11 - #612098
Review for gene: ACTC1 was set to GREEN
Added comment: Four families reported with congenital heart disease and variants in this gene. Note gene is also associated with cardiomyopathies, including paediatric-onset dilated and hypertrophic cardiomyopathy.
Sources: Expert list, Literature
Mendeliome v0.9535 MUC5B Zornitza Stark Publications for gene: MUC5B were set to
Mendeliome v0.9532 MUC5B Zornitza Stark reviewed gene: MUC5B: Rating: RED; Mode of pathogenicity: None; Publications: 21506741, 21506748; Phenotypes: {Pulmonary fibrosis, idiopathic, susceptibility to}, MIM# 178500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9531 AHDC1 Zornitza Stark Publications for gene: AHDC1 were set to
Mendeliome v0.9529 AHDC1 Zornitza Stark reviewed gene: AHDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24791903, 27148574, 30152016; Phenotypes: Xia-Gibbs syndrome, MIM# 615829, AHDC1-related intellectual disability, obstructive sleep apnoea, mild dysmorphism syndrome MONDO:0014358; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9528 AGTR1 Zornitza Stark Publications for gene: AGTR1 were set to
Mendeliome v0.9526 AGTR1 Zornitza Stark reviewed gene: AGTR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9525 AGT Zornitza Stark Publications for gene: AGT were set to
Mendeliome v0.9523 AGT Zornitza Stark reviewed gene: AGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 34234805, 33163725; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9523 PANK4 Zornitza Stark Phenotypes for gene: PANK4 were changed from Congenital posterior cataract to Cataract 49, MIM# 619593; Congenital posterior cataract
Mendeliome v0.9522 PANK4 Zornitza Stark edited their review of gene: PANK4: Changed phenotypes: Cataract 49, MIM# 619593, Congenital posterior cataract
Mendeliome v0.9521 ADAMTS17 Zornitza Stark Publications for gene: ADAMTS17 were set to
Mendeliome v0.9519 ADAMTS17 Zornitza Stark reviewed gene: ADAMTS17: Rating: GREEN; Mode of pathogenicity: None; Publications: 19836009, 22486325, 24940034, 30712880; Phenotypes: Weill-Marchesani 4 syndrome, recessive, MIM# 613195; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9518 ACY1 Zornitza Stark Publications for gene: ACY1 were set to
Mendeliome v0.9516 ACY1 Zornitza Stark reviewed gene: ACY1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16274666, 16465618, 17562838, 24117009; Phenotypes: Aminoacylase 1 deficiency, MIM# 609924; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9515 ACE Zornitza Stark Publications for gene: ACE were set to
Mendeliome v0.9513 ACE Zornitza Stark reviewed gene: ACE: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 22095942; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9511 ACADVL Zornitza Stark reviewed gene: ACADVL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: VLCAD deficiency, MIM# 201475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9509 FAN1 Zornitza Stark Publications for gene: FAN1 were set to
Mendeliome v0.9507 FAN1 Zornitza Stark reviewed gene: FAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22772369, 16678356, 7847351, 8546134; Phenotypes: Interstitial nephritis, karyomegalic, MIM# 614817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9506 MANBA Zornitza Stark Publications for gene: MANBA were set to
Mendeliome v0.9504 MANBA Zornitza Stark edited their review of gene: MANBA: Added comment: Two mono-allelic variants reported in association with isolated nystagmus. Note bi-allelic variants cause a lysosomal storage disorder.; Changed publications: 30552791, 25741867; Changed phenotypes: Mannosidosis, beta, MIM# 248510, MONDO:0009562, Nystagmus, autosomal dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9504 AHR Zornitza Stark reviewed gene: AHR: Rating: AMBER; Mode of pathogenicity: None; Publications: 31009037, 33193710; Phenotypes: Foveal hypoplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9504 RDH5 Zornitza Stark Publications for gene: RDH5 were set to 32232344
Mendeliome v0.9502 RDH5 Zornitza Stark reviewed gene: RDH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 10369264; Phenotypes: Fundus albipunctatus (MIM#136880); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9501 ETHE1 Zornitza Stark Publications for gene: ETHE1 were set to
Mendeliome v0.9499 ETHE1 Zornitza Stark reviewed gene: ETHE1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ethylmalonic encephalopathy , MIM#602473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9498 RHO Zornitza Stark Publications for gene: RHO were set to
Mendeliome v0.9496 RHO Zornitza Stark reviewed gene: RHO: Rating: GREEN; Mode of pathogenicity: None; Publications: 18487375, 27812022, 31213501, 1303237; Phenotypes: Night blindness, congenital stationary, autosomal dominant 1, MIM# 610445, Retinitis pigmentosa 4, autosomal dominant or recessive, MIM# 613731; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9495 RDH12 Zornitza Stark Publications for gene: RDH12 were set to
Mendeliome v0.9493 RDH12 Zornitza Stark reviewed gene: RDH12: Rating: GREEN; Mode of pathogenicity: None; Publications: 16269441, 15322982, 15258582, 31505163; Phenotypes: Leber congenital amaurosis 13, MIM# 612712, Retinitis pigmentosa, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9492 RD3 Zornitza Stark Publications for gene: RD3 were set to
Mendeliome v0.9490 RD3 Zornitza Stark reviewed gene: RD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23308101, 22531706, 17186464; Phenotypes: Leber congenital amaurosis 12, MIM#610612; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9488 EXOSC5 Zornitza Stark reviewed gene: EXOSC5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar ataxia, brain abnormalities, and cardiac conduction defects, MIM# 619576; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9488 ETHE1 Melanie Marty reviewed gene: ETHE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14732903, 28933811; Phenotypes: Ethylmalonic encephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9486 PRPH2 Zornitza Stark Publications for gene: PRPH2 were set to
Mendeliome v0.9484 PRPH2 Zornitza Stark reviewed gene: PRPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32660024; Phenotypes: Leber congenital amaurosis 18, MIM#608133 Macular dystrophy, vitelliform, 3, MIM#608161 Retinitis pigmentosa 7 and digenic form, MIM#608133 Choroidal dystrophy, central areolar 2, MIM#613105 Macular dystrophy, patterned, 1, MIM#169150 Retinitis punctata albescens, MIM#136880; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9484 XBP1 Zornitza Stark Publications for gene: XBP1 were set to
Mendeliome v0.9481 BCL9L Zornitza Stark Publications for gene: BCL9L were set to 23035047; 8757136
Mendeliome v0.9479 BCL9L Zornitza Stark reviewed gene: BCL9L: Rating: AMBER; Mode of pathogenicity: None; Publications: 30366904; Phenotypes: Congenital heart disease; Mode of inheritance: None
Mendeliome v0.9478 IMPDH1 Zornitza Stark Publications for gene: IMPDH1 were set to
Mendeliome v0.9476 IMPDH1 Zornitza Stark reviewed gene: IMPDH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16384941; Phenotypes: Leber congenital amaurosis 11 (MIM# 613837), Retinitis pigmentosa 10 (MIM# 180105); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9475 KCNJ13 Zornitza Stark Publications for gene: KCNJ13 were set to
Mendeliome v0.9473 KCNJ13 Zornitza Stark reviewed gene: KCNJ13: Rating: GREEN; Mode of pathogenicity: None; Publications: 27203561, 25475713, 21763485, 18179896, 23255580, 31647904; Phenotypes: Leber congenital amaurosis 16 MIM#614186, Snowflake vitreoretinal degeneration, MIM# 193230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9472 LRIT3 Zornitza Stark Publications for gene: LRIT3 were set to
Mendeliome v0.9470 LRIT3 Zornitza Stark reviewed gene: LRIT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23246293, 24598786, 31578364, 27428514; Phenotypes: Night blindness, congenital stationary (complete), 1F, autosomal recessive, MIM# 615058; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9469 BCL9L Krithika Murali gene: BCL9L was added
gene: BCL9L was added to Mendeliome. Sources: Literature,Expert list,Other
Mode of inheritance for gene: BCL9L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCL9L were set to 23035047; 8757136
Phenotypes for gene: BCL9L were set to Heterotaxy; Congenital Heart Disease
Review for gene: BCL9L was set to AMBER
Added comment: Novel gene disease assocaition. Saunders et al., 2012 (PMID: 23035047) report biallelic BCL9L variants in 2 affected brothers with heterotaxy and congenital heart disease, heterozygous in unaffected parents. Functional evidence in zebrafish (PMID 8757136)
Sources: Literature, Expert list, Other
Mendeliome v0.9469 NYX Zornitza Stark Publications for gene: NYX were set to
Mendeliome v0.9467 NYX Zornitza Stark reviewed gene: NYX: Rating: GREEN; Mode of pathogenicity: None; Publications: 11062471, 11062472, 16670814, 23714322, 34064005, 34165036; Phenotypes: Night blindness, congenital stationary (complete), 1A, X-linked MIM#310500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9467 ACTC1 Krithika Murali gene: ACTC1 was added
gene: ACTC1 was added to Mendeliome. Sources: Literature,Expert list
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to 17947298; 31430208
Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 - MIM# 612794; Cardiomyopathy, dilated, 1R - MIM# 613424; Cardiomyopathy, hypertrophic, 11 - #612098; Left ventricular noncompaction 4 - #613424
Review for gene: ACTC1 was set to GREEN
Added comment: Three families reported with congenital heart disease and variants in this gene. Gene is also associated with cardiomyopathies, including paediatric onset.
Sources: Literature, Expert list
Mendeliome v0.9466 GRM6 Zornitza Stark Publications for gene: GRM6 were set to
Mendeliome v0.9464 GRM6 Zornitza Stark reviewed gene: GRM6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22008250; Phenotypes: Night blindness, congenital stationary (complete), 1B, autosomal recessive 257270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9463 GRK1 Zornitza Stark Publications for gene: GRK1 were set to
Mendeliome v0.9461 GRK1 Zornitza Stark reviewed gene: GRK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17070587, 33252155; Phenotypes: Oguchi disease-2, 613411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9460 GPR179 Zornitza Stark Publications for gene: GPR179 were set to
Mendeliome v0.9458 GPR179 Zornitza Stark reviewed gene: GPR179: Rating: GREEN; Mode of pathogenicity: None; Publications: 22325361; Phenotypes: Night blindness, congenital stationary (complete), 1E, autosomal recessive (MIM#614565); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9457 GNAT2 Zornitza Stark Publications for gene: GNAT2 were set to
Mendeliome v0.9455 GNAT2 Zornitza Stark reviewed gene: GNAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32203983, 17251445; Phenotypes: Achromatopsia 4 MIM#613856; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9455 XBP1 Lucy Spencer reviewed gene: XBP1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 32294597, 33325615; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.9454 DEF6 Zornitza Stark Publications for gene: DEF6 were set to 31308374
Mendeliome v0.9452 DEF6 Zornitza Stark edited their review of gene: DEF6: Added comment: Additional family reported with 4 affected siblings.; Changed rating: GREEN; Changed publications: 31308374, 32562707; Changed phenotypes: Immunodeficiency 87 and autoimmunity, MIM# 619573, Systemic autoimmunity
Mendeliome v0.9451 CABP4 Zornitza Stark Publications for gene: CABP4 were set to
Mendeliome v0.9449 CABP4 Zornitza Stark reviewed gene: CABP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 16960802, 19074807, 20157620; Phenotypes: Cone-rod synaptic disorder, congenital nonprogressive, MIM# 610427; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9448 ATF6 Zornitza Stark Publications for gene: ATF6 were set to
Mendeliome v0.9446 ATF6 Zornitza Stark reviewed gene: ATF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 26063662, 26029869; Phenotypes: Achromatopsia 7, MIM#616517; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9445 AIPL1 Zornitza Stark Publications for gene: AIPL1 were set to
Mendeliome v0.9443 AIPL1 Zornitza Stark reviewed gene: AIPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10615133; Phenotypes: Leber congenital amaurosis 4, 604393 Cone-rod dystrophy, 604393 Retinitis pigmentosa, juvenile, 604393; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9442 GNAS-AS1 Zornitza Stark Publications for gene: GNAS-AS1 were set to
Mendeliome v0.9439 GNAS-AS1 Zornitza Stark reviewed gene: GNAS-AS1: Rating: RED; Mode of pathogenicity: None; Publications: 22378814, 15592469, 29959430, 25005734; Phenotypes: Pseudohypoparathyroidism type 1b MIM no: 603233; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.9438 IFT74 Zornitza Stark Publications for gene: IFT74 were set to 27486776; 32144365; 33531668
Mendeliome v0.9437 IFT74 Zornitza Stark edited their review of gene: IFT74: Added comment: Limited evidence for association with spermatogenic failure: two unrelated individuals with same homozygous missense variant.; Changed publications: 27486776, 32144365, 33531668, 33689014; Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 617119, Joubert syndrome, Spermatogenic failure 58, MIM# 619585
Mendeliome v0.9436 SFTPC Zornitza Stark Publications for gene: SFTPC were set to
Mendeliome v0.9434 SFTPC Zornitza Stark reviewed gene: SFTPC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11207353, 11991887, 11893657, 15557112, 19443464; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 2, MIM# 610913; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9433 SFTPB Zornitza Stark Publications for gene: SFTPB were set to
Mendeliome v0.9431 SFTPB Zornitza Stark reviewed gene: SFTPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 8163685, 8021783, 10378403, 10571948; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 1, MIM# 265120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9430 SFTPA2 Zornitza Stark Publications for gene: SFTPA2 were set to
Mendeliome v0.9428 SFTPA2 Zornitza Stark reviewed gene: SFTPA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19100526, 32602668; Phenotypes: Pulmonary fibrosis, idiopathic, MIM# 178500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9427 SFTPD Zornitza Stark Publications for gene: SFTPD were set to
Mendeliome v0.9425 SFTPD Zornitza Stark reviewed gene: SFTPD: Rating: RED; Mode of pathogenicity: None; Publications: 9751757; Phenotypes: Interstitial lung disease; Mode of inheritance: None
Mendeliome v0.9424 SLC7A7 Zornitza Stark Publications for gene: SLC7A7 were set to
Mendeliome v0.9422 SLC7A7 Zornitza Stark reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10080182, 18716612; Phenotypes: Lysinuric protein intolerance, MIM# 222700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9421 JAG2 Zornitza Stark reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 27, MIM# 619566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9420 STX16 Zornitza Stark Publications for gene: STX16 were set to
Mendeliome v0.9418 STX16 Zornitza Stark reviewed gene: STX16: Rating: GREEN; Mode of pathogenicity: None; Publications: 1456170, 15579741, 15800843, 33320452, 32337648, 33247854, 29959430; Phenotypes: Pseudohypoparathyroidism type 1b MIM no: 603233; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.9416 STOX1 Zornitza Stark Publications for gene: STOX1 were set to
Mendeliome v0.9412 TBX4 Zornitza Stark edited their review of gene: TBX4: Changed publications: 31761294, 31965066; Changed phenotypes: Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension MIM#147891, Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, MIM# 601360
Mendeliome v0.9411 ZNHIT3 Zornitza Stark Publications for gene: ZNHIT3 were set to
Mendeliome v0.9409 ZNHIT3 Zornitza Stark reviewed gene: ZNHIT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28335020, 28335020, 31048081; Phenotypes: PEHO syndrome, MIM# 260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9408 ADGRG1 Zornitza Stark Publications for gene: ADGRG1 were set to
Mendeliome v0.9406 ADGRG1 Zornitza Stark reviewed gene: ADGRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16240336, 33299078; Phenotypes: Polymicrogyria, bilateral frontoparietal, MIM#606854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9406 CHRNA5 Paul De Fazio reviewed gene: CHRNA5: Rating: RED; Mode of pathogenicity: None; Publications: 20643934, 18385676; Phenotypes: Lung cancer susceptibility 2 (MIM#612052), Nicotine dependence, susceptibility to (MIM#612052); Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9406 STOX1 Paul De Fazio reviewed gene: STOX1: Rating: RED; Mode of pathogenicity: None; Publications: 15806103, 17290274, 30548667, 33301424; Phenotypes: Preeclampsia/eclampsia 4 (MIM#609404); Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9405 FGF12 Zornitza Stark Publications for gene: FGF12 were set to
Mendeliome v0.9403 FGF12 Zornitza Stark reviewed gene: FGF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32645220, 27164707, 27830185, 27872899; Phenotypes: Developmental and epileptic encephalopathy 47, MIM# 617166; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9401 TBK1 Zornitza Stark Publications for gene: TBK1 were set to
Mendeliome v0.9398 KCNC2 Zornitza Stark Publications for gene: KCNC2 were set to PMID:32392612; 31972370
Mendeliome v0.9395 KCTD13 Zornitza Stark Publications for gene: KCTD13 were set to PMID: 33409479
Mendeliome v0.9392 KCTD13 Zornitza Stark reviewed gene: KCTD13: Rating: RED; Mode of pathogenicity: None; Publications: 22596160, 29088697; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9392 KCTD13 Daniel Flanagan gene: KCTD13 was added
gene: KCTD13 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCTD13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCTD13 were set to PMID: 33409479
Review for gene: KCTD13 was set to RED
Added comment: Mouse model and in vitro evidence suggesting the deletion of KCTD13 has a similar metabolic affect as adenylosuccinate lyase deficiency, which has seizures and autistic features.
Sources: Expert list
Mendeliome v0.9392 KCNC2 Daniel Flanagan gene: KCNC2 was added
gene: KCNC2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNC2 were set to PMID:32392612; 31972370
Phenotypes for gene: KCNC2 were set to epileptic encephalopathy; spastic tetraplegia; opisthotonos attacks; intellectual disability; West syndrome
Review for gene: KCNC2 was set to AMBER
Added comment: PMID: 31972370. De novo missense variant (p.Val471Leu) identified in a child with early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks.

PMID: 32392612. De novo missense variant (p.Asp167Tyr) identified in a neurofibromatosis type 1 related West syndrome patient. Functional analysis showed a significant reduction of the mean potassium current and a shift in the voltage dependence of steady-state activation. Maternally inherited NF1 variant (p.T1951Nfs*5) also identified, the mother was "clinically unremarkable".
Sources: Expert list
Mendeliome v0.9392 OSTC Belinda Chong gene: OSTC was added
gene: OSTC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OSTC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSTC were set to PMID: 32267060
Phenotypes for gene: OSTC were set to Oligosaccharyltransferase complex-congenital disorders of glycosylation
Review for gene: OSTC was set to RED
Added comment: A patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.
Patient was homozygous for a canonical splice variant (c.431 + 1G > A), mRNA from patient's fibroblast showed mRNA transcript reduced 80-90%/aberrant splicing - predicting NMD.
GnomAD - 10 hets, 0 hom
Sources: Literature
Sources: Literature
Mendeliome v0.9392 TBK1 Lucy Spencer reviewed gene: TBK1: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31000212, 25943890; Phenotypes: Frontotemporal dementia, amyotrophic lateral sclerosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9392 KCNAB3 Daniel Flanagan gene: KCNAB3 was added
gene: KCNAB3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNAB3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNAB3 were set to PMID: 32990398
Phenotypes for gene: KCNAB3 were set to febrile seizures; afebrile seizure; genetic epilepsy with febrile seizures plus
Review for gene: KCNAB3 was set to RED
Added comment: Missense variant identified in a single Han Chinese family with febrile seizures plus. Three affected carriers and one unaffected carrier. Patch clamp functional studies indicates that the variant accelerates the inactivation of the potassium channels.
Sources: Expert list
Mendeliome v0.9391 DENND5A Zornitza Stark Publications for gene: DENND5A were set to
Mendeliome v0.9389 DENND5A Zornitza Stark reviewed gene: DENND5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 27866705, 32705489; Phenotypes: Epileptic encephalopathy, early infantile, 49, MIM# 617281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9389 ZAR1 Zornitza Stark gene: ZAR1 was added
gene: ZAR1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZAR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZAR1 were set to 29574422; 31598710; 12539046
Phenotypes for gene: ZAR1 were set to Multi locus imprinting disturbance in offspring
Review for gene: ZAR1 was set to RED
Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) with some features of Beckwith Wiedemann Syndrome. Shown to be a maternal effect gene that functions at the oocyte to embryo transition.
Sources: Expert Review
Mendeliome v0.9388 UHRF1 Zornitza Stark gene: UHRF1 was added
gene: UHRF1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: UHRF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UHRF1 were set to 29574422; 28976982
Phenotypes for gene: UHRF1 were set to Multi locus imprinting disturbance in offspring
Review for gene: UHRF1 was set to RED
Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) and Silver Russell Syndrome phenotype. Maenohara et al demonstrate functions of UHRF1 during the global epigenetic reprogramming of oocytes and early embryos.
Sources: Expert Review
Mendeliome v0.9386 MAGEL2 Zornitza Stark Publications for gene: MAGEL2 were set to
Mendeliome v0.9384 MAGEL2 Zornitza Stark reviewed gene: MAGEL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24076603, 31397880, 29599419, 30302899; Phenotypes: Schaaf-Yang syndrome, MIM# 615547; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.9384 L3MBTL1 Zornitza Stark gene: L3MBTL1 was added
gene: L3MBTL1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: L3MBTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: L3MBTL1 were set to 23543057; 15123827; 30794780
Phenotypes for gene: L3MBTL1 were set to Affected tissue: myeloid lineages; Phenotype resulting from under expression: lymphoid malignancy
Review for gene: L3MBTL1 was set to RED
Added comment: Germline variation in this imprinted gene is not currently associated with disease.

Somatic deletions of 20q are associated with chronic myeloid malignancies. Aziz et al showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis.
Sources: Expert Review
Mendeliome v0.9383 KCNQ1OT1 Zornitza Stark gene: KCNQ1OT1 was added
gene: KCNQ1OT1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KCNQ1OT1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: KCNQ1OT1 were set to 22205991; 15372379; 23511928; 30794780; 29377879; 10220444; 32447323; 33177595; 29047350
Phenotypes for gene: KCNQ1OT1 were set to Beckwith-Wiedemann syndrome OMIM:130650; Russell-Silver Syndrome
Review for gene: KCNQ1OT1 was set to AMBER
Added comment: Limited evidence that isolated intragenic variation in KCNQ1OT1 is definitively associated with a phenotype.

KCNQ1OT1 encodes the regulatory antisense non-coding RNA KCNQ1OT1 (KCNQ1 overlapping) and is located within the KCNQ1OT1:TSS DMR (imprinting control region 2; IC2) at 11p15.5. IC2 is located within KCNQ1 intron 10. KCNQ1OT1 is maternally imprinted and paternally expressed. On the paternal chromosome, KCNQ1OT1 is transcribed and represses in cis the flanking imprinted genes, including the growth inhibitor CDKN1C, which is normally transcribed from the maternal allele. In 50% of the BWS patients, loss of methylation (LOM) of IC2 leads to biallelic expression of KCNQ1OT1 and biallelic silencing of CDKN1C (PMID 30635621). Expression is increased in BWS due to IC2 epimutations or paternal UPD.

Single nucleotide variants within KCNQ1OT1 have not been definitively associated with human disease. A heterozygous maternally inherited non-coding variant was identified in an individual with isolated omphalocele. This variant was shown to alter the methylation pattern of the imprinted allele (PMID 29047350).

Eggerman et al (PMID 32447323) described a 132 base pair deletion within KCNQ1OT1 associated with growth retardation in the case of paternal but not maternal transmission. This intragenic deletion did not affect IC2 methylation.

Microdeletions of IC2 involving KCNQ1OT1 on the paternal allele have been identified in a small number of patients with Russell-Silver syndrome. Similarly, microdeletions of IC2 involving KCNQ1OT1 on the maternal allele have been identified in a small number of patients with BWS. These deletions also variably involve KCNQ1 or CDKN1C. LoF in CDKN1C is a known cause of BWS. There is some evidence to suggest that disruption of KCNQ1 prevents maternal methylation at IC2 (PMID 30778172).
Sources: Expert Review
Mendeliome v0.9382 H19 Zornitza Stark gene: H19 was added
gene: H19 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: H19 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: H19 were set to 20007505; 15743916; 23118352; 21863054; 21571108; 18245780; 24916376; 25943194
Phenotypes for gene: H19 were set to Phenotypes resulting from gene over expression: Silver-Russell Syndrome (proven effects of dosage alteration rather than gene muation); Affected tissue: all; Phenotype resulting from under expression: Beckwith-Wiedemann Syndrome
Review for gene: H19 was set to RED
Added comment: Methylation changes rather than sequence variation are associated with BWS/RSS.
Sources: Expert Review
Mendeliome v0.9380 GBF1 Zornitza Stark reviewed gene: GBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate A, MIM# 606483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9379 TMEM218 Zornitza Stark reviewed gene: TMEM218: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 39, MIM#619562; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9379 OOEP Zornitza Stark gene: OOEP was added
gene: OOEP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OOEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OOEP were set to 29574422
Phenotypes for gene: OOEP were set to Multi locus imprinting disturbance in offspring
Review for gene: OOEP was set to RED
Added comment: Single report of biallelic variants in this gene in a mother of a child with Multi locus imprinting disturbance (MLID) and a transient neonatal diabetes mellitus phenotype.

This gene encodes part of the subcortical maternal complex (SCMC). Other genes in this group act as 'maternal effect' genes and are associated with early embryonic arrest, recurrent hydatiform mole and MLID in offspring.

As is the case for other genes encoding components of the SCMC, the pathogenicity of variants can be difficult to establish as reproductive outcomes are not recorded in genomic databases and variants may be listed in population databases as they are not classed as pathogenic in males or women with no reproductive history.

Functional studies of genes encoding components of the SCMC are limited as their expression is restricted to the oocyte and early embryo.
Sources: Literature
Mendeliome v0.9378 ZNF445 Zornitza Stark gene: ZNF445 was added
gene: ZNF445 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF445 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF445 were set to 34039421; 30602440; 30846001
Phenotypes for gene: ZNF445 were set to Temple syndrome; Multi locus imprinting disturbance (MLID)
Review for gene: ZNF445 was set to RED
Added comment: Single report (Kagami 2021) of a child with Temple syndrome and MLID found to have a novel homozygous truncating variant in ZNF445.

ZNF445 has been shown to play a critical role in the maintenance of postfertilisation methylation imprints (Takahashi 2019). Mechanism and parent of origin effects remain uncertain.
Sources: Literature
Mendeliome v0.9376 NSRP1 Zornitza Stark gene: NSRP1 was added
gene: NSRP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to Epilepsy; Cerebral palsy; microcephaly; Intellectual disability
Review for gene: NSRP1 was set to GREEN
Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
Sources: Literature
Mendeliome v0.9375 ERGIC1 Zornitza Stark Publications for gene: ERGIC1 were set to 28317099; 34037256
Mendeliome v0.9373 ERGIC1 Zornitza Stark edited their review of gene: ERGIC1: Added comment: Pehlivan et al. 2019 (PMID:31230720) identified the third case of arthrogryposis in a child who harboured a previously unreported homozygous variant (c.782G>A; p.Gly261Asp) in this gene. Parents were heterozygous carriers. Functional studies were not performed.; Changed rating: GREEN; Changed publications: 28317099, 34037256, 31230720
Mendeliome v0.9372 GABRD Zornitza Stark Publications for gene: GABRD were set to 15115768
Mendeliome v0.9370 GABRD Zornitza Stark edited their review of gene: GABRD: Added comment: 10 individuals with 7 unique variants reported in individuals with neurodevelopmental disorders and epilepsy. Six of the variants were demonstrated to be GoF, and those individuals with neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. In contrast, the one individual carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms.; Changed rating: GREEN; Changed publications: 15115768, 34633442; Changed phenotypes: Intellectual disability, Epilepsy, Susceptibility to epilepsy, MIM#613060
Mendeliome v0.9369 NLRP5 Zornitza Stark Publications for gene: NLRP5 were set to 32222962; 31829238; 30877238
Mendeliome v0.9366 NLRP5 Zornitza Stark edited their review of gene: NLRP5: Added comment: 'Maternal effect gene'
Part of the subcortical maternal complex

Report of five mothers carrying either monoallelic or biallelic variants in NLRP5, who had both unaffected offspring and offspring with BWS-MLID (Doherty 2015). Report of one family where the mother carried biallelic variants in NLRP5, had one offspring with BWS, one unaffected offspring and multiple miscarriages (Sparago 2019).

Reports of at least three unrelated individuals with recurrent early embryonic arrest carrying biallelic variants in NLRP5. Functional work suggesting protein degradation in affected human cell lines (Mu 2019, Xu 2020).; Changed rating: GREEN; Changed publications: 32222962, 31829238, 30877238, 26323243, 34440388; Changed phenotypes: Early embryonic arrest, Multi locus imprinting disturbance in offspring; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9365 TNPO2 Zornitza Stark reviewed gene: TNPO2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies, MIM# 619556; Mode of inheritance: None
Mendeliome v0.9364 DSTYK Ain Roesley reviewed gene: DSTYK: Rating: RED; Mode of pathogenicity: None; Publications: 23862974; Phenotypes: Congenital anomalies of kidney and urinary tract 1, MIM# 610805, Spastic paraplegia 23, MIM# 270750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9363 KCTD3 Zornitza Stark Publications for gene: KCTD3 were set to
Mendeliome v0.9361 KCTD3 Zornitza Stark reviewed gene: KCTD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29406573; Phenotypes: Epilepsy, Intellectual disability, Posterior fossa abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9360 GYPC Zornitza Stark Publications for gene: GYPC were set to
Mendeliome v0.9357 TARS2 Zornitza Stark Publications for gene: TARS2 were set to 24827421; 26811336; 33153448
Mendeliome v0.9355 GYPC Paul De Fazio reviewed gene: GYPC: Rating: RED; Mode of pathogenicity: None; Publications: 29469208; Phenotypes: [Blood group, Gerbich] MIM#616089; Mode of inheritance: Other; Current diagnostic: yes
Mendeliome v0.9355 TARS2 Krithika Murali reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33153448, 24827421, 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21 - 615918, Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9355 SLC4A3 Daniel Flanagan gene: SLC4A3 was added
gene: SLC4A3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SLC4A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC4A3 were set to PMID: 29167417; 34557911
Phenotypes for gene: SLC4A3 were set to Short QT syndrome
Review for gene: SLC4A3 was set to AMBER
Added comment: Moderate evidence for autosomal dominant short QT syndrome 1 by ClinGen /gene curation expert panel (PMID: 34557911). A single missense variant (absent gnomAD) identified in two SQTS families. In family 1, it segregated with SQTS (QTc<370ms) in 23 carriers, and 19 non-carriers had a QTc>370ms. In family 2, it segregated in 4 individuals. Experimental evidence from in vitro and zebrafish models suggests reduced membrane localization of the mutated protein leads to intracellular alkalinization and shortening of the cardiomyocyte action potential duration.
ClinGen expert panel was divided between strong (4 votes) and moderate (5 votes).
Sources: Expert Review
Mendeliome v0.9353 MARS Zornitza Stark Publications for gene: MARS were set to
Mendeliome v0.9351 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Association with interstitial lung and liver disease: More than 5 unrelated families reported. Founder variants in Reunion Island, p.Ser567Leu and p.Ala393Thr, in cis.

Pathologic examination of lung lavage is consistent with pulmonary alveolar proteinosis.; Changed rating: GREEN; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036; Changed phenotypes: Interstitial lung and liver disease, MIM#615486, Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9350 AARS Zornitza Stark Publications for gene: AARS were set to 28493438; 25817015; 20045102; 22009580; 22206013; 30373780; 26032230
Mendeliome v0.9347 USP48 Eleanor Williams gene: USP48 was added
gene: USP48 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP48 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: USP48 were set to 34059922
Phenotypes for gene: USP48 were set to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497
Penetrance for gene: USP48 were set to Incomplete
Review for gene: USP48 was set to GREEN
Added comment: PMID: 34059922 - Bassani et al 2021 - 3 cases reported with variants in USP48 and non syndromic hearing loss. They first analysed 4-generation Italian family with 6 individuals with hearing loss. The only rare variant segregating with the disease was a missense variant in USP48 (NM_032234.7:c.1216G > A, NP_115612.4:p.(Gly406Arg)). The variant is present in GnomAD v2.1.1 with a minor allele frequency (MAF) of 6.7 × 10−5 (17 allele out of 251 304 with no homozygotes). They also observed one hearing individual in the family who was heterozygous for the variant, suggesting incomplete penetrance.
In a Dutch family the found by exome sequencing a missense variant in USP48 (NM_032236.7:c.2215_2216delinsTT, NP_115612.4:p.(Thr739Leu)). The probands mother and uncle were also affected by no sequence data was available for analysis.
In a French family a proband is reported with right profound sensorineural hearing impairment (at 12 months), but normal left hearing (at 6 years old). The patient is heterozygote for a de novo splice variant in USP48 (NM_032236.7:c.3058 + 2 T > C, NP_115612.4:p.?;) which is not found in GnomAD and is predicted to result in a frameshift resulting in either NMD or a truncated protein.
In functional experiments they showed that the two missense variants found in the Italian and Dutch families, and a shortened protein as predicted for the variant found in the French variant, showed an impaired ability to cleave tetra-ubiquitin into tri-, di- and mono-ubiquitin. Using immunohistology, they show that the human USP48 protein is present in fetal inner ear specimens.
In addition zebrafish lacking usp48 showed a significant decrease of auditory response in acoustic startle response assays at 600 and 800 Hz wavelengths.
Sources: Literature
Mendeliome v0.9347 MARS Eleanor Williams reviewed gene: MARS: Rating: ; Mode of pathogenicity: None; Publications: 33909043; Phenotypes: trichothiodystrophy, MONDO:0018053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9347 AARS Eleanor Williams reviewed gene: AARS: Rating: ; Mode of pathogenicity: None; Publications: 33909043; Phenotypes: trichothiodystrophy, MONDO:0018053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9346 AIP Zornitza Stark Publications for gene: AIP were set to
Mendeliome v0.9342 CERKL Zornitza Stark Publications for gene: CERKL were set to 33322828; 32865075; 32411380
Mendeliome v0.9341 CERKL Zornitza Stark edited their review of gene: CERKL: Changed publications: 33322828, 32865075, 32411380, 14681825, 24043777, 28838317, 27208204, 28130426
Mendeliome v0.9340 CERKL Zornitza Stark Publications for gene: CERKL were set to
Mendeliome v0.9338 CERKL Zornitza Stark reviewed gene: CERKL: Rating: GREEN; Mode of pathogenicity: None; Publications: 33322828, 32865075, 32411380; Phenotypes: Retinitis pigmentosa 26, MIM# 608380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9338 AIP Paul De Fazio reviewed gene: AIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16728643, 17360484, 26187128; Phenotypes: Pituitary adenoma predisposition MIM#102200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.9337 SHANK1 Zornitza Stark Publications for gene: SHANK1 were set to
Mendeliome v0.9335 SHANK1 Zornitza Stark reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34113010, 22503632, 25188300; Phenotypes: Neurodevelopmental disorder, no OMIM#; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9334 GDF11 Zornitza Stark edited their review of gene: GDF11: Added comment: Ravenscroft et al. (2021) report additional 6 probands who presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). They found de novo and inherited variants in GDF11. gdf11 mutant zebrafish showed craniofacial abnormalities and body segmentation defects that matched some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants are partial LOF variants.; Changed rating: GREEN; Changed publications: 31215115, 34113007
Mendeliome v0.9333 PLXNA1 Zornitza Stark gene: PLXNA1 was added
gene: PLXNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature
Mendeliome v0.9331 HNRNPD Zornitza Stark Publications for gene: HNRNPD were set to 33057194
Mendeliome v0.9329 HNRNPD Zornitza Stark reviewed gene: HNRNPD: Rating: GREEN; Mode of pathogenicity: None; Publications: 33874999; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9328 UNC13B Zornitza Stark gene: UNC13B was added
gene: UNC13B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: UNC13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UNC13B were set to 33876820
Phenotypes for gene: UNC13B were set to Epilepsy
Review for gene: UNC13B was set to RED
Added comment: No OMIM human disease association. Gene encodes a presynaptic protein Munc13-2 highly expressed in the brain (predominantly cerebral cortex).

Variant interpretation data in human epilepsy cohort somewhat conflicting and restricted to a single study. Conflicting data esp regarding MOI, and evidence for pathogenicity of several of the variants is limited.

Wang et al, Brain, 2021 - trio-based whole-exome sequencing identified UNC13B in 12 individuals affected by partial epilepsy and/or febrile seizures from 8 unrelated families. Identified:
x1 de novo nonsense variant, absent in gnomad, damaging in silicos
x1 de novo splice site, absent in gnomad, damaging in silicos
x1 splice site variant present in unaffected mother (low frequency in gnomad)
x2 compound het in one individual - more severe phenotype postulated (x1 variant present in contro cohortl, the other variant present in low frequency in gnomad)
x1 missense variant - in Han Chinese major depressive disorders study, not in gnomad
x1 missense variant - highly conserved residue, not in gnomad
x2 other missense variant - highly conserved residue, low frequency in gnomad
Latter 4 missense variants cosegregated with affected individuals in the families

In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila

De novo UNC13B variants previously reported in bipolar disorder and autism spectrum disorder
Sources: Expert Review
Mendeliome v0.9326 VARS2 Zornitza Stark Publications for gene: VARS2 were set to
Mendeliome v0.9324 VARS2 Zornitza Stark reviewed gene: VARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24827421, 25058219, 29137650, 29314548, 31064326, 31623496; Phenotypes: Combined oxidative phosphorylation deficiency 20, OMIM #615917; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9323 CHD4 Zornitza Stark Publications for gene: CHD4 were set to 31388190
Mendeliome v0.9322 CHD4 Zornitza Stark reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34109749; Phenotypes: Childhood idiopathic epilepsy and sinus arrhythmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9321 BCL11A Zornitza Stark Publications for gene: BCL11A were set to
Mendeliome v0.9319 BCL11A Zornitza Stark reviewed gene: BCL11A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27453576, 32903878; Phenotypes: Dias-Logan syndrome, MIM# 617101; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9319 CFAP221 Zornitza Stark gene: CFAP221 was added
gene: CFAP221 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP221 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP221 were set to 31636325
Phenotypes for gene: CFAP221 were set to Primary ciliary dyskinesia
Review for gene: CFAP221 was set to RED
Added comment: WES in 1 family with 3 siblings with clinical symptoms of PCD identified compound heterozygous loss-of-function variants in CFAP221, which segregated with disease. No functional studies. Nasal epithelial cells from 1 of the subjects demonstrated slightly reduced beat frequency, however, waveform analysis revealed that the CFAP221 defective cilia beat in an aberrant circular pattern. A candidate gene in cases where PCD is suspected but cilia structure and beat frequency appear normal.
Sources: Literature
Mendeliome v0.9316 DAB1 Zornitza Stark Publications for gene: DAB1 were set to
Mendeliome v0.9312 DAB1 Zornitza Stark reviewed gene: DAB1: Rating: RED; Mode of pathogenicity: None; Publications: 33928188; Phenotypes: Ataxia, Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9311 ERBB4 Zornitza Stark Publications for gene: ERBB4 were set to
Mendeliome v0.9309 ERBB4 Zornitza Stark reviewed gene: ERBB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24119685, 28889094, 33603162; Phenotypes: Amyotrophic lateral sclerosis 19, MIM# MIM#615515, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9309 PANX1 Zornitza Stark Publications for gene: PANX1 were set to 30918116; 32838805
Mendeliome v0.9304 ZDHHC15 Zornitza Stark Publications for gene: ZDHHC15 were set to
Mendeliome v0.9303 PANX1 Melanie Marty reviewed gene: PANX1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33495594, 30918116, 32838805; Phenotypes: Oocyte maturation defect 7, MIM#618550; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9302 ZDHHC15 Krithika Murali reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: 34345675; Phenotypes: cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9302 WIPI2 Zornitza Stark Publications for gene: WIPI2 were set to 30968111
Mendeliome v0.9300 SNIP1 Seb Lunke Publications for gene: SNIP1 were set to 22279524
Mendeliome v0.9298 WIPI2 Dean Phelan reviewed gene: WIPI2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30968111, 34557665; Phenotypes: global developmental delay, intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures, dyskinesia, speech and visual impairment, autistic features, ataxic gait; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9297 ABHD16A Lucy Spencer gene: ABHD16A was added
gene: ABHD16A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to PMID: 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia
Review for gene: ABHD16A was set to GREEN
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
From PMID: 34587489
Sources: Literature
Mendeliome v0.9297 SNIP1 Teresa Zhao reviewed gene: SNIP1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 34570759; Phenotypes: Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9297 ATP11A Elena Savva gene: ATP11A was added
gene: ATP11A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP11A were set to PMID: 34403372
Phenotypes for gene: ATP11A were set to Neurological disorder
Mode of pathogenicity for gene: ATP11A was set to Other
Review for gene: ATP11A was set to AMBER
Added comment: PMID: 34403372:
- Single de novo missense variant reported in a patient with developmental delay and neurological deterioration.
- Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested.
- K/I heterozygous mice died perinatally.
- Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc.

gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets.
Sources: Literature
Mendeliome v0.9297 WLS Teresa Zhao gene: WLS was added
gene: WLS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to PMID: 34587386
Phenotypes for gene: WLS were set to Syndromic structural birth defects
Review for gene: WLS was set to GREEN
Added comment: - We identified homozygous mutations in 10 affected persons from 5 unrelated families.
- Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Mendeliome v0.9296 SHQ1 Zornitza Stark gene: SHQ1 was added
gene: SHQ1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645
Phenotypes for gene: SHQ1 were set to Dystonia; Neurodegeneration
Review for gene: SHQ1 was set to AMBER
Added comment: Three unrelated families reported. Family 1: isolated dystonia only; Family 2: dystonia, and neurodegeneration; Family 3: neurodegeneration.

Rated Amber as phenotypes likely represent a continuum but currently unclear.
Sources: Literature
Mendeliome v0.9294 SARS Bryony Thompson gene: SARS was added
gene: SARS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to Intellectual disability
Review for gene: SARS was set to AMBER
Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.
PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature
Mendeliome v0.9290 NDN Zornitza Stark reviewed gene: NDN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Prader-Willi syndrome, MIM# 176270; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9289 NFIB Zornitza Stark Publications for gene: NFIB were set to
Mendeliome v0.9287 NFIB Zornitza Stark reviewed gene: NFIB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30388402; Phenotypes: Macrocephaly, acquired, with impaired intellectual development, MIM#618286; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9286 EIF3F Zornitza Stark Publications for gene: EIF3F were set to 30409806
Mendeliome v0.9285 EIF3F Zornitza Stark edited their review of gene: EIF3F: Added comment: Hüffmeier et al (2021) reported 21 patients who were homozygous/compound heterozygous for Phe232Val variant in EIF3F. All affected individuals had developmental delay and speech delay. About half had behavioural problems, altered muscular tone, hearing loss, and short stature. The study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum.; Changed publications: 30409806, 33736665; Changed phenotypes: Mental retardation, autosomal recessive 67, MIM# 618295
Mendeliome v0.9284 PTPRC Zornitza Stark Publications for gene: PTPRC were set to
Mendeliome v0.9282 PTPRC Zornitza Stark reviewed gene: PTPRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11145714, 12073144, 22689986, 10700239; Phenotypes: Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive MIM# 608971, Hepatitis C virus, susceptibility to MIM# 609532; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9281 CORO1A Zornitza Stark Publications for gene: CORO1A were set to
Mendeliome v0.9277 CDH15 Zornitza Stark Publications for gene: CDH15 were set to
Mendeliome v0.9274 CDH15 Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3, MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9274 JAK3 Danielle Ariti reviewed gene: JAK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 14615376, 11668610; Phenotypes: SCID, autosomal recessive, T-negative/B-positive type MIM# 600802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9274 CORO1A Danielle Ariti reviewed gene: CORO1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25073507, 2352248, 18836449; Phenotypes: Immunodeficiency 8 MIM# 615401; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9274 POU6F2 Chloe Stutterd reviewed gene: POU6F2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.9273 ARL6IP6 Zornitza Stark gene: ARL6IP6 was added
gene: ARL6IP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARL6IP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL6IP6 were set to 31142202
Phenotypes for gene: ARL6IP6 were set to Cutis marmorata telangiectatica congenita
Review for gene: ARL6IP6 was set to RED
Added comment: A single case reported from a consanguineous family with a homozygous nonsense variant (p.Trp64Ter).
Sources: Literature
Mendeliome v0.9272 CPE Zornitza Stark Publications for gene: CPE were set to 26120850; 32936766
Mendeliome v0.9270 CPE Arina Puzriakova reviewed gene: CPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 34383079; Phenotypes: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9269 CSTB Zornitza Stark Publications for gene: CSTB were set to
Mendeliome v0.9267 CSTB Zornitza Stark reviewed gene: CSTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 32920378, 18028412, 9012407, 9054946; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM# 254800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9266 CD3E Zornitza Stark Publications for gene: CD3E were set to
Mendeliome v0.9263 CD3D Zornitza Stark Publications for gene: CD3D were set to
Mendeliome v0.9259 LEFTY2 Zornitza Stark Publications for gene: LEFTY2 were set to
Mendeliome v0.9256 CD3E Danielle Ariti reviewed gene: CD3E: Rating: GREEN; Mode of pathogenicity: None; Publications: 5546002, 28597365, 8490660; Phenotypes: Immunodeficiency 18 MIM# 615615; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9256 CD3D Danielle Ariti reviewed gene: CD3D: Rating: GREEN; Mode of pathogenicity: None; Publications: 14602880, 15546002, 21926461, 21883749; Phenotypes: Immunodeficiency 19 MIM# 615617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9256 ARHGAP26 Dean Phelan reviewed gene: ARHGAP26: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.9252 MAOB Zornitza Stark gene: MAOB was added
gene: MAOB was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MAOB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAOB were set to 31700678
Phenotypes for gene: MAOB were set to Cerebral palsy
Review for gene: MAOB was set to RED
Added comment: Variants identified in 2 unrelated individuals with CP (with same variant also identified in unaffected monozygotic twin).
Sources: Expert Review
Mendeliome v0.9250 ATP6V0C Zornitza Stark gene: ATP6V0C was added
gene: ATP6V0C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Review for gene: ATP6V0C was set to AMBER
Added comment: 9 individuals reported with deletions and ID/seizures/microcephaly, minimum overlapping region implicates ATP6V0C as the causative gene. Single case report of de novo SNV and ID/seizures.
Sources: Literature
Mendeliome v0.9249 KDM7A Zornitza Stark gene: KDM7A was added
gene: KDM7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM7A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM7A were set to 25666757
Phenotypes for gene: KDM7A were set to Cerebral palsy
Review for gene: KDM7A was set to RED
Added comment: Synonyms: JHDMID, KDM7, KIAA1718

De novo missense VUS identified in a WES CP cohort study, no other reports.
Sources: Literature
Mendeliome v0.9247 ROBO1 Zornitza Stark Publications for gene: ROBO1 were set to
Mendeliome v0.9245 ROBO1 Zornitza Stark reviewed gene: ROBO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28592524, 30530901, 30692597, 33270637, 28402530; Phenotypes: Congenital heart disease, Pituitary anomalies; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9244 ARFGEF1 Zornitza Stark gene: ARFGEF1 was added
gene: ARFGEF1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability; Epilepsy
Review for gene: ARFGEF1 was set to GREEN
Added comment: 13 individuals reported with variants in this gene and a neurodevelopmental disorder characterised by variable ID, seizures present in around half. Variants were inherited from mildly affected parents in 40% of families.
Sources: Expert Review
Mendeliome v0.9242 NPR3 Zornitza Stark Publications for gene: NPR3 were set to
Mendeliome v0.9240 NPR3 Zornitza Stark reviewed gene: NPR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30032985; Phenotypes: Boudin-Mortier syndrome, MIM#619543, Tall stature, skeletal abnormalities, aortic dilatation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9238 KCNC3 Zornitza Stark Publications for gene: KCNC3 were set to
Mendeliome v0.9236 KCNC3 Zornitza Stark reviewed gene: KCNC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16501573, 25497598, 25981959, 25981959; Phenotypes: Spinocerebellar ataxia 13, MIM# 605259; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9234 ZC4H2 Zornitza Stark Publications for gene: ZC4H2 were set to
Mendeliome v0.9232 ZC4H2 Zornitza Stark reviewed gene: ZC4H2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23623388, 34322088, 33949289, 31885220, 31206972; Phenotypes: Wieacker-Wolff syndrome, MIM# 314580; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.9232 ALG10 Zornitza Stark gene: ALG10 was added
gene: ALG10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALG10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG10 were set to 33798445
Phenotypes for gene: ALG10 were set to Progressive myoclonus epilepsy; CDG
Review for gene: ALG10 was set to RED
Added comment: Single individual with homozygous variant identified in a progressive myoclonus epilepsy cohort.
Sources: Literature
Mendeliome v0.9230 LRRK1 Zornitza Stark gene: LRRK1 was added
gene: LRRK1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LRRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRK1 were set to 27829680; 27055475; 31571209; 32119750
Phenotypes for gene: LRRK1 were set to Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198)
Review for gene: LRRK1 was set to GREEN
Added comment: At least 4 unrelated families reported.
Sources: Expert Review
Mendeliome v0.9229 KIF4A Zornitza Stark Publications for gene: KIF4A were set to 24812067
Mendeliome v0.9227 KIF4A Zornitza Stark edited their review of gene: KIF4A: Added comment: Further 11 families reported. Major structural brain abnormalities present in at least 3 (hydrocephalus), variable ID in several.; Changed rating: GREEN; Changed publications: 24812067, 34346154
Mendeliome v0.9225 IRGM Zornitza Stark Publications for gene: IRGM were set to
Mendeliome v0.9222 UTP4 Zornitza Stark Publications for gene: UTP4 were set to
Mendeliome v0.9219 UTP4 Zornitza Stark reviewed gene: UTP4: Rating: RED; Mode of pathogenicity: None; Publications: 12417987, 27535533; Phenotypes: North American Indian childhood cirrhosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9219 IRGM Paul De Fazio reviewed gene: IRGM: Rating: RED; Mode of pathogenicity: None; Publications: 17554261, 19299395, 18985712, 20106866, 21278745, 20360734; Phenotypes: {Inflammatory bowel disease (Crohn disease) 19} MIM#612278; Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9219 UTP4 Michelle Torres reviewed gene: UTP4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.9218 FMN1 Bryony Thompson gene: FMN1 was added
gene: FMN1 was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: FMN1.
Mode of inheritance for gene: FMN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FMN1 were set to 20610440; 19383632; 15202026
Phenotypes for gene: FMN1 were set to oligosyndactyly; radioulnar synostosis; hearing loss; renal defects
Review for gene: FMN1 was set to AMBER
Added comment: A 263 Kb homozygous deletion of FMN1 has been identified in a single case with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects. Also, a supporting null mouse model with oligosyndactyly. Also, a large duplication including GREM1 reported in association with Cenani–Lenz syndrome.
Sources: Literature
Mendeliome v0.9216 LBX1 Zornitza Stark gene: LBX1 was added
gene: LBX1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LBX1 were set to 30487221
Phenotypes for gene: LBX1 were set to Central hypoventilation syndrome, congenital, 3, MIM#619483
Review for gene: LBX1 was set to AMBER
Added comment: Two siblings reported with homozygous LoF variant in this gene, supportive mouse model.
Sources: Expert Review
Mendeliome v0.9214 B9D1 Bryony Thompson Publications for gene: B9D1 were set to 24886560; 21493627; 25920555
Mendeliome v0.9213 FBXW4 Bryony Thompson Publications for gene: FBXW4 were set to
Mendeliome v0.9211 FBXW4 Bryony Thompson reviewed gene: FBXW4: Rating: RED; Mode of pathogenicity: None; Publications: 12913067, 16235095, 27600068; Phenotypes: Split-hand/foot malformation 3 syndrome MIM#246560; Mode of inheritance: None
Mendeliome v0.9210 RAF1 Zornitza Stark Publications for gene: RAF1 were set to
Mendeliome v0.9207 RAF1 Zornitza Stark reviewed gene: RAF1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 17603483, 17603482, 31145547, 31030682, 29271604, 24777450; Phenotypes: Noonan syndrome 5, MIM# 611553, Cardiomyopathy, dilated, 1NN, MIM# 615916; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9206 CDKN1C Zornitza Stark Publications for gene: CDKN1C were set to
Mendeliome v0.9204 CDKN1C Zornitza Stark reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 10424811, 8841187, 22205991, 20503313, 19843502, 15372379, 23511928, 30794780, 33076988, 31976094, 31497289; Phenotypes: Beckwith-Wiedemann syndrome, MIM# 130650, IMAGe syndrome, MIM# 614732, Silver-Russell syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.9203 B9D1 Bryony Thompson reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21763481, 24886560, 34338422; Phenotypes: Meckel syndrome, Joubert syndrome, VACTERL; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9203 LEFTY2 Elena Savva reviewed gene: LEFTY2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 10518210, 10053005; Phenotypes: Heterotaxy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.9202 CARMIL2 Zornitza Stark Publications for gene: CARMIL2 were set to
Mendeliome v0.9200 CARMIL2 Zornitza Stark reviewed gene: CARMIL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29479355, 28112205, 27896283, 33723309; Phenotypes: Immunodeficiency 58, MIM# 618131, Early onset paediatric inflammatory bowel disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9199 PNLDC1 Zornitza Stark gene: PNLDC1 was added
gene: PNLDC1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PNLDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNLDC1 were set to 34347949
Phenotypes for gene: PNLDC1 were set to Spermatogenic failure 57, MIM# 619528
Review for gene: PNLDC1 was set to GREEN
Added comment: Four unrelated individuals reported.
Sources: Expert Review
Mendeliome v0.9195 HSCB Zornitza Stark gene: HSCB was added
gene: HSCB was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HSCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSCB were set to 32634119
Phenotypes for gene: HSCB were set to Anaemia, sideroblastic, 5, MIM# 619523
Review for gene: HSCB was set to AMBER
Added comment: Single individual reported with compound heterozygous variants in this gene. Good functional data including animal model.
Sources: Expert list
Mendeliome v0.9192 CADM3 Zornitza Stark reviewed gene: CADM3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2FF, MIM# 619519; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9191 BCAP31 Zornitza Stark Publications for gene: BCAP31 were set to
Mendeliome v0.9189 BCAP31 Zornitza Stark reviewed gene: BCAP31: Rating: GREEN; Mode of pathogenicity: None; Publications: 24011989, 31330203, 33603160; Phenotypes: Deafness, dystonia, and cerebral hypomyelination, MIM# 300475; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9188 AMPD2 Zornitza Stark Publications for gene: AMPD2 were set to
Mendeliome v0.9186 AMPD2 Zornitza Stark edited their review of gene: AMPD2: Added comment: Well established gene-disease association. Clinical features include severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination.; Changed rating: GREEN; Changed publications: 23911318, 27066553
Mendeliome v0.9184 HBG2 Zornitza Stark Publications for gene: HBG2 were set to
Mendeliome v0.9182 HBG2 Zornitza Stark reviewed gene: HBG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26500940; Phenotypes: Fetal hemoglobin quantitative trait locus 1, MIM# 141749, Cyanosis, transient neonatal, MIM# 613977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9181 HBG1 Zornitza Stark gene: HBG1 was added
gene: HBG1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: HBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HBG1 were set to 26500940
Phenotypes for gene: HBG1 were set to Fetal haemoglobin quantitative trait locus 1, 141749
Review for gene: HBG1 was set to GREEN
Added comment: Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or haematologic manifestations.
Sources: Expert Review
Mendeliome v0.9179 WNT9B Zornitza Stark Publications for gene: WNT9B were set to
Mendeliome v0.9176 WNT9B Zornitza Stark reviewed gene: WNT9B: Rating: AMBER; Mode of pathogenicity: None; Publications: 34145744; Phenotypes: Renal agenesis/hypoplasia/dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9175 DDX23 Zornitza Stark Publications for gene: DDX23 were set to 33057194
Mendeliome v0.9173 DDX23 Zornitza Stark reviewed gene: DDX23: Rating: GREEN; Mode of pathogenicity: None; Publications: 34050707; Phenotypes: DDX23-associated neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9173 TAF2 Zornitza Stark Publications for gene: TAF2 were set to 21937992; 22633631; 26350204; 24084144
Mendeliome v0.9171 TAF2 Zornitza Stark edited their review of gene: TAF2: Added comment: New report of 4 individuals from 2 unrelated families, with severe intellectual disability, global developmental delay, postnatal microcephaly, feet deformities and thin corpus callosum. They had homozygous TAF2 missense variants detected by Exome Sequencing.; Changed rating: GREEN; Changed publications: 21937992, 22633631, 26350204, 24084144, 34474177
Mendeliome v0.9170 ERGIC1 Zornitza Stark gene: ERGIC1 was added
gene: ERGIC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERGIC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC1 were set to 28317099; 34037256
Phenotypes for gene: ERGIC1 were set to Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100
Review for gene: ERGIC1 was set to AMBER
Added comment: Reinstein et al. (2018) used WES in a large consanguineous Israeli Arab kindred consisting of 16 patients affected with the neurogenic type of arthrogryposis multiplex congenita. They identified a homozygous missense (V98E) mutation in ERGIC1 gene, which segregated with the disorder in the kindred, and was not found in the ExAC database or in 212 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi.

Marconi et al (2021) used genome sequencing in a consanguineous family with 2 affected siblings presenting congenital arthrogryposis and some facial dysmorphism. They identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents.
Sources: Literature
Mendeliome v0.9168 HMGB1 Zornitza Stark Publications for gene: HMGB1 were set to 34159400
Mendeliome v0.9167 HMGB1 Chirag Patel reviewed gene: HMGB1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34164801; Phenotypes: Developmental delay and microcephaly, no OMIM #; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9165 FCGR2B Zornitza Stark Publications for gene: FCGR2B were set to
Mendeliome v0.9162 FCGR2B Paul De Fazio reviewed gene: FCGR2B: Rating: RED; Mode of pathogenicity: None; Publications: 12115230, 15153543, 20385827; Phenotypes: {Systemic lupus erythematosus, susceptibility to} MIM#152700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.9162 GPX1 Zornitza Stark gene: GPX1 was added
gene: GPX1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: GPX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPX1 were set to 1131421; 476008; 5766310; 2492138
Phenotypes for gene: GPX1 were set to Haemolytic anaemia due to glutathione peroxidase deficiency MIM#614164
Review for gene: GPX1 was set to RED
Added comment: No individuals reported with GPX1 variants identified as the cause of Haemolytic anaemia due to glutathione peroxidase deficiency. Multiple papers report a number of cases of Haemolytic anaemia due to glutathione peroxidase deficiency, however there is no defined link or variant to GPX1 (PMID: 5766310. PMID: 1131421, PMID: 2492138, PMID: 476008)

Overall, lowered glutathione peroxidase activity has been observed in a number of individuals with haemolytic anaemia however the evidence for a cause-and-effect relationship between the enzyme deficiency and the presenting anaemia is not evident.
Sources: Expert Review
Mendeliome v0.9160 CYP51A1 Bryony Thompson reviewed gene: CYP51A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22935719, 26622071, 27878435, 25148791; Phenotypes: Congenital cataract, infantile liver disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9159 CYB5A Zornitza Stark Publications for gene: CYB5A were set to
Mendeliome v0.9157 CYB5A Zornitza Stark reviewed gene: CYB5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22170710, 32051920; Phenotypes: Methemoglobinemia and ambiguous genitalia 250790; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9157 COL14A1 Zornitza Stark gene: COL14A1 was added
gene: COL14A1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: COL14A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL14A1 were set to 22972947
Phenotypes for gene: COL14A1 were set to Punctate palmoplantar keratoderma type 1B
Review for gene: COL14A1 was set to RED
Added comment: 4 affected individuals and 2 unaffected controls from one Chinese PPPK family where disease locus was mapped at 8q24.13-8q24.21 by previous linkage analysis. Exome sequencing analysis identified a heterozygous variant in COL14A1 gene (c.4505C>T (p.Pro1502Leu)). The variant was shared by 4 affected individuals, but not 2 controls of the family. Sanger sequencing confirmed this variant in another four cases from this family. Variant was absent in the normal controls of this family as well as 676 unrelated normal controls and 781 patients with other disease. The missense substitution occurs at a highly conserved amino acid residue across multiple species.
Sources: Expert Review
Mendeliome v0.9155 EGLN1 Zornitza Stark Publications for gene: EGLN1 were set to
Mendeliome v0.9153 EGLN1 Zornitza Stark reviewed gene: EGLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19092153, 16407130, 17579185; Phenotypes: Erythrocytosis, familial, 3, MIM# 609820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9152 FGFR2 Zornitza Stark Publications for gene: FGFR2 were set to
Mendeliome v0.9149 SLC4A1 Zornitza Stark Publications for gene: SLC4A1 were set to
Mendeliome v0.9147 FGFR2 Chern Lim reviewed gene: FGFR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29848297, 32879300, 27323706; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.9147 SLC4A1 Danielle Ariti reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16227998, 15211439, 7949112, 8640229, 16227998, 8640229, 16227998, 33881640, 32632909; Phenotypes: Cryohydrocytosis MIM# 185020, Distal renal tubular acidosis 4 with haemolytic anaemia MIM# 611590, Ovalocytosis, SA type MIM# 166900, Spherocytosis, type 4 MIM# 612653, Distal renal tubular acidosis 1 MIM# 179800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9146 STEAP3 Zornitza Stark Publications for gene: STEAP3 were set to 22031863; 25515317
Mendeliome v0.9144 STEAP3 Zornitza Stark edited their review of gene: STEAP3: Changed rating: RED; Changed publications: 22031863, 25515317, 26675350; Changed phenotypes: Anaemia, hypochromic microcytic, with iron overload 2, MIM# 615234
Mendeliome v0.9143 NT5C3A Zornitza Stark Publications for gene: NT5C3A were set to
Mendeliome v0.9141 NT5C3A Zornitza Stark reviewed gene: NT5C3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11369620, 12714505, 30951028, 25153905; Phenotypes: Anaemia, haemolytic, due to UMPH1 deficiency, MIM# 266120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9140 IMPG1 Zornitza Stark reviewed gene: IMPG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 91, MIM# 153870; Mode of inheritance: None
Mendeliome v0.9138 ABCC11 Zornitza Stark reviewed gene: ABCC11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Axillary odor, variation in] 117800, [Colostrum secretion, variation in] 117800, [Earwax, wet/dry] 117800; Mode of inheritance: None
Mendeliome v0.9138 KCNN4 Zornitza Stark Publications for gene: KCNN4 were set to 26148990; 26198474; 26178367
Mendeliome v0.9137 KCNN4 Zornitza Stark edited their review of gene: KCNN4: Changed publications: 26148990, 26198474, 26178367, 33519508, 31091145, 28619848; Changed phenotypes: Dehydrated hereditary stomatocytosis 2, MIM# 616689
Mendeliome v0.9136 MTRR Zornitza Stark Publications for gene: MTRR were set to
Mendeliome v0.9134 MTRR Zornitza Stark reviewed gene: MTRR: Rating: GREEN; Mode of pathogenicity: None; Publications: 12555939, 15714522; Phenotypes: Homocystinuria-megaloblastic anaemia, cbl E type, MIM# 236270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9133 MTR Zornitza Stark Publications for gene: MTR were set to
Mendeliome v0.9131 MTR Zornitza Stark reviewed gene: MTR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8968736, 8968737, 9683607, 12068375; Phenotypes: Homocystinuria-megaloblastic anaemia, cblG complementation type, MIM# 250940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9130 LPIN2 Zornitza Stark Publications for gene: LPIN2 were set to
Mendeliome v0.9128 LPIN2 Zornitza Stark reviewed gene: LPIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15994876, 33993107, 33670882, 33314777, 31727123; Phenotypes: Majeed syndrome, MIM# 609628, Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9128 FOXE3 Zornitza Stark Phenotypes for gene: FOXE3 were changed from to Anterior segment dysgenesis 2, multiple subtypes, MIM#610256; Cataract 34, multiple types, MIM#612968; Aortic aneurysm, familial thoracic 11, susceptibility to}, MIM#617349
Mendeliome v0.9127 FOXE3 Zornitza Stark Publications for gene: FOXE3 were set to
Mendeliome v0.9125 FOXE3 Eleanor Williams reviewed gene: FOXE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26854927, 27218149, 16826526, 19708017, 20140963, 20664696, 20361012, 24019743, 27669367, 29878917, 32436650, 34046667, 11159941, 19708017, 20806047, 21150893, 11980846, 34046667; Phenotypes: Anterior segment dysgenesis 2, multiple subtypes, MIM#610256, Cataract 34, multiple types, MIM#612968, Aortic aneurysm, familial thoracic 11, susceptibility to}, MIM#617349; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9124 SLC26A1 Zornitza Stark Publications for gene: SLC26A1 were set to
Mendeliome v0.9121 SLC26A1 Zornitza Stark reviewed gene: SLC26A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27210743, 20160351, 30383413, 27125215; Phenotypes: Nephrolithiasis, calcium oxalate, MIM#167030; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9120 RHAG Zornitza Stark Publications for gene: RHAG were set to
Mendeliome v0.9117 SPTA1 Zornitza Stark Publications for gene: SPTA1 were set to
Mendeliome v0.9115 SPTA1 Danielle Ariti reviewed gene: SPTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9075575, 8018926, 29484404, 27667160, 31333484, 8941647, 3785322; Phenotypes: Elliptocytosis-2 MIM# 130600, Pyropoikilocytosis MIM# 266140, Spherocytosis, type 3 MIM# 270970; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9114 SPTB Zornitza Stark Publications for gene: SPTB were set to
Mendeliome v0.9111 TF Zornitza Stark Publications for gene: TF were set to
Mendeliome v0.9109 SLC11A2 Danielle Ariti reviewed gene: SLC11A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21871825, 15459009; Phenotypes: Anaemia, hypochromic microcytic, with iron overload 1 MIM#206100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9109 RHAG Danielle Ariti reviewed gene: RHAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 30990901, 28470789, 4962358, 18931342, 21849667, 23406318; Phenotypes: Anaemia, haemolytic, Rh-null, regulator type MIM# 268150, Overhydrated hereditary stomatocytosis MIM#185000; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9109 SPTB Danielle Ariti reviewed gene: SPTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 19538529, 8102379, 9075575, 7883966, 9005995, 32256302; Phenotypes: Spherocytosis, type 2 MIM# 616649, Elliptocytosis-3 MIM# 617948, Anaemia, neonatal haemolytic, fatal or near-fatal MIM# 617948; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9109 TF Danielle Ariti reviewed gene: TF: Rating: GREEN; Mode of pathogenicity: None; Publications: 11110675, 3472216; Phenotypes: Atransferrinaemia MIM# 209300, iron overload, hypochromic anaemia, low serum transferrin, Hemosiderosis of the heart and/or liver, Congestive heart failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9107 GSR Zornitza Stark Publications for gene: GSR were set to
Mendeliome v0.9104 GSR Zornitza Stark reviewed gene: GSR: Rating: AMBER; Mode of pathogenicity: None; Publications: 17185460, 31122244; Phenotypes: Haemolytic anaemia due to glutathione reductase deficiency, MIM# 618660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9104 MKRN3 Anna Le Fevre reviewed gene: MKRN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32480405 33214675 31041429 32407292; Phenotypes: Central Precocious Puberty; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.9104 MAGEL2 Anna Le Fevre reviewed gene: MAGEL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33820833, 24076603, 31397880, 29599419, 30302899; Phenotypes: Schaaf-Yang syndrome, Chitayat-Hall Syndrome, Arthrogryposis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.9103 UMPS Zornitza Stark Publications for gene: UMPS were set to
Mendeliome v0.9101 UMPS Zornitza Stark edited their review of gene: UMPS: Added comment: 20 unrelated patients have been reported with biallelic missense variants; one mouse model

Orotic aciduria is characterised by megaloblastic anaemia and orotic acid crystalluria, frequently associated with a degree of physical and intellectual disability. Other features include, congenital malformations (Atrial/ Ventricular septal defect) and immunodeficiencies (T-cell dysfunction, failure to thrive, recurrent infections).

Haematology features
- Megaloblastic anaemia
- Low to normal reticulocyte count
- Anisocytosis
- Poikilocytosis
- Hypochromia; Changed publications: 9042911, 33489760; Changed phenotypes: Orotic aciduria, MIM# 258900
Mendeliome v0.9100 TMPRSS6 Zornitza Stark Publications for gene: TMPRSS6 were set to
Mendeliome v0.9098 TPI1 Zornitza Stark edited their review of gene: TPI1: Added comment: More than 10 unrelated families reported; bi-allelic (missense, nonsense, frameshift) variants; Common p.Glu104Asp variant in Northern European population

Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterised by early childhood onset congenital hemolytic anaemia, and progressive neuromuscular dysfunction. Many patients die from respiratory failure in childhood. The neurological features are variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Other features include intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells and increased susceptibility to infections.; Changed publications: 9338582, 32873690, 8503454; Changed phenotypes: Haemolytic anaemia due to triosephosphate isomerase deficiency, MIM# 615512
Mendeliome v0.9097 YARS2 Zornitza Stark Publications for gene: YARS2 were set to
Mendeliome v0.9095 YARS2 Zornitza Stark reviewed gene: YARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24430573, 24344687; Phenotypes: Myopathy, lactic acidosis, and sideroblastic anaemia 2 MIM# 613561, sideroblastic anaemia, muscle atrophy, myopathy, lactic acidosis, Hypertrophic cardiomyopathy, Hepatomegaly, Decreased cytochrome C oxidase activity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9095 TMPRSS6 Danielle Ariti reviewed gene: TMPRSS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18408718, 8596229, 18596229, 19592582; Phenotypes: Iron-refractory iron deficiency anaemia MIM# 206200, Iron malabsorption, hypochromic microcytic anaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9094 GCLC Zornitza Stark Publications for gene: GCLC were set to
Mendeliome v0.9092 GCLC Zornitza Stark reviewed gene: GCLC: Rating: GREEN; Mode of pathogenicity: None; Publications: 10515893, 28571779; Phenotypes: Haemolytic anaemia due to gamma-glutamylcysteine synthetase deficiency, MIM# 230450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9091 PDGFRL Michelle Torres reviewed gene: PDGFRL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown; Current diagnostic: yes
Mendeliome v0.9090 IFIH1 Zornitza Stark Publications for gene: IFIH1 were set to
Mendeliome v0.9088 IFIH1 Sarah Pantaleo changed review comment from: Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. seven carriers of LoF variants (three of whom have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.; to: IFIH1 encodes MDA5, a key cystolic sensor for viral nucleic acids. Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. There were seven carriers of LoF variants identified (range of onset 6 months to 6 years of age). In three of these cases, a second hypomorphic missense variant was identified.
Luciferase reporter assays were employed to assess MDA5 activity. In some cases, the second missense variant was either proven to not affect protein function or was in cis with the LoF variant.
Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
Mendeliome v0.9088 IFIH1 Sarah Pantaleo changed review comment from: Rare, likely loss-of-functions IFIH1 variants identified in eight patients with Very Early Onset Inflammatory Bowel Disease (VEOIBD) with VEOIBD from a combined cohort of 42 children. One homozygous truncating variant in a neonate from a consanguineous family, seven carriers of LoF variants (three of whom also have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.; to: Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. seven carriers of LoF variants (three of whom have a second hypomorphic missense variant). Luciferase reporter assays employed to assess MDA5 activity (encoded by IFIH1). In three cases, the functional studies demonstrated that the second missense variant either did not affect protein function or was in cis with the LoF variant.
Mendeliome v0.9088 IFIH1 Sarah Pantaleo reviewed gene: IFIH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34185153; Phenotypes: Inflammatory Bowel Disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.9087 FGF8 Zornitza Stark Publications for gene: FGF8 were set to
Mendeliome v0.9085 FGF8 Zornitza Stark reviewed gene: FGF8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9084 PRICKLE2 Zornitza Stark Publications for gene: PRICKLE2 were set to
Mendeliome v0.9082 PRICKLE2 Hazel Phillimore reviewed gene: PRICKLE2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34092786; Phenotypes: Neurodevelopmental disorder, global developmental delay, behavioural difficulties ± epilepsy, autistic features, and attention deficit hyperactive disorder.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9082 UBE2U Ee Ming Wong changed review comment from: - one missense UBE2U variant identified in one family with four other affected individuals (includes proband)
- in silico analyses predicts the UBE2U variant to be damaging
- no functional
- another STUM missense variant identified in the same family predicted to be benign
- additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome
Sources: Literature; to: - one missense UBE2U variant identified in one family with five affected individuals (includes proband)
- in silico analyses predicts the UBE2U variant to be damaging
- no functional
- another STUM missense variant identified in the same family predicted to be benign
- additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome
Sources: Literature
Mendeliome v0.9081 FGF8 Dean Phelan reviewed gene: FGF8: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34433009; Phenotypes: Femoral hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9081 LRP1 Seb Lunke Added comment: Comment on list classification: Two papers without related phenotypes and little overall evidence for gene disease association.
Mendeliome v0.9079 COPB2 Zornitza Stark Publications for gene: COPB2 were set to 29036432
Mendeliome v0.9075 UBE2U Ee Ming Wong gene: UBE2U was added
gene: UBE2U was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to PMID: 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay
Penetrance for gene: UBE2U were set to Complete
Review for gene: UBE2U was set to RED
gene: UBE2U was marked as current diagnostic
Added comment: - one missense UBE2U variant identified in one family with four other affected individuals (includes proband)
- in silico analyses predicts the UBE2U variant to be damaging
- no functional
- another STUM missense variant identified in the same family predicted to be benign
- additional clinical assessment indicated that the family shared some systemic dysmorphisms and learning disabilities similar to RIDDLE syndrome
Sources: Literature
Mendeliome v0.9075 LRP1 Elena Savva reviewed gene: LRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26142438, 33776059; Phenotypes: ?Keratosis pilaris atrophicans MIM#604093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9075 COPB2 Belinda Chong reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34450031; Phenotypes: Osteoporosis and developmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9074 CFAP206 Seb Lunke Publications for gene: CFAP206 were set to
Mendeliome v0.9073 GRIK2 Zornitza Stark Publications for gene: GRIK2 were set to
Mendeliome v0.9068 CACNA1I Kristin Rigbye gene: CACNA1I was added
gene: CACNA1I was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Review for gene: CACNA1I was set to GREEN
Added comment: 4 different missense variants identified and shown to result in a gain of function.

2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy.

1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases.
Sources: Literature
Mendeliome v0.9068 GRIK2 Danielle Ariti reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, nonsyndromic neurodevelopmental disorder (NDD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9068 ZNF668 Paul De Fazio changed review comment from: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature; to: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Mendeliome v0.9067 ZNF668 Paul De Fazio changed review comment from: 5 individuals from 3 consanguineous families reported with different truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature; to: 5 individuals from 3 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Mendeliome v0.9067 ZNF668 Paul De Fazio gene: ZNF668 was added
gene: ZNF668 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Review for gene: ZNF668 was set to GREEN
gene: ZNF668 was marked as current diagnostic
Added comment: 5 individuals from 3 consanguineous families reported with different truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Mendeliome v0.9067 GLIS1 Seb Lunke gene: GLIS1 was added
gene: GLIS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GLIS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLIS1 were set to 34385434
Phenotypes for gene: GLIS1 were set to Increased ocular pressure
Review for gene: GLIS1 was set to RED
Added comment: Functional studies in KO mice show increased intra-ocular pressure (IOT) caused by defects in the ocular drainage system. IOT is frequently associated with Glaucoma, however mice were not investigated for glaucoma, and no patients described.
Sources: Literature
Mendeliome v0.9065 SLC32A1 Zornitza Stark gene: SLC32A1 was added
gene: SLC32A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC32A1 were set to 34038384
Phenotypes for gene: SLC32A1 were set to Genetic epilepsy with febrile seizures plus
Review for gene: SLC32A1 was set to GREEN
Added comment: 8 unrelated families reported, including segregation evidence in two large pedigrees. Variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition.
Sources: Literature
Mendeliome v0.9062 G6PD Zornitza Stark Publications for gene: G6PD were set to
Mendeliome v0.9060 G6PD Zornitza Stark reviewed gene: G6PD: Rating: GREEN; Mode of pathogenicity: None; Publications: 18177777; Phenotypes: Haemolytic anemia, G6PD deficient (favism), MIM# 300908; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.9059 EPB42 Zornitza Stark Publications for gene: EPB42 were set to
Mendeliome v0.9057 EPB42 Zornitza Stark reviewed gene: EPB42: Rating: GREEN; Mode of pathogenicity: None; Publications: 1558976, 7803799, 7772513; Phenotypes: Spherocytosis, type 5, MIM# 612690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9056 EPB41 Zornitza Stark Publications for gene: EPB41 were set to
Mendeliome v0.9054 EPB41 Zornitza Stark reviewed gene: EPB41: Rating: GREEN; Mode of pathogenicity: None; Publications: 33942936, 32807033, 27667160, 21839655; Phenotypes: Elliptocytosis-1, MIM# 611804; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9053 DHFR Zornitza Stark Publications for gene: DHFR were set to
Mendeliome v0.9051 DHFR Zornitza Stark reviewed gene: DHFR: Rating: GREEN; Mode of pathogenicity: None; Publications: 21310276, 21310277; Phenotypes: Megaloblastic anaemia due to dihydrofolate reductase deficiency, MIM# 613839; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9050 CYB5R3 Zornitza Stark Publications for gene: CYB5R3 were set to
Mendeliome v0.9048 CYB5R3 Zornitza Stark reviewed gene: CYB5R3: Rating: GREEN; Mode of pathogenicity: None; Publications: 2107882, 1707593, 12393396; Phenotypes: Methaemoglobinaemia, type I and II, MIM# 250800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9047 CD59 Zornitza Stark Publications for gene: CD59 were set to
Mendeliome v0.9045 CD59 Zornitza Stark reviewed gene: CD59: Rating: GREEN; Mode of pathogenicity: None; Publications: 24382084, 23149847; Phenotypes: Haemolytic anaemia, CD59-mediated, with or without immune-mediated polyneuropathy, MIM# 612300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9044 NEDD4L Zornitza Stark Publications for gene: NEDD4L were set to
Mendeliome v0.9042 NEDD4L Zornitza Stark reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 34087865, 27694961, 32117442; Phenotypes: Periventricular nodular heterotopia 7, MIM# 617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9042 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155
Mendeliome v0.9039 AMN Zornitza Stark Publications for gene: AMN were set to
Mendeliome v0.9037 AMN Zornitza Stark reviewed gene: AMN: Rating: GREEN; Mode of pathogenicity: None; Publications: 12590260, 15024727, 17285242, 24156255, 26040326; Phenotypes: Imerslund-Grasbeck syndrome 2, MIM# 618882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9036 AK1 Zornitza Stark Publications for gene: AK1 were set to
Mendeliome v0.9034 AK1 Zornitza Stark reviewed gene: AK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2542324, 9432020, 10233365, 34321014; Phenotypes: Haemolytic anemia due to adenylate kinase deficiency, MIM# 612631; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9033 ALAS2 Zornitza Stark Publications for gene: ALAS2 were set to
Mendeliome v0.9031 ALAS2 Zornitza Stark reviewed gene: ALAS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10029606, 7949148, 10029606, 25615817; Phenotypes: Anaemia, sideroblastic, 1, MIM# 300751, Protoporphyria, erythropoietic, X-linked, MIM# 300752; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9030 ABCG5 Zornitza Stark Publications for gene: ABCG5 were set to
Mendeliome v0.9028 ABCG5 Zornitza Stark reviewed gene: ABCG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 34304999, 33907061, 32546081, 23556150; Phenotypes: Sitosterolaemia 2, MIM# 618666; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9026 CLCN3 Zornitza Stark reviewed gene: CLCN3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512; Mode of inheritance: None
Mendeliome v0.9026 TOM1 Zornitza Stark gene: TOM1 was added
gene: TOM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TOM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TOM1 were set to 31263572
Phenotypes for gene: TOM1 were set to Immunodeficiency 85 and autoimmunity, MIM# 619510
Review for gene: TOM1 was set to RED
Added comment: Parent and child reported with onset of atopic eczema and recurrent respiratory infections in the first decade of life; autoimmune enteropathy with vomiting, diarrhoea, and poor overall growth. More variable features included autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Laboratory studies showed hypogammaglobulinaemia and abnormal T-cell function, consistent with a combined immunodeficiency. Missense variant in TOM1, with limited functional data.
Sources: Expert list
Mendeliome v0.9025 ARF1 Arina Puzriakova reviewed gene: ARF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28868155, 34353862; Phenotypes: Periventricular nodular heterotopia 8, OMIM:618185; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.9025 GINS2 Arina Puzriakova gene: GINS2 was added
gene: GINS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS2 were set to 34353863
Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome with craniosynostosis
Review for gene: GINS2 was set to RED
Added comment: Sa et al., 2021 (PMID: 34353863) identified a patient presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. A homozygous missense variant (c.341G>T, p.Arg114Leu) in GINS2 was identified that was heterozygous in both unaffected parents. Some supportive functional data included.

GINS2 is not currently not associated with any phenotype in OMIM or G2P and no additional cases have been identified to date.
Sources: Literature
Mendeliome v0.9024 DNAH10 Zornitza Stark reviewed gene: DNAH10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 56, MIM# 619515; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9021 CHRM1 Bryony Thompson gene: CHRM1 was added
gene: CHRM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism
Review for gene: CHRM1 was set to AMBER
Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways.
PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu)
PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction.
Sources: Literature
Mendeliome v0.9019 FGF20 Zornitza Stark gene: FGF20 was added
gene: FGF20 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FGF20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF20 were set to 22698282
Phenotypes for gene: FGF20 were set to Renal hypodysplasia/aplasia 2, MIM#615721
Review for gene: FGF20 was set to AMBER
Added comment: Multiple affected fetuses in a consanguineous family; functional data.
Sources: Expert Review
Mendeliome v0.9017 ITGA8 Zornitza Stark Publications for gene: ITGA8 were set to
Mendeliome v0.9015 ITGA8 Zornitza Stark reviewed gene: ITGA8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24439109; Phenotypes: Renal hypodysplasia/aplasia 1, MIM# 191830; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9014 NPR2 Zornitza Stark Publications for gene: NPR2 were set to
Mendeliome v0.9012 NPR2 Zornitza Stark edited their review of gene: NPR2: Changed publications: 31555216, 16384845, 15146390, 22870295, 24057292, 24259409, 16384845, 24471569; Changed phenotypes: Acromesomelic dysplasia, Maroteaux type MIM# 602875, Epiphyseal chondrodysplasia, Miura type, MIM# 615923, Short stature with nonspecific skeletal abnormalities, MIM# 616255; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.9012 NPR2 Zornitza Stark reviewed gene: NPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31555216, 16384845, 15146390; Phenotypes: Acromesomelic dysplasia, Maroteaux type MIM# 602875, Short stature, disproportionate, Oval vertebral bodies in infancy, Progressive shortening of humerus, radius and ulna in first year, dwarfism, Prominent forehead; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9011 RPS6KA3 Zornitza Stark Publications for gene: RPS6KA3 were set to
Mendeliome v0.9009 RPS6KA3 Zornitza Stark reviewed gene: RPS6KA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 6879200; Phenotypes: Coffin-Lowry syndrome MIM# 303600, Intellectual disability, short stature, delayed bone age, hearing deficit, hypotonia, tapering fingers, abnormal facies (hypertelorism, anteverted nares, prominent frontal region); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.9009 SHOX2 Zornitza Stark gene: SHOX2 was added
gene: SHOX2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SHOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SHOX2 were set to 30443179
Phenotypes for gene: SHOX2 were set to Sinus Node Dysfunction; Atrial Fibrillation
Review for gene: SHOX2 was set to RED
Added comment: Single family reported with LoF in this gene and AF.
Sources: Expert Review
Mendeliome v0.9006 KCTD7 Zornitza Stark Publications for gene: KCTD7 were set to
Mendeliome v0.9004 KCTD7 Kristin Rigbye reviewed gene: KCTD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22693283, 22748208; Phenotypes: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9002 ROR2 Zornitza Stark Publications for gene: ROR2 were set to
Mendeliome v0.9000 ROR2 Zornitza Stark reviewed gene: ROR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10932186, 10932187, 10986040, 19461659; Phenotypes: Robinow syndrome, autosomal recessive MIM# 268310, hypertelorism, short stature, mesomelic shortening of the limbs, hypoplastic genitalia, rib/vertebral anomalies, abnormal morphogenesis of the face, Brachydactyly, type B1 MIM# 113000, hypoplasia/aplasia of distal phalanges and nails (2-5); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8999 PROP1 Zornitza Stark Publications for gene: PROP1 were set to
Mendeliome v0.8997 PROP1 Zornitza Stark reviewed gene: PROP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301521, 31090814; Phenotypes: Pituitary hormone deficiency, combined, 2 MIM# 262600, Ateliotic dwarfism with hypogonadism, growth failure, short stature, failure to thrive, absent sexual development at puberty, GH, PRL, TSH, LH, and FSH deficiency, pituitary hypoplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8996 WRN Zornitza Stark Publications for gene: WRN were set to
Mendeliome v0.8994 WRN Zornitza Stark reviewed gene: WRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 28476236, 8602509, 8968742, 9012406; Phenotypes: Werner syndrome, MIM# 277700, MONDO:0010196; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8993 POU1F1 Zornitza Stark Publications for gene: POU1F1 were set to
Mendeliome v0.8991 POU1F1 Zornitza Stark reviewed gene: POU1F1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1302000, 1472057, 9392392, 15928241, 7833912, 12773133; Phenotypes: Pituitary hormone deficiency, combined, 1 MIM# 613038, pituitary hypoplasia, severe growth failure, combined GH, PRL and TSH deficiency, distinct facial features (prominent forehead, mid-facial hypoplasia, depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8990 OPDM2 Bryony Thompson STR: OPDM2 was added
STR: OPDM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: OPDM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: OPDM2 were set to 32413282; 33374016
Phenotypes for STR: OPDM2 were set to Oculopharyngodistal myopathy 2 MIM#618940
Review for STR: OPDM2 was set to GREEN
STR: OPDM2 was marked as clinically relevant
Added comment: NM_005716.4:c.-211GGC[X]
>15 Chinese families/probands with a heterozygous trinucleotide repeat expansion (CGG(n)) in 5'UTR exon 1 of the GIPC1 gene. The expansion was found by a combination of linkage analysis, whole-exome sequencing, long-range sequencing, and PCR analysis, and segregated with the disorder in the family. Repeat lengths in the patients ranged from 70 to 138. Normal repeat lengths ranged from 12 to 32.
Sources: Literature
Mendeliome v0.8989 GIPC1 Bryony Thompson Added comment: Comment on list classification: Added to panel as an STR under OPDM2
Mendeliome v0.8987 FAME2 Bryony Thompson STR: FAME2 was added
STR: FAME2 was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: FAME2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FAME2 were set to 11701600; 24114805; 31664034
Phenotypes for STR: FAME2 were set to Epilepsy, familial adult myoclonic, 2 MIM#607876
Review for STR: FAME2 was set to GREEN
STR: FAME2 was marked as clinically relevant
Added comment: NM_020151.3(STARD7):c.291-1572ATTTT[X]ATTTC[X]
158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy with a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat, similar molecular finding in other forms of FAME. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and no effect on STARD7 gene expression, suggesting ATTTC expansions may cause FAME irrespective of the genomic locus involved.
Sources: Literature
Mendeliome v0.8986 STARD7 Bryony Thompson Added comment: Comment on list classification: Added to panel as an STR under FAME2
Mendeliome v0.8985 PNPLA6 Zornitza Stark Publications for gene: PNPLA6 were set to 25480986; 24355708
Mendeliome v0.8984 PNPLA6 Zornitza Stark edited their review of gene: PNPLA6: Changed publications: 25480986, 33818269, 32758583, 30097146; Changed phenotypes: Oliver-McFarlane syndrome, MIM# 275400, Laurence-Moon syndrome, MIM# 245800
Mendeliome v0.8983 PI4KA Zornitza Stark Publications for gene: PI4KA were set to 25855803
Mendeliome v0.8981 PI4KA Zornitza Stark edited their review of gene: PI4KA: Added comment: Neurodevelopmental syndrome with hypomyelinating leukodystrophy: 10 unrelated patients harbouring biallelic variants in PI4KA reported with a spectrum of severe global neurodevelopmental delay, hypomyelination, and developmental brain abnormalities, and pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells.; Changed rating: GREEN; Changed publications: 25855803, 34415322; Changed phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531, Neurodevelopmental syndrome with hypomyelinating leukodystrophy
Mendeliome v0.8980 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102; 34333668
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Oculopharyngodistal myopathy 3 MIM#619473; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[X]
Expanded repeat in NOTCH2NLC sequence is (GGC)9(GGA)2(GGC)2.
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 4-40, 1 control had 61 repeats and may have been a presymptomatic carrier.
Intermediate range: 41-60 identified in Parkinson's disease
Pathogenic repeat range: >=60-520
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Mendeliome v0.8977 SUCO Bryony Thompson gene: SUCO was added
gene: SUCO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SUCO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUCO were set to 29620724; 20440000
Phenotypes for gene: SUCO were set to Osteogenesis imperfecta
Review for gene: SUCO was set to AMBER
Added comment: A single case with diffuse osteopenia, multiple fractures with limb deformities, and short long bones, with biallelic variants (a missense and a splice site variant). Also, a null mouse model with acute onset skeletal defects that include impaired bone formation and spontaneous fractures.
Sources: Literature
Mendeliome v0.8975 IGFALS Zornitza Stark Publications for gene: IGFALS were set to
Mendeliome v0.8973 IGFALS Zornitza Stark reviewed gene: IGFALS: Rating: GREEN; Mode of pathogenicity: None; Publications: 14762184, 21396577, 34136918; Phenotypes: Acid-labile subunit, deficiency of, MIM# 615961; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8972 FAME1 Bryony Thompson STR: FAME1 was added
STR: FAME1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: FAME1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for STR: FAME1 were set to 30194086; 29507423
Phenotypes for STR: FAME1 were set to Epilepsy, familial adult myoclonic, 1 MIM#601068
Review for STR: FAME1 was set to GREEN
STR: FAME1 was marked as clinically relevant
Added comment: NC_000008.10:g.119379055_119379157TGAAA[X]TAAAA[X]
A heterozygous or homozygous 5-bp expanded TTTCA(n) insertion associated with an upstream 5-bp TTTTA(n) repeat expansion in a noncoding region within intron 4 of the SAMD12 gene, was identified in over 50 Chinese and Japanese families. 4 homozygous cases from 3 families had a more severe phenotype. The TTTTA repeat was present in controls, while the TTTCA was absent and only present in cases (100-3680 repeats reported). RNA toxicity is expected to be the mechanism of disease.
Sources: Expert list
Mendeliome v0.8971 SAMD12 Bryony Thompson Added comment: Comment on list classification: Added as an STR to panel under FAME1.
Mendeliome v0.8970 SCA36 Bryony Thompson Publications for STR: SCA36 were set to 25101480
Mendeliome v0.8969 SCA36 Bryony Thompson edited their review of STR: SCA36: Changed publications: 21683323
Mendeliome v0.8969 MYO1H Zornitza Stark gene: MYO1H was added
gene: MYO1H was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction, MIM#619482
Review for gene: MYO1H was set to RED
Added comment: Single family reported with three affected children, homozygous LoF variant.
Sources: Literature
Mendeliome v0.8967 BLM Zornitza Stark Publications for gene: BLM were set to
Mendeliome v0.8964 PRKDC Zornitza Stark Publications for gene: PRKDC were set to
Mendeliome v0.8962 PRKDC Zornitza Stark reviewed gene: PRKDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 19075392, 23722905; Phenotypes: Immunodeficiency 26, with or without neurologic abnormalities MIM# 615966, Absent T and B cells, normal NK cells, SCID, recurrent respiratory infections, microcephaly, seizures, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8961 TBX1 Zornitza Stark Publications for gene: TBX1 were set to
Mendeliome v0.8959 TBX1 Zornitza Stark reviewed gene: TBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301696, 31830774, 16684884; Phenotypes: DiGeorge syndrome MIM# 188400, Velocardiofacial syndrome MIM# 192430, Decreased T cells, Hypoparathyroidism, Conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies (cleft palate, prominent tubular nose etc), intellectual disability, Immunodeficiency, thymic hypoplasia or aplasia with resultant T‐cell dysfunction, renal anomalies, autoimmunity; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8958 RTEL1 Zornitza Stark Publications for gene: RTEL1 were set to
Mendeliome v0.8956 RTEL1 Zornitza Stark reviewed gene: RTEL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301779, 23329068, 15210109, 23453664, 19461895, 25848748, 25607374; Phenotypes: Dyskeratosis congenita, autosomal dominant 4 MIM# 615190, Dyskeratosis congenita, autosomal recessive 5 MIM# 615190, Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 MIM# 616373; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8956 RMRP Zornitza Stark changed review comment from: Over 60 pathogenic RMRP variants have been reported resulting in CHH phenotypes; multiple mouse models

Homozygous and Compound heterozygous (insertions, duplications and missense) variants have been reported resulting in loss of function.
*Founder variant g.70A>G (Amish and Finnish populations)

CHH individuals present with variable features that may include: shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities and a spectrum of combined immunodeficiency.; to: Over 60 pathogenic RMRP variants have been reported resulting in CHH phenotypes; multiple mouse models

Homozygous and Compound heterozygous (insertions, duplications and missense) variants have been reported resulting in loss of function.
*Founder variant g.70A>G (Amish and Finnish populations)

CHH individuals present with variable features that may include: shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities and a spectrum of combined immunodeficiency.

Anauxetic dysplasia 1, MIM# 607095 is a more severe phenotype, whereas Metaphyseal dysplasia without hypotrichosis, MIM# 250460 is milder.
Mendeliome v0.8956 RMRP Zornitza Stark edited their review of gene: RMRP: Changed publications: 16244706, 21396580, 22420014, 11940090, 16252239
Mendeliome v0.8955 RMRP Zornitza Stark Publications for gene: RMRP were set to
Mendeliome v0.8953 RMRP Zornitza Stark reviewed gene: RMRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16244706, 21396580, 22420014; Phenotypes: Cartilage hair hypoplasia (CHH) MIM#250250, shortened limbs, short stature, metaphysical dysplasia, fine, sparse and/or light-coloured hair, hematologic abnormalities, CID, impaired lymphocyte proliferation, low Ig levels, antibodies variably decreased, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8953 BLM Danielle Ariti reviewed gene: BLM: Rating: GREEN; Mode of pathogenicity: None; Publications: 17407155, 9285778, 7585968, 8079989, 12242442, 11101838; Phenotypes: Bloom Syndrome MIM# 210900, Short stature, dysmorphic facies, sun-sensitive, immunoglobulin deficiency (IgA, IgG, IgM), erythema, marrow failure, leukaemia, lymphoma, chromosomal instability, predisposition to malignancies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8952 RFX5 Zornitza Stark Publications for gene: RFX5 were set to
Mendeliome v0.8950 RFX5 Zornitza Stark reviewed gene: RFX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 9401005, 29527204, 30170160, 7990905, 8642248, 7699327; Phenotypes: Bare lymphocyte syndrome, type II, complementation group C MIM# 209920, Bare lymphocyte syndrome, type II, complementation group E MIM# 209920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8948 TYK2 Zornitza Stark Publications for gene: TYK2 were set to
Mendeliome v0.8946 TYK2 Zornitza Stark reviewed gene: TYK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17088085, 17521577, 26304966; Phenotypes: Immunodeficiency 35, MIM# 611521; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8945 RAG1 Zornitza Stark Publications for gene: RAG1 were set to
Mendeliome v0.8942 RAG2 Zornitza Stark Publications for gene: RAG2 were set to
Mendeliome v0.8939 EDEM3 Zornitza Stark reviewed gene: EDEM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type 2V, MIM# 619493; Mode of inheritance: None
Mendeliome v0.8939 RAG2 Danielle Ariti reviewed gene: RAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9630231, 11313270, 31885011, 8810255, 15025726, 18463379; Phenotypes: Omenn syndrome MIM# 603554, Severe combined immunodeficiency, B cell-negative MIM# 601457, Combined cellular and humoral immune defects with granulomas MIM# 233650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8938 RAC2 Zornitza Stark Publications for gene: RAC2 were set to
Mendeliome v0.8937 RAG1 Danielle Ariti reviewed gene: RAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16276422, 18463379, 20489056, 9630231, 11313270, 17476359, 8810255, 6823332; Phenotypes: Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity MIM# 609889, Combined cellular and humoral immune defects with granulomas MIM# 233650, Omenn syndrome MIM# 603554, Severe combined immunodeficiency, B cell-negative MIM# 601457; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8935 RAC2 Danielle Ariti reviewed gene: RAC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 21167572, 10758162, 10072071, 25512081, 32542921, 31919089; Phenotypes: Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis MIM# 608203, Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia MIM# 618987, Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8935 MTHFD1 Danielle Ariti reviewed gene: MTHFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780, Decreased Ig levels, poor antibody responses to conjugated polysaccharide antigens, low B/T/NK cells, Recurrent bacterial infection, megaloblastic anaemia, failure to thrive, neutropenia, seizures, intellectual disability, folate-responsive, Lymphopaenia; Phenotypes: 32414565, 19033438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8934 GLI2 Zornitza Stark Publications for gene: GLI2 were set to
Mendeliome v0.8932 GLI2 Zornitza Stark reviewed gene: GLI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 14581620, 17096318, 33235745, 27585885, 15994174, 20685856, 30629636, 30583238; Phenotypes: Culler-Jones syndrome, MIM#615849, Holoprosencephaly 9, MIM# 61082); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8931 GHSR Zornitza Stark Publications for gene: GHSR were set to
Mendeliome v0.8928 GHSR Zornitza Stark reviewed gene: GHSR: Rating: AMBER; Mode of pathogenicity: None; Publications: 25557026, 19789204, 16511605; Phenotypes: Growth hormone deficiency, isolated partial, MIM# 615925; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8928 PDE6D Zornitza Stark edited their review of gene: PDE6D: Changed publications: 30423442, 24166846
Mendeliome v0.8926 GHRHR Zornitza Stark Publications for gene: GHRHR were set to
Mendeliome v0.8924 GHRHR Zornitza Stark reviewed gene: GHRHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8528260, 10084571, 11232012; Phenotypes: Growth hormone deficiency, isolated, type IV, MIM# 618157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8923 GHR Zornitza Stark Publications for gene: GHR were set to
Mendeliome v0.8921 GHR Zornitza Stark reviewed gene: GHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 1999489, 8488849, 7565946; Phenotypes: Growth hormone insensitivity, partial, MIM# 604271, Laron dwarfism, MIM# 262500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8920 SCA12 Bryony Thompson STR: SCA12 was added
STR: SCA12 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA12 were set to 27864267; 33811808
Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326
Review for STR: SCA12 was set to GREEN
STR: SCA12 was marked as clinically relevant
Added comment: NM_181675.3:c.27CAG[X]
Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase
Normal: ≤32 repeats
Uncertain: ~40-50 repeats have been reported, 43 repeats is the lowest reported in an established affected individual in a family with SCA12
Established pathogenic (used as diagnostic cut-off): ≥51 repeats
Sources: Expert list
Mendeliome v0.8918 RNU7-1 Zornitza Stark reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 9, MIM# 619487; Mode of inheritance: None
Mendeliome v0.8917 LSM11 Zornitza Stark reviewed gene: LSM11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 8, MIM# 619486; Mode of inheritance: None
Mendeliome v0.8916 WDR11 Zornitza Stark Publications for gene: WDR11 were set to
Mendeliome v0.8914 WDR11 Zornitza Stark reviewed gene: WDR11: Rating: GREEN; Mode of pathogenicity: None; Publications: 34413497; Phenotypes: Intellectual disability, Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8912 GH1 Zornitza Stark Publications for gene: GH1 were set to
Mendeliome v0.8910 GH1 Zornitza Stark reviewed gene: GH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2840669, 1603635, 12655557, 15671105, 8552145, 9276733, 15713716; Phenotypes: Growth hormone deficiency, isolated, type IA, MIM# 262400, Growth hormone deficiency, isolated, type II, MIM# 173100, Kowarski syndrome, MIM# 262650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8909 EPHX1 Zornitza Stark Publications for gene: EPHX1 were set to
Mendeliome v0.8906 EPHX1 Zornitza Stark reviewed gene: EPHX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34342583; Phenotypes: Lipoatrophic diabetes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8904 ATM Zornitza Stark Publications for gene: ATM were set to
Mendeliome v0.8903 ATM Zornitza Stark reviewed gene: ATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 30137827; Phenotypes: Ataxia-telangiectasia, MIM# 208900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8901 RNU4ATAC Zornitza Stark Publications for gene: RNU4ATAC were set to 23794361; 26522830; 30455926
Mendeliome v0.8900 RNU4ATAC Zornitza Stark edited their review of gene: RNU4ATAC: Added comment: Lowry-Wood syndrome (LWS) is characterized by multiple epiphyseal dysplasia and microcephaly. Patients exhibit intrauterine growth retardation and short stature, as well as developmental delay and intellectual disability. Retinal degeneration has been reported in some patients.

Four unrelated families reported.

Note features between the three RNU4ATAC-related conditions overlap and they may not represent distinct disorders.; Changed rating: GREEN; Changed publications: 29265708, 12605445; Changed phenotypes: Lowry-Wood syndrome, MIM# 226960; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8899 TRPS1 Zornitza Stark Publications for gene: TRPS1 were set to
Mendeliome v0.8897 TRPS1 Zornitza Stark reviewed gene: TRPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11112658, 10615131; Phenotypes: Trichorhinophalangeal syndrome, type I, OMIM # 190350, Trichorhinophalangeal syndrome, type III, OMIM # 190351; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8896 FGD1 Zornitza Stark Publications for gene: FGD1 were set to
Mendeliome v0.8894 FGD1 Zornitza Stark reviewed gene: FGD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7954831, 20082460; Phenotypes: Aarskog-Scott syndrome, MIM # 305400, Mental retardation, X-linked syndromic 16, MIM# 305400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8893 BRD4 Zornitza Stark Publications for gene: BRD4 were set to
Mendeliome v0.8891 BRD4 Zornitza Stark reviewed gene: BRD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29379197, 30302754, 11997514, 34035299; Phenotypes: Cornelia de Lange syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8889 ZNF699 Zornitza Stark gene: ZNF699 was added
gene: ZNF699 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections.

12 unrelated families reported, 5 different homozygous frameshift variants.
Sources: Literature
Mendeliome v0.8887 SMC1A Zornitza Stark Publications for gene: SMC1A were set to 17273969; 22106055; 19701948; 26752331; 28166369
Mendeliome v0.8886 SMC1A Zornitza Stark reviewed gene: SMC1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29023665, 31409060, 31334757, 28166369; Phenotypes: Cornelia de Lange syndrome 2, MIM# 300590, Epileptic encephalopathy, early infantile, 85, with or without midline brain defects, MIM# 301044; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.8885 DCLRE1B Zornitza Stark Publications for gene: DCLRE1B were set to
Mendeliome v0.8883 DCLRE1B Zornitza Stark reviewed gene: DCLRE1B: Rating: RED; Mode of pathogenicity: None; Publications: 20479256, 21647296; Phenotypes: Dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome; Mode of inheritance: Unknown
Mendeliome v0.8883 TOR1AIP1 Zornitza Stark Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness; Contractures to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Congenital myasthenic syndrome
Mendeliome v0.8882 TOR1AIP1 Zornitza Stark Publications for gene: TOR1AIP1 were set to 24856141; 31299614; 30723199; 27342937; 32055997
Mendeliome v0.8881 TOR1AIP1 Zornitza Stark edited their review of gene: TOR1AIP1: Added comment: Gene is associated with multiple muscle phenotypes as already noted. Single family myasthenic syndrome and supportive mouse model data.; Changed rating: GREEN; Changed publications: 33215087; Changed phenotypes: Congenital myasthenic syndrome; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8880 PAPPA2 Zornitza Stark gene: PAPPA2 was added
gene: PAPPA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PAPPA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAPPA2 were set to 26902202; 34272725; 32739295
Phenotypes for gene: PAPPA2 were set to Short stature, Dauber-Argente type, MIM#619489
Review for gene: PAPPA2 was set to GREEN
Added comment: Short stature of the Dauber-Argente type (SSDA) is characterized by progressive postnatal growth failure, moderate microcephaly, thin long bones, and mildly decreased bone density. Patients have elevated circulating levels of total IGF1 due to impaired proteolysis of IGFBP3 and IGFBP5, resulting in reduced free IGF1.

7 individuals from 3 unrelated families reported, mouse model.
Sources: Literature
Mendeliome v0.8878 ATR Zornitza Stark Publications for gene: ATR were set to
Mendeliome v0.8876 ATR Zornitza Stark reviewed gene: ATR: Rating: GREEN; Mode of pathogenicity: None; Publications: 12640452, 19620979, 30199583, 23111928; Phenotypes: Seckel syndrome 1, MIM# 210600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8874 SHOX Zornitza Stark reviewed gene: SHOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Langer mesomelic dysplasia, MIM# 249700, Leri-Weill dyschondrosteosis, MIM# 127300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8873 ORC4 Zornitza Stark Publications for gene: ORC4 were set to
Mendeliome v0.8871 ORC4 Zornitza Stark reviewed gene: ORC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 21358631, 23023959, 22333897; Phenotypes: Meier-Gorlin syndrome 2, MIM# 613800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8870 ORC1 Zornitza Stark Publications for gene: ORC1 were set to
Mendeliome v0.8868 ORC1 Zornitza Stark reviewed gene: ORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358633, 21358632, 21358631, 23023959; Phenotypes: Meier-Gorlin syndrome 1, MIM# 224690, MONDO:0009143; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8867 ORC6 Zornitza Stark Publications for gene: ORC6 were set to
Mendeliome v0.8865 ORC6 Zornitza Stark reviewed gene: ORC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 22333897, 25691413, 26139588; Phenotypes: Meier-Gorlin syndrome 3, MIM# 613803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8864 IGF1 Zornitza Stark Publications for gene: IGF1 were set to
Mendeliome v0.8862 IGF1 Zornitza Stark reviewed gene: IGF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8857020, 15769976, 14684690, 31539878, 28768959, 34125705, 22832530; Phenotypes: Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8860 OBSL1 Zornitza Stark Publications for gene: OBSL1 were set to
Mendeliome v0.8858 OBSL1 Zornitza Stark reviewed gene: OBSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21737058, 19481195, 23018678, 19877176; Phenotypes: 3-M syndrome 2, MIM #612921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8857 PIK3R1 Zornitza Stark Publications for gene: PIK3R1 were set to
Mendeliome v0.8855 PIK3R1 Zornitza Stark reviewed gene: PIK3R1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23810378, 23810379, 23810382; Phenotypes: SHORT syndrome, MIM # 269880; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8855 PLAG1 Zornitza Stark Publications for gene: PLAG1 were set to 28796236; 29913240
Mendeliome v0.8853 PLAG1 Zornitza Stark edited their review of gene: PLAG1: Added comment: Additional families reported, upgrade to Green.

Silver-Russell syndrome-4 (SRS4) is characterised by intrauterine growth retardation followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face and prominent forehead, and relative macrocephaly at birth may be observed. So far 4 families have been reported with some functional studies of the role of the gene in the growth pathway.

Abi Habib et al. (2018) reported 1 family (child, sister and mother) patient with Silver-Russell syndrome (with normal methylation on chromosomes 7, 11, and 14, and exclusion of maternal UPD and chromosomal rearrangements). Using WES they identified a heterozygous 1-bp deletion in the PLAG1 gene. The variant segregated with disease, and was not present in polymorphism databases or ExAC. They also reported another patient with a different heterozygous 1-bp deletion in the PLAG1 gene. This was not found in her unaffected twin brother, older brother, or parents. Experiments in Hep3b cells demonstrated that PLAG1 positively regulates expression of the IGF2 promoter P3, independently and via the HMGA2-PLAG1-IGF2 pathway. Disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (SRS1; 180860), except for body asymmetry, which is not expected to occur since the molecular defects are present in all cells of the body, unlike the mosaic epigenetic changes at the 11p15.5 locus.

Inoue et al. (2020) reported 1 family with 2 affected people with Silver-Russell syndrome with a nonsense variant in the PLAG1 gene, which segregated with disease.

Vado et al. (2020) reported 1 family with multiple affected people with Silver-Russell syndrome with a frameshift variant in the PLAG1 gene, which segregated with disease.; Changed rating: GREEN; Changed publications: 28796236, 29913240, 33291420, 32546215
Mendeliome v0.8853 PACRG Zornitza Stark Publications for gene: PACRG were set to
Mendeliome v0.8851 PACRG Zornitza Stark reviewed gene: PACRG: Rating: RED; Mode of pathogenicity: None; Publications: 31116684, 31182890, 14737177, 27193298; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.8850 WIPF1 Zornitza Stark Publications for gene: WIPF1 were set to
Mendeliome v0.8848 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list; to: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homozygous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Mendeliome v0.8848 TCN2 Zornitza Stark Publications for gene: TCN2 were set to 19373259
Mendeliome v0.8847 TCN2 Zornitza Stark edited their review of gene: TCN2: Changed publications: 19373259, 32841161, 33023511, 30124850
Mendeliome v0.8847 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.
Sources: Expert list; to: Well established gene-disease association.

26 pathogenic TCN2 variants have been reported in over 40 individuals; multiple mouse models

Homologous and Compound Heterozygous TCN2 variants (deletions or insertions, nonsense mutations, and point mutations) have been reported; deletions or insertions are the most common, causing frameshifts that result in protein truncation.

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Mendeliome v0.8846 TCN2 Zornitza Stark Publications for gene: TCN2 were set to
Mendeliome v0.8843 TAP2 Zornitza Stark Publications for gene: TAP2 were set to
Mendeliome v0.8840 TAP1 Zornitza Stark Publications for gene: TAP1 were set to
Mendeliome v0.8838 PGRMC1 Bryony Thompson Phenotypes for gene: PGRMC1 were changed from Premature ovarian failure to Premature ovarian failure; Isolated paediatric cataract
Mendeliome v0.8837 PGRMC1 Bryony Thompson Publications for gene: PGRMC1 were set to 25246111; 18782852
Mendeliome v0.8836 WIPF1 Danielle Ariti reviewed gene: WIPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22231303, 27742395, 11869681, 14757742; Phenotypes: Wiskott-Aldrich syndrome 2 MIM# 614493, Reduced T cells, defective lymphocyte responses to anti-CD3, high IgE, Thrombocytopenia with or without small platelets, recurrent bacterial and viral Infections, eczema, bloody diarrhoea, gastrointestinal bleeding, WAS protein absent; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8835 PGRMC1 Bryony Thompson reviewed gene: PGRMC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33867527, 23783460; Phenotypes: Isolated paediatric cataract; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8835 TAP2 Danielle Ariti reviewed gene: TAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7517574, 9232449, 10560675, 27861817; Phenotypes: Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571, Low CD8, absent MHC I on lymphocytes, Vasculitis, pyoderma gangrenosum, recurrent bacterial/viral respiratory infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8835 TAP1 Danielle Ariti reviewed gene: TAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28161407, 10074494, 1473153; Phenotypes: Bare lymphocyte syndrome, type I MIM#604571, Low CD8, absent MHC I on lymphocytes, vasculitis, pyoderma gangrenosum, skin lesions, recurrent respiratory tract infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8835 ALS2 Teresa Zhao gene: ALS2 was added
gene: ALS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALS2 were set to PMID: 30128655; 33409823
Phenotypes for gene: ALS2 were set to Infantile onset ascending spastic paralysis (MIM#607225); Juvenile amyotrophic lateral sclerosis 2 (MIM#205100); Juvenile primary lateral sclerosis (MIM#606353)
Review for gene: ALS2 was set to GREEN
Added comment: >50 variants reported in multiple individuals with Infantile onset ascending spastic paralysis, mostly originated from the Middle East and Mediterranean countries.
Sources: Literature
Mendeliome v0.8834 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9).

The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263).

Extensive segregation analyses were carried out including several affected and unaffected members.

RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Mendeliome v0.8832 NBAS Zornitza Stark Publications for gene: NBAS were set to
Mendeliome v0.8830 NBAS Zornitza Stark reviewed gene: NBAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31761904; Phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, Infantile liver failure syndrome 2, MIM# 616483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8829 ARF3 Zornitza Stark gene: ARF3 was added
gene: ARF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Review for gene: ARF3 was set to AMBER
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu.

Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both.

ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively.

Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons.

There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185).

In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val).

This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia.

Evidence to support the effect of each variant include:

Arg99Leu:
Had identical Golgi localization to that of wt
Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF)
In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF).
In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu)

Asp67Val:
Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant)
Displayed decreased protein stability
In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF)
In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye.

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Mendeliome v0.8827 CEP57 Zornitza Stark Publications for gene: CEP57 were set to
Mendeliome v0.8825 CEP57 Zornitza Stark reviewed gene: CEP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 24259107, 21552266, 32861809, 30147898; Phenotypes: Mosaic variegated aneuploidy syndrome 2, #MIM 614114; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8824 PLXNA2 Zornitza Stark gene: PLXNA2 was added
gene: PLXNA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNA2 were set to 34327814
Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Review for gene: PLXNA2 was set to AMBER
Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members.

Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)).

Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed).

The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed).

Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved.

Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele.

As the authors discuss:
*PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration.
*Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch.
*Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD.
*Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus.

Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg:
- Cyanotic heart disease explaining discordance in cognitive outcome among sibs
- Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or
- Additional pathogenic variants possibly explaining the CHD in the first subject.

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature
Mendeliome v0.8823 SLC51A Zornitza Stark gene: SLC51A was added
gene: SLC51A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51A were set to 31863603
Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484
Review for gene: SLC51A was set to RED
Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated.
Sources: Literature
Mendeliome v0.8820 MOCOS Zornitza Stark Publications for gene: MOCOS were set to
Mendeliome v0.8818 MOCOS Zornitza Stark reviewed gene: MOCOS: Rating: GREEN; Mode of pathogenicity: None; Publications: 11302742, 17368066, 14624414, 25967871, 34356852, 32073534, 30758870, 27919260; Phenotypes: Xanthinuria type II, MIM#603592; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8817 HNMT Zornitza Stark Publications for gene: HNMT were set to
Mendeliome v0.8815 HNMT Zornitza Stark reviewed gene: HNMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 26206890, 30744146, 33310825, 33739554; Phenotypes: Mental retardation, autosomal recessive 51, MIM#616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8814 BLNK Zornitza Stark Publications for gene: BLNK were set to
Mendeliome v0.8812 BLNK Zornitza Stark reviewed gene: BLNK: Rating: GREEN; Mode of pathogenicity: None; Publications: 10583958, 32194234, 25893637; Phenotypes: Agammaglobulinaemia 4, MIM# 613502; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8811 AICDA Zornitza Stark Publications for gene: AICDA were set to
Mendeliome v0.8809 AICDA Zornitza Stark reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11007475; Phenotypes: Immunodeficiency with hyper-IgM, type 2, MIM# 605258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8807 VPS50 Zornitza Stark gene: VPS50 was added
gene: VPS50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.
Sources: Literature
Mendeliome v0.8806 SP6 Zornitza Stark Publications for gene: SP6 were set to 32167558; 18156176; 18297738; 22676574
Mendeliome v0.8803 SP6 Zornitza Stark reviewed gene: SP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33652941; Phenotypes: Hypoplastic amelogenesis imperfecta; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8803 AMTN Zornitza Stark gene: AMTN was added
gene: AMTN was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: AMTN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMTN were set to 27412008; 25715379; 26620968
Phenotypes for gene: AMTN were set to Amelogenesis imperfecta, type IIIB
Mode of pathogenicity for gene: AMTN was set to Other
Review for gene: AMTN was set to RED
Added comment: In a Costa Rican family segregating autosomal dominant hypomineralized amelogenesis imperfecta, Smith et al. (2016) identified a heterozygous deletion/insertion mutation in the amelotin gene that segregated with the phenotype in the family. The mutation was predicted to result in an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 amino acids. Mode of pathogenicity not established. Toxic gain of function proposed as Atmn KO and +/- mice did not recapitulate the human phenotype.
Sources: Expert Review
Mendeliome v0.8801 WDR72 Zornitza Stark Publications for gene: WDR72 were set to
Mendeliome v0.8799 WDR72 Zornitza Stark reviewed gene: WDR72: Rating: GREEN; Mode of pathogenicity: None; Publications: 21196691, 27259663, 20938048, 26502894, 23293580, 25008349, 19853237; Phenotypes: Amelogenesis imperfecta, type IIA3, MIM# 613211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8798 SLC24A4 Zornitza Stark Publications for gene: SLC24A4 were set to
Mendeliome v0.8796 SLC24A4 Zornitza Stark reviewed gene: SLC24A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23375655, 24621671, 25442250, 24532815, 26502894, 27129268; Phenotypes: Amelogenesis imperfecta, type IIA5, MIM# 615887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8795 ROGDI Zornitza Stark Publications for gene: ROGDI were set to
Mendeliome v0.8793 ROGDI Zornitza Stark reviewed gene: ROGDI: Rating: GREEN; Mode of pathogenicity: None; Publications: 22424600, 23086778, 33866847; Phenotypes: Kohlschutter-Tonz syndrome, MIM# 226750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8792 RELT Zornitza Stark gene: RELT was added
gene: RELT was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RELT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RELT were set to 30506946
Phenotypes for gene: RELT were set to Amelogenesis imperfecta, type IIIC, MIM# 618386
Review for gene: RELT was set to GREEN
Added comment: Amelogenesis imperfecta type IIIC is characterized by hypocalcified enamel in both the primary and secondary dentition. The enamel is rough and yellow-brown; under normal use, the enamel disintegrates from occlusal surfaces of the molars, leaving a ring of intact enamel remaining on the sides. At least 3 families and a mouse model.
Sources: Expert Review
Mendeliome v0.8790 LAMB3 Zornitza Stark Publications for gene: LAMB3 were set to 11023379; 7706760
Mendeliome v0.8788 LAMB3 Zornitza Stark edited their review of gene: LAMB3: Changed publications: 11023379, 7706760, 23958762, 7706760, 23632796, 26502894, 27220909, 25769099, 24494736; Changed phenotypes: Amelogenesis imperfecta, type IA, MIM# 104530, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.8787 KIAA0753 Zornitza Stark Publications for gene: KIAA0753 were set to 31816441; 28220259; 29138412; 26643951
Mendeliome v0.8786 KIAA0753 Zornitza Stark edited their review of gene: KIAA0753: Added comment: At least 5 families reported with a skeletal ciliopathy.; Changed publications: 29138412, 31816441, 33875766, 34016807; Changed phenotypes: Orofaciodigital syndrome XV 617127, Joubert syndrome, Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Mendeliome v0.8785 SPTBN1 Zornitza Stark reviewed gene: SPTBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475; Mode of inheritance: None
Mendeliome v0.8784 NIID Zornitza Stark reviewed STR: NIID: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oculopharyngodistal myopathy 3, MIM# 619473; Mode of inheritance: None
Mendeliome v0.8783 KLK4 Zornitza Stark Publications for gene: KLK4 were set to
Mendeliome v0.8781 KLK4 Zornitza Stark reviewed gene: KLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 15235027, 23355523, 28611678, 27066511; Phenotypes: Amelogenesis imperfecta, type IIA1, MIM# 204700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8780 ITGB6 Zornitza Stark gene: ITGB6 was added
gene: ITGB6 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ITGB6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGB6 were set to 25431241; 26695873; 24305999; 24319098
Phenotypes for gene: ITGB6 were set to Amelogenesis imperfecta, type IH, MIM# 616221
Review for gene: ITGB6 was set to GREEN
Added comment: At least 3 unrelated families reported.
Sources: Expert Review
Mendeliome v0.8778 STAT3 Zornitza Stark Publications for gene: STAT3 were set to
Mendeliome v0.8776 STAT3 Zornitza Stark reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17881745, 14566054, 25349174, 25038750, 25359994; Phenotypes: Hyper-IgE recurrent infection syndrome MIM# 147060, Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8775 STK4 Zornitza Stark Publications for gene: STK4 were set to
Mendeliome v0.8772 SP110 Zornitza Stark Publications for gene: SP110 were set to
Mendeliome v0.8769 SMARCAL1 Zornitza Stark Publications for gene: SMARCAL1 were set to
Mendeliome v0.8767 STK4 Danielle Ariti reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22294732, 26117625, 22174160, 22952854; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868, CD4/CD8 lymphopaenia, cardiac malformations, reduced naïve T cells, increased TEM and TEMRA cells, poor T cell Proliferation, Reduced memory B cells, Reduced IgM, increased IgG, IgA, IgE, impaired antibody responses, intermittent neutropaenia, bacterial/ viral/ fungal infections, autoimmune cytopaenias, mucocutaneous candidiasis, cutaneous warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SPINK5 Danielle Ariti reviewed gene: SPINK5: Rating: ; Mode of pathogenicity: None; Publications: 33534181, 20657595; Phenotypes: Netherton syndrome MIM# 256500, Low switched and non-switched B cells, High IgE and IgA, Antibody variably decreased, Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive, food allergies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SP110 Danielle Ariti reviewed gene: SP110: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301448, 31721003; Phenotypes: Hepatic veno-occlusive disease with immunodeficiency MIM#235550, Hepatic veno-occlusive disease, susceptibility to Pneumocystis jirovecii pneumonia, cytomegalovirus, thrombocytopaenia, hepatosplenomegaly, cerebrospinal leukodystrophy, memory T/B cell deficiency, low Ig levels, absent tissue plasma cells, absent lymph node germinal centers, hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SMARCAL1 Danielle Ariti reviewed gene: SMARCAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301550, 17089404, 20036229; Phenotypes: Schimke immune-osseous dysplasia MIM# 242900, T cell deficiency, Short stature, spondyloepiphyseal dysplasia, renal dysfunction, lymphocytopaenia, nephropathy, bacterial/viral/fungal infections, may present as SCID, bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8766 GPR68 Zornitza Stark Publications for gene: GPR68 were set to
Mendeliome v0.8764 GPR68 Zornitza Stark reviewed gene: GPR68: Rating: GREEN; Mode of pathogenicity: None; Publications: 27693231, 32279993; Phenotypes: Amelogenesis imperfecta, hypomaturation type, IIA6 MIM#617217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8763 FAM83H Zornitza Stark Publications for gene: FAM83H were set to
Mendeliome v0.8761 FAM83H Zornitza Stark reviewed gene: FAM83H: Rating: GREEN; Mode of pathogenicity: None; Publications: 18484629, 19407157, 19825039, 26481691, 21702852, 20160442, 26142250, 22414746, 19828885, 19220331, 26502894, 18252228, 21597265, 21118793, 26788537, 26171361; Phenotypes: Amelogenesis imperfecta, type IIIA MIM#130900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8760 ENAM Zornitza Stark Publications for gene: ENAM were set to
Mendeliome v0.8758 ENAM Zornitza Stark reviewed gene: ENAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 11487571, 28334996, 14684688, 33864320; Phenotypes: Amelogenesis imperfecta, type IB, MIM# 104500, Amelogenesis imperfecta, type IC, MIM# 204650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8757 FAM20A Zornitza Stark Publications for gene: FAM20A were set to
Mendeliome v0.8755 FAM20A Zornitza Stark reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23434854, 23697977, 23468644, 24756937, 21549343, 24259279, 24196488, 26502894, 25827751, 21990045; Phenotypes: Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8754 C4orf26 Zornitza Stark Publications for gene: C4orf26 were set to
Mendeliome v0.8752 C4orf26 Zornitza Stark reviewed gene: C4orf26: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901946, 27558265; Phenotypes: Amelogenesis imperfecta, type IIA4, MIM# 614832; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8751 AMELX Zornitza Stark Publications for gene: AMELX were set to
Mendeliome v0.8749 AMELX Zornitza Stark reviewed gene: AMELX: Rating: GREEN; Mode of pathogenicity: None; Publications: 17189466, 22243263, 7599636, 23251683, 1483698 1916828, 9188994, 15111628, 11201048, 26502894, 7782077, 11922869, 28130977, 8406474, 11839357, 25117480, 19610109; Phenotypes: Amelogenesis imperfecta, type 1E, MIM# 301200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.8748 AMBN Zornitza Stark Publications for gene: AMBN were set to
Mendeliome v0.8746 AMBN Zornitza Stark reviewed gene: AMBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24858907, 26502894, 31402633, 30174330; Phenotypes: Amelogenesis imperfecta, type IF MIM#616270; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8746 ACP4 Zornitza Stark reviewed gene: ACP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28513613, 27843125, 33552707; Phenotypes: Amelogenesis imperfecta, type IJ MIM#617297; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8743 TCF7L2 Zornitza Stark Publications for gene: TCF7L2 were set to 33057194
Mendeliome v0.8741 TCF7L2 Zornitza Stark changed review comment from: 2 reviews
Konstantinos Varvagiannis (Other)
I don't know

Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants.

Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11).

One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury.

TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts.

Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development.

Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1].

The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA).

No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism.

There are no variant or other studies performed, nor any animal models discussed.

In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs).

Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm.

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.; to: Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants.

Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11).

One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury.

TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts.

Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development.

Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1].

The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA).

No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism.

There are no variant or other studies performed, nor any animal models discussed.

In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs).

Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm.

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.
Mendeliome v0.8741 TCF7L2 Zornitza Stark reviewed gene: TCF7L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34003604; Phenotypes: Global developmental delay, Intellectual disability, Autism, Attention deficit hyperactivity disorder, Myopia, Abnormality of skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8740 LTBP3 Zornitza Stark Publications for gene: LTBP3 were set to
Mendeliome v0.8738 LTBP3 Zornitza Stark reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19344874, 25899461, 25669657, 29625025, 27068007, 34150014; Phenotypes: Dental anomalies and short stature, MIM# 601216, Geleophysic dysplasia 3, MIM# 617809, Thoracic aneurysm; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8738 ARIH1 Zornitza Stark reviewed gene: ARIH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8736 PIDD1 Zornitza Stark gene: PIDD1 was added
gene: PIDD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.
Sources: Expert Review
Mendeliome v0.8734 COLGALT1 Bryony Thompson gene: COLGALT1 was added
gene: COLGALT1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3 MIM#618360
Review for gene: COLGALT1 was set to GREEN
Added comment: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos.
Sources: Other
Mendeliome v0.8732 JAKMIP1 Seb Lunke gene: JAKMIP1 was added
gene: JAKMIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; Seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model.

Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H).

Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available.

KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Mendeliome v0.8730 ARIH1 Bryony Thompson gene: ARIH1 was added
gene: ARIH1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ARIH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARIH1 were set to 29689197; 32102558
Phenotypes for gene: ARIH1 were set to Thoracic aortic aneurysm
Review for gene: ARIH1 was set to GREEN
Added comment: 3 unrelated families: A de novo case (R171*) with thoracic aortic aneurysm (TAA), and 2 siblings with TAA and a missense (E15Q). Another proband with cerebrovascular aneurysm (family history of TAA) and a missense variant (E44G). Supporting functional assays of the variants and a drosophila model.
Sources: Other
Mendeliome v0.8727 PRPF31 Zornitza Stark Publications for gene: PRPF31 were set to
Mendeliome v0.8725 PRPF31 Zornitza Stark reviewed gene: PRPF31: Rating: GREEN; Mode of pathogenicity: None; Publications: 32014492; Phenotypes: Retinitis pigmentosa 11, MIM#600138; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8724 RNF168 Zornitza Stark Publications for gene: RNF168 were set to
Mendeliome v0.8721 RFXAP Zornitza Stark Publications for gene: RFXAP were set to
Mendeliome v0.8718 RFXANK Zornitza Stark Publications for gene: RFXANK were set to
Mendeliome v0.8715 RBCK1 Zornitza Stark Publications for gene: RBCK1 were set to
Mendeliome v0.8713 RFXANK Danielle Ariti reviewed gene: RFXANK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12618906; Phenotypes: MHC class II deficiency, complementation group B MIM# 209920, Bare Lymphocyte Syndrome, type II, complementation group B, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RFXAP Danielle Ariti reviewed gene: RFXAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9118943, 32875002, 11258423; Phenotypes: Bare lymphocyte syndrome, type II, complementation group D MIM# 209920, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RNF168 Danielle Ariti reviewed gene: RNF168: Rating: GREEN; Mode of pathogenicity: None; Publications: 19203578, 21394101, 29255463, 21552324; Phenotypes: RIDDLE syndrome MIM# 611943, Radiosensitivity, Immune Deficiency, Dysmorphic Features, Learning difficulties, Low IgG or IgA, Short stature, mild defect of motor control to ataxia, normal intelligence to learning difficulties, mild facial dysmorphism to microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RBCK1 Danielle Ariti reviewed gene: RBCK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29260357, 29695863; Phenotypes: Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895, muscular weakness, cardiomyopathy, recurrent bacterial/viral infections, autoinflammation, immunodeficiency, Poor antibody responses to polysaccharides, failure to thrive, fever, pneumonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8711 ABCC2 Zornitza Stark reviewed gene: ABCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dubin-Johnson syndrome, MIM# 237500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8711 CLDN9 Bryony Thompson Publications for gene: CLDN9 were set to 31175426; 19696885
Mendeliome v0.8709 CLDN9 Bryony Thompson reviewed gene: CLDN9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19696885, 31175426, 34265170; Phenotypes: Deafness, autosomal recessive 116 MIM#619093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8708 UBR1 Zornitza Stark Publications for gene: UBR1 were set to
Mendeliome v0.8706 UBR1 Zornitza Stark reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24599544; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8705 ACTL6A Zornitza Stark Publications for gene: ACTL6A were set to
Mendeliome v0.8703 ACTL6A Zornitza Stark edited their review of gene: ACTL6A: Changed publications: 28649782, 31994175
Mendeliome v0.8703 VAV1 Zornitza Stark gene: VAV1 was added
gene: VAV1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: VAV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VAV1 were set to 20638113; 23058036
Phenotypes for gene: VAV1 were set to Common variable immnodeficiency
Review for gene: VAV1 was set to RED
Added comment: Reduced VAV1 expression has been reported in multiple T-CVID cases, however only one large deletion (exon 2-27) has been reported in a single case in a publication from 2012. The CNV was detected using real-time qPCR, but was not confirmed by an orthogonal method.
Sources: Expert Review
Mendeliome v0.8701 TCF3 Zornitza Stark Publications for gene: TCF3 were set to
Mendeliome v0.8699 TCF3 Zornitza Stark reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24216514, 28532655, 30063982, 8001124, 8001125; Phenotypes: Agammaglobulinaemia 8, autosomal dominant, MIM# 616941; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8698 PRKCD Zornitza Stark Publications for gene: PRKCD were set to
Mendeliome v0.8696 PRKCD Zornitza Stark reviewed gene: PRKCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 23319571, 23666743, 23430113, 11976687, 33047643, 29867916; Phenotypes: Autoimmune lymphoproliferative syndrome, type III, MIM# 615559, CVID 9; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8696 CD19 Zornitza Stark changed review comment from: More than 5 unrelated families reported.; to: More than 5 unrelated families reported. Clinical features include increased susceptibility to infection, hypogammaglobulinaemia, and normal numbers of mature B cells in blood, indicating a B-cell antibody-deficient immunodeficiency disorder.
Mendeliome v0.8695 CD19 Zornitza Stark Publications for gene: CD19 were set to
Mendeliome v0.8693 CD19 Zornitza Stark reviewed gene: CD19: Rating: GREEN; Mode of pathogenicity: None; Publications: 16672701, 17882224, 17882224, 21330302, 21159371; Phenotypes: Immunodeficiency, common variable, 3, MIM# 613493; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8692 SNRPB Zornitza Stark Publications for gene: SNRPB were set to
Mendeliome v0.8690 SNRPB Zornitza Stark reviewed gene: SNRPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25047197, 25504470, 26971886; Phenotypes: Cerebrocostomandibular syndrome, MIM# 117650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8689 RBM10 Zornitza Stark Publications for gene: RBM10 were set to
Mendeliome v0.8687 RBM10 Zornitza Stark reviewed gene: RBM10: Rating: GREEN; Mode of pathogenicity: None; Publications: 20451169, 24259342, 30450804, 30189253, 33340101; Phenotypes: TARP syndrome, MIM# 311900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8686 OTX2 Zornitza Stark edited their review of gene: OTX2: Added comment: Three families reported with variants in OTX2 and otocyephaly-dysgnathia. Note variants were inherited in two of the families: in one family, from mother with microphthalmia (recognised OTX2 phenotype) and the other from an unaffected father. Lamb animal model reported.; Changed publications: 24167467, 25589041, 31969185; Changed phenotypes: Microphthalmia, syndromic 5, MIM# 610125, Pituitary hormone deficiency, combined, 6, MIM# 613986, Retinal dystrophy, early-onset, with or without pituitary dysfunction, MIM# 610125, Otocephaly-dysgnathia complex
Mendeliome v0.8685 POLR1D Zornitza Stark Publications for gene: POLR1D were set to
Mendeliome v0.8683 POLR1D Zornitza Stark reviewed gene: POLR1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131976, 24603435, 27448281, 25790162; Phenotypes: Treacher Collins syndrome 2, MIM# 613717; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8682 TP73 Zornitza Stark reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Mode of inheritance: None
Mendeliome v0.8680 POLR1C Zornitza Stark Publications for gene: POLR1C were set to
Mendeliome v0.8678 POLR1C Zornitza Stark reviewed gene: POLR1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131976, 30957429, 26151409, 32042905; Phenotypes: Treacher Collins syndrome 3, MIM# 248390, Leukodystrophy, hypomyelinating, 11, MIM# 616494; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8677 SF3B4 Zornitza Stark Publications for gene: SF3B4 were set to
Mendeliome v0.8675 SF3B4 Zornitza Stark reviewed gene: SF3B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541558, 23568615, 24003905; Phenotypes: Acrofacial dysostosis 1, Nager type, MIM# 154400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8674 TMCO1 Zornitza Stark Publications for gene: TMCO1 were set to
Mendeliome v0.8672 TMCO1 Zornitza Stark reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20018682, 23320496, 17351359, 30556256, 31102500; Phenotypes: Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8671 SPTBN4 Zornitza Stark reviewed gene: SPTBN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33772159, 29861105; Phenotypes: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, MIM# 617519; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8671 RGS10 Zornitza Stark gene: RGS10 was added
gene: RGS10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS10 were set to 34315806; 34339853
Phenotypes for gene: RGS10 were set to Immunodeficiency; short stature
Review for gene: RGS10 was set to RED
Added comment: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented. Further experimental data linking RGS10 to immune function presented in PMID 34339853.
Sources: Literature
Mendeliome v0.8669 MAST3 Zornitza Stark gene: MAST3 was added
gene: MAST3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST3 were set to 34185323
Phenotypes for gene: MAST3 were set to Developmental and epileptic encephalopathy
Review for gene: MAST3 was set to GREEN
Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data.
Sources: Literature
Mendeliome v0.8667 SF3B2 Zornitza Stark gene: SF3B2 was added
gene: SF3B2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B2 were set to 34344887
Phenotypes for gene: SF3B2 were set to Craniofacial microsomia
Review for gene: SF3B2 was set to GREEN
Added comment: Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities.

Targeted morpholino knockdown of SF3B2 in Xenopus resulted in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease.

The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
Sources: Literature
Mendeliome v0.8665 IMPG1 Zornitza Stark Publications for gene: IMPG1 were set to
Mendeliome v0.8663 IMPG1 Arina Puzriakova reviewed gene: IMPG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23993198, 28644393, 30589393, 30688845, 32817297; Phenotypes: Macular dystrophy, vitelliform, 4, OMIM:616151, Retinitis pigmentosa, MONDO:0019200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8660 CUL7 Zornitza Stark Publications for gene: CUL7 were set to
Mendeliome v0.8658 CUL7 Zornitza Stark reviewed gene: CUL7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16142236, 19225462, 17675530; Phenotypes: 3-M syndrome 1, MIM# 273750, Yakut short stature syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8658 ACAN Zornitza Stark Publications for gene: ACAN were set to
Mendeliome v0.8657 ACAN Zornitza Stark edited their review of gene: ACAN: Added comment: Patients with SSOAD exhibit a broad phenotypic spectrum involving short stature associated with advanced bone maturation and early-onset osteoarthritis (OA), as well as mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disc disease and osteochondritis dissecans, which is characterized by separation of articular cartilage and subchondral bone from the articular surface. Phenotypes are highly variable even among patients within the same family, and there are no apparent genotype-phenotype correlations.

Well established gene-disease association, multiple families reported.

Note fewer families reported with bi-allelic variants in this gene and extreme short stature.; Changed publications: 24762113, 27870580, 19110214, 30124491, 28331218, 20137779; Changed phenotypes: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800, Spondyloepimetaphyseal dysplasia, aggrecan type 612813
Mendeliome v0.8653 NFKB2 Zornitza Stark Publications for gene: NFKB2 were set to
Mendeliome v0.8650 NFKB1 Zornitza Stark Publications for gene: NFKB1 were set to
Mendeliome v0.8647 MCM4 Zornitza Stark Publications for gene: MCM4 were set to
Mendeliome v0.8644 MCM4 Zornitza Stark reviewed gene: MCM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 22354167, 22354170, 22499342; Phenotypes: Immunodeficiency 54 MIM# 609981, Decreased NK cell number and function, Viral infections (EBV, HSV, VZV), Short stature, B cell lymphoma, Adrenal failure, Failure to thrive, Microcephaly, Increased chromosomal breakage, Hyperpigmentation, Lymphadenopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8643 MAP3K14 Zornitza Stark Publications for gene: MAP3K14 were set to
Mendeliome v0.8641 MAP3K14 Zornitza Stark reviewed gene: MAP3K14: Rating: GREEN; Mode of pathogenicity: None; Publications: 10319865, 11238593, 12352969; Phenotypes: NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8640 LRBA Zornitza Stark Publications for gene: LRBA were set to
Mendeliome v0.8638 LRBA Zornitza Stark reviewed gene: LRBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22608502, 22721650, 25468195, 26206937, 33155142; Phenotypes: Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700, Normal-decreased CD4 numbers, T cell dysregulation, Low-normal B cells, Reduced IgG and IgA, Recurrent infections, chronic diarrhoea, inflammatory bowel disease, hypogammaglobulinaemia, pneumonitis, autoimmune disorders, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8638 NFKBIA Danielle Ariti reviewed gene: NFKBIA: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 28597146, 23864385, 23708964; Phenotypes: Ectodermal dysplasia and immunodeficiency 2 MIM# 612132, Ectodermal dysplasia, TCR/ BCR activation impaired, low memory and isotype switched B cells, decreased IgG and IgA, elevated IgM, poor specific antibody responses, diarrhoea, agammaglobulinaemia, ectodermal dysplasia, recurrent respiratory and gastrointestinal infections, colitis, variable defects of skin, hair and teeth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8638 NFKB2 Danielle Ariti reviewed gene: NFKB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140114, 24888602, 25524009, 31417880; Phenotypes: Immunodeficiency, common variable, 10 MIM# 615577, Low serum IgG, IgA, IgM, low B cell numbers, low switched memory B cells, Recurrent sinopulmonary infections, Alopecia, endocrinopathies, ACTH deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8638 NFKB1 Danielle Ariti reviewed gene: NFKB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26279205, 32278790, 27022143, 7834752; Phenotypes: Immunodeficiency, common variable, 12 MIM# 616576, Normal-low IgG, IgA, IgM, low-normal B cells, low switched memory B cells, hypogammaglobulinaemia, recurrent respiratory and gastrointestinal infections, Chronic obstructive pulmonary disease COPD, EBV proliferation, autoimmunity, alopecia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8637 AQP2 Zornitza Stark Publications for gene: AQP2 were set to
Mendeliome v0.8635 AQP2 Zornitza Stark reviewed gene: AQP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7537761, 11536078; Phenotypes: Diabetes insipidus, nephrogenic, MIM#125800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8634 RNF2 Zornitza Stark reviewed gene: RNF2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Lou-Schoch-Yamamoto syndrome , MIM#619460; Mode of inheritance: None
Mendeliome v0.8632 GIMAP5 Zornitza Stark gene: GIMAP5 was added
gene: GIMAP5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GIMAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP5 were set to 33956074
Phenotypes for gene: GIMAP5 were set to Portal hypertension, noncirrhotic, 2, MIM# 619463
Review for gene: GIMAP5 was set to GREEN
Added comment: 8 individuals from 4 unrelated families reported with onset of disease in the first decade of life. Clinical features included jaundice, hyperbilirubinaemia, pancytopaenia, including neutropaenia, lymphopaenia, and thrombocytopaenia, hepatosplenomegaly, and oesophageal varices. Some individuals had recurrent infections or features suggestive of an immunodeficiency. Liver biopsy was notable for the absence of cirrhosis and the presence of nodular regeneration.
Sources: Expert list
Mendeliome v0.8628 IL7R Zornitza Stark Publications for gene: IL7R were set to
Mendeliome v0.8625 MALT1 Zornitza Stark Publications for gene: MALT1 were set to
Mendeliome v0.8622 IL2RG Zornitza Stark Publications for gene: IL2RG were set to
Mendeliome v0.8620 IL2RG Zornitza Stark reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301584, 8462096, 8401490, 7883965, 9399950; Phenotypes: Combined immunodeficiency, X-linked, moderate MIM# 312863, Severe combined immunodeficiency, X-linked MIM# 300400, recurrent viral/fungal/bacterial infections, Low T/NK cells, Low Ig levels, lymphocytopaenia, hypogammaglobulinaemia, failure to thrive, diarrhoea, Pneumonia, Thymic hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8619 IKZF1 Zornitza Stark Publications for gene: IKZF1 were set to
Mendeliome v0.8617 IKZF1 Zornitza Stark reviewed gene: IKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317; Phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8616 ITK Zornitza Stark Publications for gene: ITK were set to
Mendeliome v0.8614 IL7R Danielle Ariti reviewed gene: IL7R: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843216, 19890784, 26123418, 11023514, 7964471; Phenotypes: Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971, fever, rash, failure to thrive, recurrent respiratory and gastric infections, diarrhoea, lymphadenopathy, pneumonitis, Pancytopaenia, low T-cell numbers, decreased immunoglobulins, normal-high B/NK-cell numbers.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8614 ITK Danielle Ariti reviewed gene: ITK: Rating: GREEN; Mode of pathogenicity: None; Publications: 19425169, 22289921, 25061172, 26056787, 9311799, 10213685; Phenotypes: Lymphoproliferative syndrome 1 MIM# 613011, Lymphadenopathy, Recurrent infections, Hypogammaglobulinaemia, Evidence of EBV infection, EBV associated B cell Lymphoproliferation, High EBV viral load, Normal-low serum Ig, Depleted CD4+ T cells, Anaemia, Thrombocytopaenia, Hepatosplenomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8614 MALT1 Danielle Ariti reviewed gene: MALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23727036, 24332264, 14576442, 31037583; Phenotypes: Immunodeficiency 12 MIM# 615468, poor T-cell proliferation, normal T/B cell numbers, poor specific antibody response, recurrent bacterial/fungal/viral infections, bronchiectasis, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8613 PLCB4 Zornitza Stark Publications for gene: PLCB4 were set to
Mendeliome v0.8611 PLCB4 Zornitza Stark reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8610 PBX1 Zornitza Stark Publications for gene: PBX1 were set to
Mendeliome v0.8608 PBX1 Zornitza Stark reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28566479, 29036646; Phenotypes: Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8607 VRK1 Zornitza Stark Publications for gene: VRK1 were set to 19646678; 21937992; 25609612; 24126608; 27281532
Mendeliome v0.8606 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed publications: 19646678, 21937992, 25609612, 24126608, 27281532, 34169149, 26583493; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia
Mendeliome v0.8602 ZDHHC15 Daniel Flanagan reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8601 CLCN3 Kristin Rigbye gene: CLCN3 was added
gene: CLCN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to PMID: 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Mendeliome v0.8601 TNPO2 Elena Savva gene: TNPO2 was added
gene: TNPO2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to PMID: 34314705
Phenotypes for gene: TNPO2 were set to Developmental delays, neurologic deficits and dysmorphic features
Mode of pathogenicity for gene: TNPO2 was set to Other
Review for gene: TNPO2 was set to GREEN
Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia).

Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF.

gnomAD: minimal PTCs present
Sources: Literature
Mendeliome v0.8601 DNAH10 Ain Roesley gene: DNAH10 was added
gene: DNAH10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH10 were set to 34237282
Phenotypes for gene: DNAH10 were set to primary male infertility with asthenoteratozoospermia
Penetrance for gene: DNAH10 were set to unknown
Review for gene: DNAH10 was set to GREEN
Added comment: 4x families with 5 affecteds (chets and homs - 4 missense and 2 fs). Knockout mouse models were infertile and showed significant reduction in count and motility compared to heterozygous mice
Sources: Literature
Mendeliome v0.8600 SEMA3D Ain Roesley edited their review of gene: SEMA3D: Added comment: Reported as a common susceptibility loci. No reported evidence for an association with Mendelian disease. Sema3d null heterozygote and homozygote mouse model had normal intestinal innervation.; Changed publications: 28334784, 25839327; Changed phenotypes: Hirschsprung disease
Mendeliome v0.8600 AP1G1 Danielle Ariti gene: AP1G1 was added
gene: AP1G1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Mode of pathogenicity for gene: AP1G1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Mendeliome v0.8598 SPTBN1 Belinda Chong changed review comment from: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature; to: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures (9/29); behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Mendeliome v0.8597 SPTBN4 Zornitza Stark Publications for gene: SPTBN4 were set to
Mendeliome v0.8595 TP73 Seb Lunke Publications for gene: TP73 were set to PMID: 31130284
Mendeliome v0.8589 UBA2 Zornitza Stark Publications for gene: UBA2 were set to PMID: 31332306; 31587267
Mendeliome v0.8587 ALDH1A2 Ain Roesley reviewed gene: ALDH1A2: Rating: RED; Mode of pathogenicity: None; Publications: 34159400; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.8586 SEMA3D Ain Roesley gene: SEMA3D was added
gene: SEMA3D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEMA3D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEMA3D were set to 34159400
Penetrance for gene: SEMA3D were set to unknown
Review for gene: SEMA3D was set to RED
Added comment: 1x de novo missense in a proband with short stature, absent distal phalanges of the 5th fingers and toes, and dysplastic middle phalanges of the toes.

However, there is 4 hets in gnomAD v2
Sources: Literature
Mendeliome v0.8586 SPTBN4 Melanie Marty reviewed gene: SPTBN4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33772159; Phenotypes: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM #617519); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8586 TP73 Ee Ming Wong reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34077761; Phenotypes: chronic airway disease, brain malformation, lissencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.8586 HMGB1 Ain Roesley gene: HMGB1 was added
gene: HMGB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HMGB1 were set to 34159400
Phenotypes for gene: HMGB1 were set to Mirror image foot polydactyly
Penetrance for gene: HMGB1 were set to unknown
Review for gene: HMGB1 was set to RED
Added comment: 1x de novo fs, no functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development
Sources: Literature
Mendeliome v0.8586 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179; PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Mendeliome v0.8586 UBA2 Ain Roesley reviewed gene: UBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34159400; Phenotypes: isolated split hand malformation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.8586 EDEM3 Michelle Torres gene: EDEM3 was added
gene: EDEM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to EDEM3-congenital disorder of glycosylation
Review for gene: EDEM3 was set to GREEN
Added comment: PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional show LoF of EDEM3 enzymatic activity.
Sources: Literature
Mendeliome v0.8586 GCNA Ain Roesley gene: GCNA was added
gene: GCNA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GCNA was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GCNA were set to 33963445
Phenotypes for gene: GCNA were set to primary spermatogenic failure
Penetrance for gene: GCNA were set to unknown
Review for gene: GCNA was set to GREEN
Added comment: 7x probands all missense except 1 fs. Variants had <0.0005 MAF in gnomad v2 male cohort and absent in 5784 Dutch control cohort
no functional studies were done except for histology of Ser659Trp, revealing a Sertoli-cell only
Sources: Literature
Mendeliome v0.8585 ANK2 Zornitza Stark gene: ANK2 was added
gene: ANK2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 31983240; 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Phenotypes for gene: ANK2 were set to Long QT syndrome 4, MIM# 600919; Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: ANK2 was set to GREEN
Added comment: Link with cardiac abnormalities such as LongQT is DISPUTED. More than 10 unrelated individuals reported with neurodevelopmental phenotype, comprising autism/ID and de novo truncating variants, in addition to many other individuals as part of large NDD cohorts. This association has been assessed as DEFINITIVE by ClinGen.
Sources: Expert Review
Mendeliome v0.8583 PRDX3 Hazel Phillimore changed review comment from: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature; to: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mendeliome v0.8583 PRDX3 Hazel Phillimore gene: PRDX3 was added
gene: PRDX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDX3 were set to PMID: 33889951
Phenotypes for gene: PRDX3 were set to cerebellar ataxia (early onset, mild to moderate, progressive)
Penetrance for gene: PRDX3 were set to unknown
Review for gene: PRDX3 was set to GREEN
Added comment: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mendeliome v0.8582 GSC Zornitza Stark Publications for gene: GSC were set to
Mendeliome v0.8580 GSC Zornitza Stark reviewed gene: GSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 24290375; Phenotypes: Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8579 GNAI3 Zornitza Stark Publications for gene: GNAI3 were set to
Mendeliome v0.8577 GNAI3 Zornitza Stark reviewed gene: GNAI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091; Phenotypes: Auriculocondylar syndrome 1, OMIM #602483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8576 EIF4A3 Zornitza Stark Publications for gene: EIF4A3 were set to
Mendeliome v0.8574 EIF4A3 Zornitza Stark reviewed gene: EIF4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360810; Phenotypes: Robin sequence with cleft mandible and limb anomalies, MIM# 268305, Richieri-Costa-Pereira syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8572 ERBB3 Zornitza Stark Publications for gene: ERBB3 were set to 17701904; 31752936; 33720042
Mendeliome v0.8571 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Added comment: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.; Changed rating: GREEN; Changed publications: 17701904, 31752936, 33497358; Changed phenotypes: Lethal congenital contractural syndrome 2, MIM# 607598, Neurodevelopmental disorder with gut dysmotility
Mendeliome v0.8570 PDCL3 Zornitza Stark gene: PDCL3 was added
gene: PDCL3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PDCL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCL3 were set to 32621347
Phenotypes for gene: PDCL3 were set to Megacystis-microcolon
Review for gene: PDCL3 was set to AMBER
Added comment: Single publication (PMID 32621347): one family with two affected fetuses - one with megacystis and microcolon, and the other with megacystisis and bilateral diaphragmatic hernia (prune-belly phenotype). Compound het LOF variants in PDCL3 (one frameshift and one missense). Complete absence of PDLC3 expression demonstrated in one of the affected fetuses. No homozygous LOF PDCL3 variants in gnomAD. PCDL3 negatively modulates actin folding and is strongly expressed in smooth muscle of bladder and colon.
Sources: Expert Review
Mendeliome v0.8568 SGO1 Zornitza Stark Publications for gene: SGO1 were set to
Mendeliome v0.8565 SGO1 Zornitza Stark reviewed gene: SGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25282101; Phenotypes: Chronic atrial and intestinal dysrhythmia, MIM# 616201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8564 TYMP Zornitza Stark Publications for gene: TYMP were set to
Mendeliome v0.8562 TYMP Zornitza Stark reviewed gene: TYMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9924029, 14757860; Phenotypes: Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041, MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8561 ZNF687 Zornitza Stark Publications for gene: ZNF687 were set to
Mendeliome v0.8559 ZNF687 Zornitza Stark reviewed gene: ZNF687: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Paget disease of bone 6, MIM#616833; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8558 GRHPR Zornitza Stark Publications for gene: GRHPR were set to
Mendeliome v0.8556 GRHPR Zornitza Stark reviewed gene: GRHPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 10484776, 11030416, 24116921; Phenotypes: Hyperoxaluria, primary, type II, MIM# 260000, MONDO:0009824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8555 AGXT Zornitza Stark Publications for gene: AGXT were set to
Mendeliome v0.8553 AGXT Zornitza Stark reviewed gene: AGXT: Rating: GREEN; Mode of pathogenicity: None; Publications: 2039493, 19479957; Phenotypes: Hyperoxaluria, primary, type 1, MIM# 259900, MONDO:0009823; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8552 HOGA1 Zornitza Stark Publications for gene: HOGA1 were set to
Mendeliome v0.8550 ZNF687 Ain Roesley reviewed gene: ZNF687: Rating: AMBER; Mode of pathogenicity: None; Publications: 26849110, 29493781, 32106343; Phenotypes: Paget disease of bone 6, MIM#616833; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.8550 HOGA1 Paul De Fazio reviewed gene: HOGA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20797690, 21896830, 22391140; Phenotypes: Hyperoxaluria, primary, type III MIM#613616; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.8549 VPS45 Zornitza Stark Publications for gene: VPS45 were set to
Mendeliome v0.8547 VPS45 Zornitza Stark reviewed gene: VPS45: Rating: GREEN; Mode of pathogenicity: None; Publications: 23738510, 23599270, 33623350, 32037586, 30294941; Phenotypes: Neutropaenia, severe congenital, 5, autosomal recessive, MIM# 615285; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8546 LAMTOR2 Zornitza Stark Publications for gene: LAMTOR2 were set to
Mendeliome v0.8543 LAMTOR2 Zornitza Stark reviewed gene: LAMTOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 17195838, 24092934; Phenotypes: Immunodeficiency due to defect in MAPBP-interacting protein, MIM# 610798; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8542 IKZF3 Zornitza Stark gene: IKZF3 was added
gene: IKZF3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IKZF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKZF3 were set to 34155405
Phenotypes for gene: IKZF3 were set to Immunodeficiency 84, MIM# 619437
Review for gene: IKZF3 was set to AMBER
Added comment: Single family reported where heterozygous missense variant in this gene segregated with immunodeficiency in a mother and two children. Findings included low levels of B cells and impaired early B-cell development, variable T-cell abnormalities, hypogammaglobulinaemia, increased susceptibility to infection with Epstein-Barr virus (EBV). One individual developed lymphoma in adulthood. Mouse model recapitulated phenotype.
Sources: Expert Review
Mendeliome v0.8540 HSD17B4 Zornitza Stark Publications for gene: HSD17B4 were set to
Mendeliome v0.8538 HSD17B4 Zornitza Stark reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8538 HSD17B4 Michelle Torres reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27790638; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8537 LCK Zornitza Stark Publications for gene: LCK were set to
Mendeliome v0.8533 LCK Zornitza Stark reviewed gene: LCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22985903, 1579166, 11021796; Phenotypes: Immunodeficiency 22 MIM# 615758, Recurrent infections, Immune dysregulation, autoimmunity, Low CD4+, low CD8+, restricted T cell repertoire, poor TCR signaling, Normal IgG/IgA, high IgM, failure to thrive, diarrhoea, lymphopenia, hypogammaglobulinemia, anaemia, thrombocytopaenia, CD4+ T-cell lymphopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8532 DOCK8 Zornitza Stark Publications for gene: DOCK8 were set to
Mendeliome v0.8529 DOCK2 Zornitza Stark Publications for gene: DOCK2 were set to
Mendeliome v0.8527 DOCK2 Zornitza Stark reviewed gene: DOCK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26083206, 29204803, 33928462, 30826364, 30838481, 11518968; Phenotypes: Immunodeficiency 40 MIM# 616433, T/B-cell lymphopaenia, early-onset invasive herpes/viral/bacterial Infections, function defects in T/B/NK cells, immunodeficiency, defective IFN-mediated immunity, elevated IgM, normal IgG/IgA levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8527 DOCK8 Danielle Ariti reviewed gene: DOCK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 19776401, 20622910, 21931011, 26659092, 19898472, 25422492; Phenotypes: Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700, T cell Lymphopaenia, decraese T/B/NK cells, Eosinophilia, low IgM, elevated IgE, recurrent cutaneous/ viral/ bacterial/ fungal/ infections, severe atopy/allergic disease, autoimmune haemolytic anaemia, eczema, cancer diathesisc; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8526 DNMT3B Zornitza Stark Publications for gene: DNMT3B were set to
Mendeliome v0.8524 DNMT3B Zornitza Stark reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8523 TMPO Bryony Thompson reviewed gene: TMPO: Rating: RED; Mode of pathogenicity: None; Publications: 16247757; Phenotypes: Hypertrophic cardiomyopathy, dilated cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8522 SYNCRIP Zornitza Stark gene: SYNCRIP was added
gene: SYNCRIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to GREEN
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.

The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.

Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.

Overall the variants reported to date include [NM_006372.5]:
1 - c.858_859del p.(Gly287Leufs*5)
2 - c.854dupA p.(Asn285Lysfs*8)
3 - c.734T>C p.(Leu245Pro)
4 - chr6:85605276-85683190 deletion (GRCh38)
5 - c.629T>C p.(Phe210Ser)
6 - c.1573_1574delinsTT p.(Gln525Leu)
7 - c.1247_1250del p.(Arg416Lysfs*145)
8 - c.1518_1519insC p.(Ala507Argfs*14)

[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]

SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.

Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.

The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.

There are no additional studies performed.

Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]

Animal models are not discussed.

There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Mendeliome v0.8520 MSN Zornitza Stark Publications for gene: MSN were set to
Mendeliome v0.8518 MSN Zornitza Stark reviewed gene: MSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 27405666; Phenotypes: Immunodeficiency 50, MIM# 300988; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8517 JAGN1 Zornitza Stark Publications for gene: JAGN1 were set to
Mendeliome v0.8515 JAGN1 Zornitza Stark reviewed gene: JAGN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25129144; Phenotypes: Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8514 ITGB2 Zornitza Stark Publications for gene: ITGB2 were set to
Mendeliome v0.8512 ITGB2 Zornitza Stark reviewed gene: ITGB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1968911, 1694220, 33957747, 32279896, 31374327; Phenotypes: Leukocyte adhesion deficiency, MIM# 116920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8511 CAMK4 Zornitza Stark gene: CAMK4 was added
gene: CAMK4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms.

CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).

The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].

Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.

Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.

Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).

Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function.

Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.

---

The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy.

Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F

Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one.

Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.

Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.

To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.

Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.

----

Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).
Sources: Expert Review
Mendeliome v0.8509 FERMT3 Zornitza Stark Publications for gene: FERMT3 were set to
Mendeliome v0.8507 FERMT3 Zornitza Stark reviewed gene: FERMT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234460, 19064721; Phenotypes: Leukocyte adhesion deficiency, type III, MIM# 612840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8505 CYBB Zornitza Stark Publications for gene: CYBB were set to
Mendeliome v0.8503 CYBB Zornitza Stark reviewed gene: CYBB: Rating: GREEN; Mode of pathogenicity: None; Publications: 2556453, 1710153, 9585602; Phenotypes: Chronic granulomatous disease, X-linked, MIM# 306400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8501 CSF3R Zornitza Stark Publications for gene: CSF3R were set to
Mendeliome v0.8499 CSF3R Zornitza Stark reviewed gene: CSF3R: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753537, 26324699, 33511998, 32966608; Phenotypes: Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8496 DPYSL5 Zornitza Stark reviewed gene: DPYSL5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ritscher-Schinzel syndrome 4, MIM# 619435; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8494 CEBPE Zornitza Stark Publications for gene: CEBPE were set to
Mendeliome v0.8492 CEBPE Zornitza Stark reviewed gene: CEBPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 10359588, 11313242, 31256937, 29651288; Phenotypes: Specific granule deficiency, MIM# 245480; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8491 NCF1 Zornitza Stark Publications for gene: NCF1 were set to
Mendeliome v0.8489 NCF1 Zornitza Stark reviewed gene: NCF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2011585, 11133775, 10706888, 16972229, 16972229; Phenotypes: Chronic granulomatous disease 1, autosomal recessive, MIM# 233700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8489 COL25A1 Zornitza Stark Publications for gene: COL25A1 were set to 25500261; 26486031
Mendeliome v0.8487 COL25A1 Zornitza Stark edited their review of gene: COL25A1: Added comment: PMID: 2643702 - Patient: 273182 reported in DECIPHER, chet COL25A1 missense variants (listed as Likely Pathogenic). Phenotype includes Duane anomaly of the eye.

PMID: 31875546 - Mouse models, including Col25a1 KO and muscle-specific KO mice showed a significant reduction in the number of motor neurons in the cranial nerve nuclei, including the oculomotor, trochlear, trigeminal, and facial motor nuclei. Abnormalities in motor innervation of muscles of the head, such as the extraocular and masseter muscles, were also observed

PMID: 31875546 - Functional studies in human cell lines showed that the reported COL25A1 variants (G382R and G497X) impaired the interaction of COL25A1 with receptor protein tyrosine phosphatases, thereby reducing the ability to attract motor axons.; Changed rating: GREEN; Changed publications: 25500261, 26486031, 31875546, 26437029
Mendeliome v0.8483 C1QA Zornitza Stark Publications for gene: C1QA were set to
Mendeliome v0.8481 C1QA Zornitza Stark reviewed gene: C1QA: Rating: GREEN; Mode of pathogenicity: None; Publications: 9225968, 21654842, 9590289; Phenotypes: C1q deficiency, MIM# 613652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8480 CIITA Zornitza Stark Publications for gene: CIITA were set to
Mendeliome v0.8478 CIITA Zornitza Stark reviewed gene: CIITA: Rating: GREEN; Mode of pathogenicity: None; Publications: 8402893, 9099848, 11862382, 28676232, 24789686, 20197681, 11466404, 15821736, 12910265; Phenotypes: Bare Lymphocyte Syndrome, type II, complementation group A MIM# 209920, varied ID, bronchiolitis, pneumonia, severe autoimmune cytopaenia, CD4 T-cell lymphopaenia, hypogammaglobulinemia, absence of antigen-induced immune response, chronic diarrhoea, recurrent respiratory infections, recurrent gastroenteritis, failure to thrive, liver/biliary tract disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8477 CD40LG Zornitza Stark Publications for gene: CD40LG were set to
Mendeliome v0.8474 CD3G Zornitza Stark Publications for gene: CD3G were set to
Mendeliome v0.8471 WDR26 Zornitza Stark Publications for gene: WDR26 were set to
Mendeliome v0.8468 CD40LG Danielle Ariti reviewed gene: CD40LG: Rating: GREEN; Mode of pathogenicity: None; Publications: 7679801, 7679206, 8094231, 9933119, 15358621, 15997875, 7678782, 7915248, 15367912, 7518839, 16311023, 9933119, 12402041, 7882172, 33475257; Phenotypes: mmunodeficiency, X-linked, with hyper-IgM MIM# 308230, Severe opportunistic infections (recurrent), idiopathic neutropaenia, dysgammaglobulinaemia hepatitis, cholangitis, cholangiocarcinoma, autoimmune blood cytopenias, haemolytic anaemia, thrombocytopaenia, diarrhoea, peripheral neuroectodermal tumours; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8468 CD3G Danielle Ariti reviewed gene: CD3G: Rating: GREEN; Mode of pathogenicity: None; Publications: 2872416, 1635567, 17277165, 23590417, 24910257, 18482219, 31921117, 11160319; Phenotypes: Immunodeficiency 17, CD3 gamma deficient MIM# 615607, immune deficiency, autoimmunity, failure to thrive, recurrent gastrointestinal infections, recurrent respiratory infections, autoimmune haemolytic anaemia, bronchiolitis obliterans, low CD3 complex, partial T lymphocytopenia, intractable diarrhoea.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8468 WDR26 Paul De Fazio reviewed gene: WDR26: Rating: GREEN; Mode of pathogenicity: None; Publications: 28686853, 33506510, 33675273; Phenotypes: Skraban-Deardorff syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.8468 ABCD4 Zornitza Stark Publications for gene: ABCD4 were set to 22922874; 31113616; 30651581; 28572511
Mendeliome v0.8467 ABCD4 Zornitza Stark reviewed gene: ABCD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33729671; Phenotypes: Methylmalonic aciduria and homocystinuria, cblJ type, MIM# 614857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8466 ABCD4 Zornitza Stark Publications for gene: ABCD4 were set to
Mendeliome v0.8461 RAD21 Zornitza Stark Publications for gene: RAD21 were set to 31334757; 25575569; 32193685; 31704779
Mendeliome v0.8460 RAD21 Zornitza Stark reviewed gene: RAD21: Rating: GREEN; Mode of pathogenicity: None; Publications: 14638363, 32193685, 25575569; Phenotypes: Mungan syndrome, MIM# 611376: Barrett esophagus, megaduodenum, cardiac abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8459 CCBE1 Zornitza Stark Publications for gene: CCBE1 were set to
Mendeliome v0.8457 CCBE1 Zornitza Stark reviewed gene: CCBE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19935664, 19911200, 19287381, 25925991, 27345729, 21778431; Phenotypes: Hennekam lymphangiectasia- lymphoedema syndrome MIM# 235510, lymphangiectasia and lymphoedema, facial abnormalities, dysmorphic features, hypoalbuminaemia, intellectual disability, hypoglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8456 CD27 Zornitza Stark Publications for gene: CD27 were set to
Mendeliome v0.8454 CD27 Zornitza Stark reviewed gene: CD27: Rating: GREEN; Mode of pathogenicity: None; Publications: 22197273, 22801960, 22365582, 25843314, 11062504; Phenotypes: Lymphoproliferative syndrome 2, CD27-deficiency MIM# 615122, hepatosplenomegaly, reduced CD8+ T-cell function, lymphadenopathy, hepatosplenomegaly, fever, increased susceptibility to EBV infection, aplastic anaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8451 PCLO Zornitza Stark Publications for gene: PCLO were set to
Mendeliome v0.8449 ZNF148 Natalie Tan gene: ZNF148 was added
gene: ZNF148 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF148 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF148 were set to PMID: 27964749
Phenotypes for gene: ZNF148 were set to Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies; MIM#617260
Review for gene: ZNF148 was set to GREEN
Added comment: Four unrelated individuals with de novo heterozygous nonsense or frameshift mutations (all resulting in premature termination codons in the last exon of ZNF148, predicted to escape nonsense-mediated mRNA decay and result in expression of a truncated protein). Phenotype characterised by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. No functional studies to date.
Sources: Literature
Mendeliome v0.8449 RAC3 Natalie Tan gene: RAC3 was added
gene: RAC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAC3 were set to PMID: 30293988; 29276006
Phenotypes for gene: RAC3 were set to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, MIM#618577
Review for gene: RAC3 was set to GREEN
Added comment: Multiple unrelated individuals with heterozygous missense variants and a concordant phenotype (severe intellectual disability with brain malformations). No functional studies to date.
Sources: Literature
Mendeliome v0.8448 CHRNA4 Zornitza Stark Publications for gene: CHRNA4 were set to
Mendeliome v0.8445 CHRNA4 Zornitza Stark reviewed gene: CHRNA4: Rating: GREEN; Mode of pathogenicity: Other; Publications: 14623738, 23114665; Phenotypes: Epilepsy, nocturnal frontal lobe, 1, MIM# 600513; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8445 SYP Elena Savva reviewed gene: SYP: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 23966691, 19377476; Phenotypes: Mental retardation, X-linked 96 MIM#300802; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8444 ZIC3 Zornitza Stark Publications for gene: ZIC3 were set to
Mendeliome v0.8440 VPS13B Zornitza Stark reviewed gene: VPS13B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cohen syndrome, MIM# 216550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8439 TULP1 Zornitza Stark Publications for gene: TULP1 were set to
Mendeliome v0.8437 TULP1 Zornitza Stark edited their review of gene: TULP1: Changed publications: 15024725
Mendeliome v0.8437 TULP1 Zornitza Stark reviewed gene: TULP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 15, MIM# 613843; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8436 TOPORS Zornitza Stark Publications for gene: TOPORS were set to
Mendeliome v0.8433 SUFU Zornitza Stark Publications for gene: SUFU were set to
Mendeliome v0.8431 SUFU Zornitza Stark edited their review of gene: SUFU: Added comment: Mono-allelic variants are also associated with Basal cell nevus syndrome/predisposition to medulloblastoma.; Changed rating: GREEN; Changed publications: 28965847, 19533801, 31485359; Changed phenotypes: Joubert syndrome 32, MIM#617757, Basal cell nevus syndrome, MIM# 109400; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8430 SCNN1G Zornitza Stark Publications for gene: SCNN1G were set to
Mendeliome v0.8427 SCLT1 Zornitza Stark Publications for gene: SCLT1 were set to
Mendeliome v0.8424 RPGR Zornitza Stark Publications for gene: RPGR were set to
Mendeliome v0.8421 PRKCSH Zornitza Stark Publications for gene: PRKCSH were set to
Mendeliome v0.8418 PRKCSH Zornitza Stark reviewed gene: PRKCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 11047756, 29038287, 12529853, 12577059; Phenotypes: Polycystic liver disease 1 (MIM#174050); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8417 POC1B Zornitza Stark Publications for gene: POC1B were set to
Mendeliome v0.8414 PMM2 Zornitza Stark Publications for gene: PMM2 were set to
Mendeliome v0.8412 PMM2 Zornitza Stark edited their review of gene: PMM2: Added comment: Well established gene-disease association.; Changed rating: GREEN; Changed publications: 28108845
Mendeliome v0.8410 MUC1 Zornitza Stark edited their review of gene: MUC1: Changed publications: 29186029, 29156055, 29520014
Mendeliome v0.8409 MUC1 Zornitza Stark Publications for gene: MUC1 were set to
Mendeliome v0.8407 MUC1 Zornitza Stark edited their review of gene: MUC1: Added comment: Well established gene-disease association, but note main variant type not readily tractable by NGS.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed publications: Medullary cystic kidney disease 1 (MIM#174000); Changed phenotypes: Medullary cystic kidney disease 1 (MIM#174000); Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8406 KIF7 Zornitza Stark Publications for gene: KIF7 were set to
Mendeliome v0.8403 KIAA0753 Zornitza Stark Publications for gene: KIAA0753 were set to
Mendeliome v0.8400 KIAA0586 Zornitza Stark Publications for gene: KIAA0586 were set to
Mendeliome v0.8397 IFT52 Zornitza Stark Publications for gene: IFT52 were set to
Mendeliome v0.8394 IFT27 Zornitza Stark Publications for gene: IFT27 were set to
Mendeliome v0.8391 POLG2 Zornitza Stark Publications for gene: POLG2 were set to
Mendeliome v0.8389 POLG2 Zornitza Stark reviewed gene: POLG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16685652, 21555342, 27592148, 31778857; Phenotypes: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, MIM# 610131, Mitochondrial DNA depletion syndrome 16 , MIM# 618528; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8388 PCDHGC4 Zornitza Stark gene: PCDHGC4 was added
gene: PCDHGC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to Intellectual disability; Seizures
Review for gene: PCDHGC4 was set to GREEN
Added comment: Eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty in eight families and seizures in four families. Four of the variants were LoF, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Mendeliome v0.8386 ATP6V0A4 Zornitza Stark Publications for gene: ATP6V0A4 were set to
Mendeliome v0.8384 ATP6V0A4 Zornitza Stark reviewed gene: ATP6V0A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12414817, 10973252; Phenotypes: Renal tubular acidosis, distal, autosomal recessive, MIM#602722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8383 ICK Zornitza Stark Publications for gene: ICK were set to
Mendeliome v0.8378 GDF1 Zornitza Stark Publications for gene: GDF1 were set to
Mendeliome v0.8376 GDF1 Zornitza Stark edited their review of gene: GDF1: Added comment: PMID: 32144877 - founder PTC in Arab population causing congenital heart detects AND right isomerism in 3 (unrelated?) families. Reviews other publications and reports additional chet (two PTC) or homozygous (missense) families with situs inversus and/or heart defects. No apparent genotype-phenotype correlation btw dominant and recessive disease.; Changed rating: GREEN; Changed publications: 32144877; Changed phenotypes: Congenital heart defects, multiple types, 6 613854, Right atrial isomerism (Ivemark) 208530; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8375 EVC2 Zornitza Stark Publications for gene: EVC2 were set to
Mendeliome v0.8372 EVC Zornitza Stark Publications for gene: EVC were set to
Mendeliome v0.8369 DCDC2 Zornitza Stark Publications for gene: DCDC2 were set to
Mendeliome v0.8367 DCDC2 Zornitza Stark edited their review of gene: DCDC2: Changed rating: GREEN; Changed publications: 25557784, 27319779, 27469900; Changed phenotypes: Nephronophthisis 19, MIM# 616217, Sclerosing cholangitis, neonatal, MIM# 617394; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8366 CRELD1 Zornitza Stark Publications for gene: CRELD1 were set to
Mendeliome v0.8364 CRELD1 Zornitza Stark reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740159; Phenotypes: Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8363 CRB2 Zornitza Stark Publications for gene: CRB2 were set to
Mendeliome v0.8361 CRB2 Zornitza Stark edited their review of gene: CRB2: Changed publications: 25557780, 33687977, 32051522, 30212996, 33575434, 31438467, 30593785, 25557779; Changed phenotypes: Ventriculomegaly with cystic kidney disease, MIM# 219730, Focal segmental glomerulosclerosis 9, MIM# 616220
Mendeliome v0.8360 CEP55 Zornitza Stark Publications for gene: CEP55 were set to
Mendeliome v0.8358 CEP55 Zornitza Stark reviewed gene: CEP55: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, MIM# 236500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8357 CENPF Zornitza Stark Publications for gene: CENPF were set to
Mendeliome v0.8354 C8orf37 Zornitza Stark Publications for gene: C8orf37 were set to
Mendeliome v0.8351 C2CD3 Zornitza Stark Publications for gene: C2CD3 were set to
Mendeliome v0.8347 CHRM3 Zornitza Stark Publications for gene: CHRM3 were set to
Mendeliome v0.8345 CHRM3 Zornitza Stark reviewed gene: CHRM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22077972, 31441039; Phenotypes: Prune belly syndrome, MIM# 100100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8345 ARHGAP42 Zornitza Stark gene: ARHGAP42 was added
gene: ARHGAP42 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGAP42 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGAP42 were set to 34232960
Phenotypes for gene: ARHGAP42 were set to Interstitial lung disease; systemic hypertension; immunological abnormalities
Review for gene: ARHGAP42 was set to RED
Added comment: Single individual reported with homozygous LoF variant, chILD disorder, systemic hypertension, and immunological findings.
Sources: Literature
Mendeliome v0.8343 KIAA0556 Zornitza Stark Publications for gene: KIAA0556 were set to
Mendeliome v0.8341 KIAA0556 Zornitza Stark reviewed gene: KIAA0556: Rating: GREEN; Mode of pathogenicity: None; Publications: 26714646, 27245168; Phenotypes: Joubert syndrome 26, MIM# 616784; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8335 LINGO4 Laura Raiti gene: LINGO4 was added
gene: LINGO4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LINGO4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LINGO4 were set to PMID: 33098801
Phenotypes for gene: LINGO4 were set to Developmental Delay, Intellectual disability, speech disorder
Review for gene: LINGO4 was set to GREEN
Added comment: 3 unrelated individuals
1 x individual compound heterozygous for 2x missense variants:
c.679C>A; c.1262G>A p.Leu227Met; p.Arg421Gln comp het. Phenotype: infancy-onset
generalized dystonia; DD/hypo, ID, speech disorder (isolated plus non-MD symptoms) NDD

1 x individual homozygous for missense variant: c.679C>A p.Leu227Met Phenotype: DD/hypo, ID, speech disorder

1 x individual homozygous for missense variant: c.1673G>A p.Ser558Asn Phenotype: DD/hypo, ID, speech disorder
Sources: Literature
Mendeliome v0.8335 ARFGEF3 Laura Raiti gene: ARFGEF3 was added
gene: ARFGEF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARFGEF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF3 were set to PMID: 33098801
Phenotypes for gene: ARFGEF3 were set to Dystonia
Review for gene: ARFGEF3 was set to GREEN
Added comment: 3 x unrelated individuals
1 x de novo missense variant: c.6212T>C p.Met2071Thr, phenotype: infancy-onset generalized dystonia (isolated)
1x stop-gain variant c.1773T>G p.Tyr591* (inherited from mosaic mother), phenotype: infancy-onset generalized dystonia (isolated)
1 x de novo missense variant (Gene Matcher) c.250A>C p.Met84Leu childhood-onset generalized dystonia (isolated)
Sources: Literature
Mendeliome v0.8335 IMPDH2 Laura Raiti gene: IMPDH2 was added
gene: IMPDH2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to PMID: 33098801
Phenotypes for gene: IMPDH2 were set to Dystonia
Review for gene: IMPDH2 was set to GREEN
Added comment: 6 unrelated individuals
1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein.
IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition.
1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified:
3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg)
1 x deletion: c.478_480delTCC (p.Ser160del)
The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair.
The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1.

The variant carriers shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing. Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2.
Sources: Literature
Mendeliome v0.8335 DYNC2H1 Zornitza Stark Publications for gene: DYNC2H1 were set to 19442771; 19361615; 22499340; 23456818; 27925158
Mendeliome v0.8334 DYNC2H1 Zornitza Stark edited their review of gene: DYNC2H1: Changed publications: 19442771, 19361615, 22499340, 23456818, 27925158, 32753734; Changed phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM# 613091, MONDO:0013127, Non-syndromic retinitis pigmentosa
Mendeliome v0.8333 KIF20A Zornitza Stark gene: KIF20A was added
gene: KIF20A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF20A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF20A were set to 29357359
Phenotypes for gene: KIF20A were set to Cardiomyopathy, familial restrictive, 6, MIM# 619433
Review for gene: KIF20A was set to GREEN
Added comment: Single family reported, two affected sibs, perinatal lethal cardiomyopathy, compound het variants in this gene.
Sources: Literature
Mendeliome v0.8330 B2M Zornitza Stark Publications for gene: B2M were set to
Mendeliome v0.8328 B2M Zornitza Stark reviewed gene: B2M: Rating: GREEN; Mode of pathogenicity: None; Publications: 4186801, 16549777, 25702838, 11118151, 6165007, 22693999; Phenotypes: Immunodeficiency 43 MIM# 241600, Sinopulmonary infections, Purple-red skin lesions, Decreased serum IgG, Decreased B cells, Absent β2m associated proteins MHC-I, CD1a, CD1b, and CD1c, MONDO:0009434, Amyloidosis, familial visceral, MIM# 105200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8327 AK2 Zornitza Stark Publications for gene: AK2 were set to 19043416
Mendeliome v0.8326 AK2 Zornitza Stark edited their review of gene: AK2: Changed publications: 19043416, 19043417
Mendeliome v0.8325 TMEM126A Zornitza Stark Publications for gene: TMEM126A were set to
Mendeliome v0.8323 TMEM126A Zornitza Stark reviewed gene: TMEM126A: Rating: GREEN; Mode of pathogenicity: None; Publications: 19327736, 20405026, 22815638, 33879611, 31119195, 30961538; Phenotypes: Optic atrophy 7, MIM# 612989, MONDO:0013069, Syndromic auditory neuropathy spectrum disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8320 MYC Zornitza Stark reviewed gene: MYC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Burkitt lymphoma, somatic, MIM# 113970; Mode of inheritance: Other
Mendeliome v0.8318 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Mendeliome v0.8318 ATG7 Zornitza Stark changed review comment from: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.
Sources: Literature; to: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model.
Sources: Literature
Mendeliome v0.8317 ATG7 Zornitza Stark gene: ATG7 was added
gene: ATG7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, SCAR31, MIM#619422
Review for gene: ATG7 was set to GREEN
Added comment: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The ore severely affected individuals had spastic paraplegia and inability to walk.
Sources: Literature
Mendeliome v0.8315 ADA Zornitza Stark Publications for gene: ADA were set to
Mendeliome v0.8313 ADA Zornitza Stark reviewed gene: ADA: Rating: GREEN; Mode of pathogenicity: None; Publications: 3007108, 3475710, 8178821, 8227344, 2783588; Phenotypes: Severe combined immunodeficiency due to ADA deficiency, MIM# 102700, MONDO:0007064; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8312 C2orf69 Zornitza Stark gene: C2orf69 was added
gene: C2orf69 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 34038740; 33945503
Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency-53 (COXPD53), MIM#619423
Review for gene: C2orf69 was set to GREEN
Added comment: PMID 34038740: 20 affected children from 8 unrelated families reported, presenting with fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. Endogenous C2ORF69 was found to be (1) loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. Zebrafish model.

PMID 33945503: 8 individuals from 5 families reported with muscle hypotonia, developmental delay, progressive microcephaly, and brain MRI abnormalities. Age at onset ranged from birth to 6 months of age. Six patients had vision impairment, liver abnormalities, inflammation/inflammatory arthritis, and 5 patients had seizures.
Sources: Literature
Mendeliome v0.8307 FBXW7 Zornitza Stark Publications for gene: FBXW7 were set to 33057194
Mendeliome v0.8306 FBXW7 Zornitza Stark reviewed gene: FBXW7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30885698, 26482194; Phenotypes: Wilms tumour predisposition; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8306 NYNRIN Laura Raiti gene: NYNRIN was added
gene: NYNRIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NYNRIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NYNRIN were set to PMID: 30885698
Review for gene: NYNRIN was set to AMBER
Added comment: 3 individuals with Wilms Tumour reported (2 children from 1 family, the 3rd child from a second family).
Biallelic truncating mutations in NYNRIN in three children with Wilms Tumour from two families, each parent was heterozygous for one of the mutations.
One of the affected children had an inguinal hernia and another had epilepsy, hypothyroidism, and intellectual disability.
Sources: Literature
Mendeliome v0.8305 ZC3H14 Zornitza Stark Publications for gene: ZC3H14 were set to 21734151; 28666327
Mendeliome v0.8304 ZC3H14 Zornitza Stark edited their review of gene: ZC3H14: Added comment: PMID: 33710394
1 Finnish family with a hom splice variant, severe ID. Classed a VUS. No functional evidence; Changed publications: 21734151, 28666327, 33710394
Mendeliome v0.8304 ZC3H14 Zornitza Stark edited their review of gene: ZC3H14: Changed publications: 21734151, 28666327
Mendeliome v0.8304 ZC3H14 Zornitza Stark Publications for gene: ZC3H14 were set to 21734151
Mendeliome v0.8299 IRX5 Zornitza Stark Publications for gene: IRX5 were set to
Mendeliome v0.8296 IRX5 Zornitza Stark reviewed gene: IRX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22581230, 27453922; Phenotypes: Hamamy syndrome, MIM# 611174; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8296 IRX6 Zornitza Stark reviewed gene: IRX6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8294 RAB3GAP1 Zornitza Stark Publications for gene: RAB3GAP1 were set to 15696165; 20512159; 23420520
Mendeliome v0.8293 RAB3GAP1 Zornitza Stark changed review comment from: Rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. Multiple families reported.; to: Warburg micro: Rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe ID, spastic diplegia, and hypogonadism. Multiple families reported.

Martsolf syndrome is characterised by cataracts, mild to severe ID, dysmorphic features. Two families reported.
Mendeliome v0.8293 RAB3GAP1 Zornitza Stark edited their review of gene: RAB3GAP1: Changed publications: 15696165, 20512159, 23420520, 23420520, 30730599; Changed phenotypes: Warburg micro syndrome 1, MIM# 600118, Martsolf syndrome 2, MIM# 619420
Mendeliome v0.8293 CXCR2 Zornitza Stark gene: CXCR2 was added
gene: CXCR2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CXCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CXCR2 were set to 24777453
Phenotypes for gene: CXCR2 were set to WHIM syndrome 2, 619407
Review for gene: CXCR2 was set to RED
Added comment: 2 sisters with neutropaenia, myelokathexis, and recurrent bacterial infections and homozygous frameshift variant in this gene.
Sources: Expert list
Mendeliome v0.8292 RING1 Eleanor Williams gene: RING1 was added
gene: RING1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RING1 were set to 29386386
Phenotypes for gene: RING1 were set to microcephaly; intellectual disability
Review for gene: RING1 was set to RED
Added comment: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Early motor and language development were normal but were delayed after the first year of life. Cognitive testing showed a verbal IQ of 55 and a visual performance IQ of 63. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Mendeliome v0.8292 RNF2 Eleanor Williams gene: RNF2 was added
gene: RNF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNF2 were set to 33864376
Phenotypes for gene: RNF2 were set to epilepsy; intellectual disability; intrauterine growth retardation
Review for gene: RNF2 was set to AMBER
Added comment: Not associated with any phenotype in OMIM.

PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
Mendeliome v0.8292 IRX5 Eleanor Williams edited their review of gene: IRX5: Changed publications: 33891002, 28041643, 32045705, 22581230, 17230486; Changed phenotypes: cone dystrophy, MONDO:0000455, retinitis pigmentosa, MONDO:0019200
Mendeliome v0.8292 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Cone dystrophy
-------------------
PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Mendeliome v0.8292 IRX6 Eleanor Williams changed review comment from: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature; to: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature
Mendeliome v0.8292 GNB2 Zornitza Stark Publications for gene: GNB2 were set to 31698099
Mendeliome v0.8290 GNB2 Zornitza Stark reviewed gene: GNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31698099, 33971351, 34183358; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8289 HID1 Zornitza Stark gene: HID1 was added
gene: HID1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Review for gene: HID1 was set to GREEN
Added comment: 7 individuals from 6 unrelated families reported. Clinical features included: hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy
Sources: Literature
Mendeliome v0.8287 KIF1B Zornitza Stark Publications for gene: KIF1B were set to
Mendeliome v0.8285 KIF1B Zornitza Stark reviewed gene: KIF1B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8283 FYCO1 Zornitza Stark Phenotypes for gene: FYCO1 were changed from to Cataract 18, MIM#610019
Mendeliome v0.8282 FYCO1 Zornitza Stark Publications for gene: FYCO1 were set to
Mendeliome v0.8280 FYCO1 Zornitza Stark reviewed gene: FYCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32355443; Phenotypes: Cataract 18, MIM#610019; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8280 JPH3 Seb Lunke Publications for gene: JPH3 were set to
Mendeliome v0.8279 MYT1 Zornitza Stark Publications for gene: MYT1 were set to 28612832; 32871052; 27358179
Mendeliome v0.8277 JPH3 Seb Lunke Added comment: Comment on list classification: Only STRs disease causing, see separate STR list. No evidence for SNVs etc.
Mendeliome v0.8276 MYT1 Zornitza Stark edited their review of gene: MYT1: Changed publications: 28612832, 32871052, 27358179, 33710394
Mendeliome v0.8275 MYT1 Zornitza Stark Publications for gene: MYT1 were set to
Mendeliome v0.8273 MYT1 Zornitza Stark reviewed gene: MYT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28612832, 32871052, 27358179; Phenotypes: Craniofacial microsomia, OAV spectrum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8271 ATP1A2 Zornitza Stark Publications for gene: ATP1A2 were set to
Mendeliome v0.8269 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Added comment: Association with alternating hemiplegia is well established.

PMID 31608932: Three individuals from two unrelated families reported with balleliic LoF variants in this gene and hydrops/congenital abnormalities. Mouse model is perinatal lethal.

PMID 33880529: six individuals with de novo missense variants reported and DD/EE/PMG.; Changed rating: GREEN; Changed publications: 31608932, 33880529; Changed phenotypes: Alternating hemiplegia of childhood 1, MIM#104290, Hydrops fetalis, microcephaly, arthrogryposis, extensive cortical malformations, Developmental and epileptic encephalopathy, polymicrogyria; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8268 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Changed publications: 15260953, 22842232, 24468074, 33762331, 33880529
Mendeliome v0.8267 SAMD9L Zornitza Stark Publications for gene: SAMD9L were set to 27259050; 30923096; 30322869
Mendeliome v0.8266 SAMD9L Zornitza Stark edited their review of gene: SAMD9L: Changed publications: 27259050, 30923096, 30322869, 33710394
Mendeliome v0.8264 IRX6 Eleanor Williams gene: IRX6 was added
gene: IRX6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IRX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IRX6 were set to 33891002
Phenotypes for gene: IRX6 were set to cone dystrophy, MONDO:0000455
Mode of pathogenicity for gene: IRX6 was set to Other
Review for gene: IRX6 was set to GREEN
Added comment: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.
Sources: Literature
Mendeliome v0.8264 IRX5 Eleanor Williams reviewed gene: IRX5: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33891002; Phenotypes: cone dystrophy, MONDO:0000455; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.8263 EPHA7 Zornitza Stark gene: EPHA7 was added
gene: EPHA7 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA7 were set to 34176129
Phenotypes for gene: EPHA7 were set to Intellectual disability
Review for gene: EPHA7 was set to AMBER
Added comment: Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder.

The authors report on 12 individuals belonging to 9 unrelated families, all harboring with 6q microdeletions spanning EPHA7.

Overlapping features included DD (13/13), ID (10/10 - mild in most cases, individuals with larger CNVs/additional variants had more severe phenotype), speech delay and behavioral disorders. Variable other features incl. hypotonia (70%), non specific facial features, eye abnormalities (40%) and cardiac defects (25%).

The CNVs ranged from 152 kb to few Mb in size but in 4 subjects (P5-8) were only minimal, involving only EPHA7.

9 out of 12 individuals had inherited the deletion (5 subjects paternal, 4 maternal), in 1 subject (P12) this occured de novo, while for 2 others inheritance was not specified. Most deletions were inherited from an unaffected parent (in 6/7 families), with unclear contribution in a further one.

The authors discuss on previous studies suggesting an important role for EphA7 in brain development (modulation of cell-cell adhesion and repulsion, regulation of dendrite morphogenesis in early corticogenesis, role in dendritic spine formation later in development. EphA7 has also been proposed to drive neuronal maturation and synaptic function).

Haploinsufficiency for other ephrins or ephrin receptors has been implicated in other NDDs.

Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1].
Sources: Expert Review
Mendeliome v0.8261 DNM1 Zornitza Stark Publications for gene: DNM1 were set to
Mendeliome v0.8259 DNM1 Zornitza Stark reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25262651, 27066543, 33372033, 34172529; Phenotypes: Developmental and epileptic encephalopathy 31, OMIM:616346; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8258 GRK2 Zornitza Stark gene: GRK2 was added
gene: GRK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GRK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRK2 were set to 33200460
Phenotypes for gene: GRK2 were set to Jeune asphyxiating thoracic dystrophy (ATD)
Review for gene: GRK2 was set to AMBER
Added comment: Two unrelated families reported and some functional data.
Sources: Literature
Mendeliome v0.8256 WDR60 Zornitza Stark Publications for gene: WDR60 were set to
Mendeliome v0.8254 WDR60 Zornitza Stark reviewed gene: WDR60: Rating: GREEN; Mode of pathogenicity: None; Publications: 23910462, 29271569, 26874042; Phenotypes: Short-rib thoracic dysplasia 8 with or without polydactyly, MIM# 615503, Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8253 WDR34 Zornitza Stark Publications for gene: WDR34 were set to
Mendeliome v0.8251 WDR34 Zornitza Stark reviewed gene: WDR34: Rating: GREEN; Mode of pathogenicity: None; Publications: 24183449, 24183451, 33124039, 30649997, 29241935, 28379358; Phenotypes: Short-rib thoracic dysplasia 11 with or without polydactyly, MIM# 615633, Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8250 WDR19 Zornitza Stark Publications for gene: WDR19 were set to
Mendeliome v0.8248 WDR19 Zornitza Stark reviewed gene: WDR19: Rating: GREEN; Mode of pathogenicity: None; Publications: 33946315, 33875766, 33606107, 22019273, 23559409, 23683095, 32055034; Phenotypes: Nephronophthisis 13, MIM# 614377, Senior-Loken syndrome 8, MIM# 616307, Short-rib thoracic dysplasia 5 with or without polydactyly, MIM# 614376, Cranioectodermal dysplasia 4, MIM# 614378; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8247 TXNDC15 Zornitza Stark Publications for gene: TXNDC15 were set to
Mendeliome v0.8245 TXNDC15 Zornitza Stark reviewed gene: TXNDC15: Rating: GREEN; Mode of pathogenicity: None; Publications: 30851085, 27894351; Phenotypes: Meckel-Gruber syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8244 TTC8 Zornitza Stark Publications for gene: TTC8 were set to
Mendeliome v0.8242 TTC8 Zornitza Stark reviewed gene: TTC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 14520415, 19797195; Phenotypes: Bardet-Biedl syndrome 8, MIM# 615985; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8241 TTC21B Zornitza Stark Publications for gene: TTC21B were set to
Mendeliome v0.8239 TTC21B Zornitza Stark reviewed gene: TTC21B: Rating: GREEN; Mode of pathogenicity: None; Publications: 21258341, 25492405, 18327258, 33875766; Phenotypes: Nephronophthisis 12, MIM# 613820, Short-rib thoracic dysplasia 4 with or without polydactyly, MIM# 613819, Joubert syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8238 TRAF3IP1 Zornitza Stark Publications for gene: TRAF3IP1 were set to
Mendeliome v0.8236 TRAF3IP1 Zornitza Stark reviewed gene: TRAF3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26487268, 18364699, 21945076; Phenotypes: Senior-Loken syndrome 9, MIM# 616629, MONDO:0014712; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8234 OBSCN Zornitza Stark Publications for gene: OBSCN were set to 30681346; 26573135; 17716621; 25173926; 28630914
Mendeliome v0.8233 P2RX2 Zornitza Stark Publications for gene: P2RX2 were set to 23345450; 24211385
Mendeliome v0.8232 AP2S1 Zornitza Stark Publications for gene: AP2S1 were set to 33729479; 33057194; 23222959; 33729479; 33168530; 3204769; 31723423; 29479578
Mendeliome v0.8231 AP2S1 Zornitza Stark Publications for gene: AP2S1 were set to 33729479; 33057194; 23222959; 33729479; 33168530; 3204769; 31723423; 2947957; 8
Mendeliome v0.8230 AP2S1 Zornitza Stark Publications for gene: AP2S1 were set to 33057194; 23222959; 33729479; 33168530; 3204769; 31723423; 29479578
Mendeliome v0.8229 ATP9A Arina Puzriakova gene: ATP9A was added
gene: ATP9A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Phenotypes for gene: ATP9A were set to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms
Review for gene: ATP9A was set to AMBER
Added comment: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree (2 mild, 1 severe), postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature
Mendeliome v0.8229 ATP2C2 Eleanor Williams gene: ATP2C2 was added
gene: ATP2C2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2C2 were set to 33864365; 28440294
Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463
Review for gene: ATP2C2 was set to RED
Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment.

PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W).
Sources: Literature
Mendeliome v0.8229 OBSCN Eleanor Williams reviewed gene: OBSCN: Rating: RED; Mode of pathogenicity: None; Publications: 33438037; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.8229 P2RX2 Eleanor Williams reviewed gene: P2RX2: Rating: ; Mode of pathogenicity: None; Publications: 33791800; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.8229 AP2S1 Eleanor Williams reviewed gene: AP2S1: Rating: ; Mode of pathogenicity: None; Publications: 33729479; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.8228 TMEM67 Zornitza Stark Publications for gene: TMEM67 were set to
Mendeliome v0.8226 TMEM67 Zornitza Stark edited their review of gene: TMEM67: Added comment: Bi-allelic variants in this gene are associated with a range of ciliopathies, including JBTS, Meckel syndrome and nephronophthisis. Multiple families with each.; Changed publications: 16415887, 17377820, 17160906, 19508969; Changed phenotypes: Joubert syndrome 6, MIM# 610688, Meckel syndrome 3, MIM# 607361, Nephronophthisis 11, MIM# 613550, COACH syndrome 1, MIM# 216360
Mendeliome v0.8225 XDH Zornitza Stark Publications for gene: XDH were set to
Mendeliome v0.8223 XDH Ain Roesley reviewed gene: XDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 32071838; Phenotypes: Xanthinuria, type I (MIM#278300); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.8222 TCTEX1D2 Zornitza Stark Publications for gene: TCTEX1D2 were set to
Mendeliome v0.8220 TCTEX1D2 Zornitza Stark reviewed gene: TCTEX1D2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26044572, 25830415; Phenotypes: Short-rib thoracic dysplasia 17 with or without polydactyly, MIM# 617405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8219 TCTN3 Zornitza Stark Publications for gene: TCTN3 were set to
Mendeliome v0.8217 TCTN3 Zornitza Stark edited their review of gene: TCTN3: Changed publications: 22883145, 32139166, 25118024, 34096792; Changed phenotypes: Joubert syndrome 18, MIM# 614815, MONDO:0013896, Orofaciodigital syndrome IV, MIM# 258860, Mohr-Majewski syndrome, Meckel-Gruber syndrome
Mendeliome v0.8216 SDCCAG8 Zornitza Stark Publications for gene: SDCCAG8 were set to
Mendeliome v0.8214 SDCCAG8 Zornitza Stark reviewed gene: SDCCAG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 20835237, 22626039, 22626039, 32432520, 31534065, 26968886; Phenotypes: Bardet-Biedl syndrome 16, MIM# 615993, MONDO:0014444, Senior-Loken syndrome 7, MIM# 613615, MONDO:0013326, Nephronophthisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8212 SBDS Zornitza Stark reviewed gene: SBDS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Shwachman-Diamond syndrome, MIM# 260400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8211 RPGRIP1L Zornitza Stark Publications for gene: RPGRIP1L were set to
Mendeliome v0.8209 RPGRIP1L Zornitza Stark edited their review of gene: RPGRIP1L: Added comment: Bi-allelic variants in this gene are associated with a range of ciliopathies, including JBTS and Meckel syndrome. Mouse model.; Changed publications: 17558409, 17558407, 17960139, 26071364, 19574260, 29991045; Changed phenotypes: Joubert syndrome 7, MIM# 611560, Meckel syndrome 5, MIM# 611561, COACH syndrome 3, MIM# 619113, Nephronophthisis
Mendeliome v0.8208 NPHP4 Zornitza Stark Publications for gene: NPHP4 were set to
Mendeliome v0.8206 NPHP4 Zornitza Stark reviewed gene: NPHP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12244321, 12205563, 34013113; Phenotypes: Nephronophthisis 4, MIM# 606966, Senior-Loken syndrome 4, MIM# 606996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8205 NPHP1 Zornitza Stark Publications for gene: NPHP1 were set to
Mendeliome v0.8203 NPHP1 Zornitza Stark reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15138899, 32139166, 28347285, 8852662, 9856524; Phenotypes: Joubert syndrome 4, MIM# 609583, Nephronophthisis 1, juvenile, MIM# 256100, Senior-Loken syndrome-1, MIM# 266900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8202 TIE1 Zornitza Stark gene: TIE1 was added
gene: TIE1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TIE1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TIE1 were set to 32947856; 24764452
Phenotypes for gene: TIE1 were set to Lymphatic malformation 11, MIM# 619401
Review for gene: TIE1 was set to AMBER
Added comment: Three families reported, supportive animal model, though variants are missense and present at a low frequency in gnomad.
Sources: Literature
Mendeliome v0.8201 KIF1B Paul De Fazio reviewed gene: KIF1B: Rating: RED; Mode of pathogenicity: None; Publications: 33710394; Phenotypes: Hypotonia, coloboma, hypoplasia of the corpus callosum, severe neurodevelopmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.8201 NUF2 Dean Phelan gene: NUF2 was added
gene: NUF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUF2 were set to PMID: 33721060
Phenotypes for gene: NUF2 were set to microcephaly; short stature; bilateral vocal cord paralysis; micrognathia; atrial septal defect
Review for gene: NUF2 was set to RED
Added comment: PMID: 33721060 - de novo missense variant identified in one male patient with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect.
Sources: Literature
Mendeliome v0.8201 ERGIC3 Elena Savva gene: ERGIC3 was added
gene: ERGIC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC3 were set to PMID: 33710394; 31585110
Phenotypes for gene: ERGIC3 were set to Intellectual disability
Review for gene: ERGIC3 was set to AMBER
Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS.

PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation.
Sources: Literature
Mendeliome v0.8201 JPH3 Teresa Zhao reviewed gene: JPH3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33824468; Phenotypes: Huntington disease-like 2 (MIM#606438) AD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8201 HEATR5B Teresa Zhao gene: HEATR5B was added
gene: HEATR5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to PMID: 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia
Review for gene: HEATR5B was set to AMBER
Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay.

Two homozygous splice variants were reported ((c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated
with reduced levels of HEATR5B protein.

Homozygous knockout mice were not viable.

*NOTE: gene (and alias) not found in OMIM
Sources: Literature
Mendeliome v0.8200 NEK8 Zornitza Stark Publications for gene: NEK8 were set to
Mendeliome v0.8198 NEK8 Zornitza Stark reviewed gene: NEK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 33131162, 23418306, 26862157, 26697755, 26967905, 23274954, 31633649; Phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8197 MKKS Zornitza Stark Publications for gene: MKKS were set to
Mendeliome v0.8195 MKKS Zornitza Stark reviewed gene: MKKS: Rating: GREEN; Mode of pathogenicity: None; Publications: 10802661, 26900326, 10973251; Phenotypes: Bardet-Biedl syndrome 6 (MIM#605231), McKusick-Kaufman syndrome, MIM# 236700, Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8194 IQCB1 Zornitza Stark Publications for gene: IQCB1 were set to
Mendeliome v0.8192 IQCB1 Zornitza Stark reviewed gene: IQCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15723066, 21220633, 20881296, 21901789, 33512896, 33535056, 29219953; Phenotypes: Senior-Loken syndrome 5, MIM# 609254, MONDO:0012225; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8191 IFT80 Zornitza Stark Publications for gene: IFT80 were set to
Mendeliome v0.8189 IFT80 Zornitza Stark reviewed gene: IFT80: Rating: GREEN; Mode of pathogenicity: None; Publications: 17468754, 19648123, 30767363; Phenotypes: Short-rib thoracic dysplasia 2 with or without polydactyly, MIM# 611263, MONDO:0012644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8188 LZTFL1 Zornitza Stark Publications for gene: LZTFL1 were set to
Mendeliome v0.8186 LZTFL1 Zornitza Stark reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22510444, 23692385, 27312011, 22072986; Phenotypes: Bardet-Biedl syndrome 17 (MIM#615994); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8185 TTC26 Zornitza Stark gene: TTC26 was added
gene: TTC26 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 34177428; 32617964; 31595528; 24596149; 22718903
Phenotypes for gene: TTC26 were set to Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations
Review for gene: TTC26 was set to GREEN
Added comment: Three unrelated families and functional data including zebrafish model.
Sources: Literature
Mendeliome v0.8184 IFT43 Zornitza Stark Publications for gene: IFT43 were set to 28400947; 28973684; 21378380
Mendeliome v0.8183 IFT43 Zornitza Stark edited their review of gene: IFT43: Changed publications: 28400947, 28973684, 21378380, 29896747
Mendeliome v0.8182 IFT43 Zornitza Stark Publications for gene: IFT43 were set to
Mendeliome v0.8180 IFT43 Zornitza Stark reviewed gene: IFT43: Rating: GREEN; Mode of pathogenicity: None; Publications: 28400947, 28973684, 21378380; Phenotypes: Short-rib thoracic dysplasia 18 with polydactyly, MIM# 617866, Retinitis pigmentosa 81 , MIM#617871, Cranioectodermal dysplasia 3, MIM# 614099; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8179 IFT140 Zornitza Stark Publications for gene: IFT140 were set to
Mendeliome v0.8177 IFT140 Zornitza Stark reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: None; Publications: 22503633, 23418020, 28288023, 28724397, 26216056, 26968735; Phenotypes: Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920, Retinitis pigmentosa 80, MIM# 617781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8174 DYNC2H1 Zornitza Stark Publications for gene: DYNC2H1 were set to
Mendeliome v0.8172 DYNC2H1 Zornitza Stark reviewed gene: DYNC2H1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19442771, 19361615, 22499340, 23456818, 27925158; Phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM# 613091, MONDO:0013127; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8171 DDX59 Zornitza Stark Publications for gene: DDX59 were set to
Mendeliome v0.8169 DDX59 Zornitza Stark reviewed gene: DDX59: Rating: GREEN; Mode of pathogenicity: None; Publications: 29127725, 23972372, 28711741; Phenotypes: Orofaciodigital syndrome V (MIM#174300); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8168 CEP83 Zornitza Stark Publications for gene: CEP83 were set to
Mendeliome v0.8166 CEP83 Zornitza Stark reviewed gene: CEP83: Rating: GREEN; Mode of pathogenicity: None; Publications: 24882706, 33938610; Phenotypes: Nephronophthisis 18, MIM# 615862, MONDO:0014374, Retinal dystrophy, ID; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8165 RNU12 Bryony Thompson gene: RNU12 was added
gene: RNU12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 34085356; 27863452
Phenotypes for gene: RNU12 were set to CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations
Review for gene: RNU12 was set to GREEN
Added comment: 5 CDAGS syndrome families with biallelic variants all including NC_000022.10:g.43011402C>T and another variant on the second allele. Whole transcriptome sequencing analysis of patient lymphoblastoid cells identified differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events. Also, limited evidence for an association with cerebellar ataxia with a single large consanguineous family reported with a homozygous variant.
Sources: Literature
Mendeliome v0.8163 FHOD3 Zornitza Stark Publications for gene: FHOD3 were set to
Mendeliome v0.8161 FHOD3 Zornitza Stark reviewed gene: FHOD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32335906, 31742804, 30442288; Phenotypes: Cardiomyopathy, familial hypertrophic, 28, MIM# 619402; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8159 KCNJ16 Zornitza Stark gene: KCNJ16 was added
gene: KCNJ16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNJ16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNJ16 were set to 33811157; 33840812
Phenotypes for gene: KCNJ16 were set to Renal tubulopathy; deafness
Review for gene: KCNJ16 was set to GREEN
Added comment: 8 unrelated families reported.
Sources: Literature
Mendeliome v0.8157 KLHL7 Zornitza Stark Publications for gene: KLHL7 were set to
Mendeliome v0.8154 SLC34A3 Zornitza Stark Publications for gene: SLC34A3 were set to
Mendeliome v0.8151 TNC Zornitza Stark Publications for gene: TNC were set to
Mendeliome v0.8148 TNC Zornitza Stark reviewed gene: TNC: Rating: AMBER; Mode of pathogenicity: None; Publications: 23936043, 34093110, 33763067; Phenotypes: Deafness, autosomal dominant 56, MIM# 615629; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8147 RIPK4 Zornitza Stark Publications for gene: RIPK4 were set to
Mendeliome v0.8145 RIPK4 Zornitza Stark reviewed gene: RIPK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940926, 22197489, 22197488; Phenotypes: Popliteal pterygium syndrome, Bartsocas-Papas type, MIM# 263650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8145 KLHL7 Ain Roesley reviewed gene: KLHL7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31953236, 30300710, 31856884; Phenotypes: PERCHING syndrome (MIM#617055), Retinitis pigmentosa 42 (MIM#612943); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.8145 SLC34A3 Ain Roesley reviewed gene: SLC34A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32524022; Phenotypes: Hypophosphatemic rickets with hypercalciuria, (MIM#241530); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8144 CEP290 Zornitza Stark Publications for gene: CEP290 were set to
Mendeliome v0.8142 CEP290 Zornitza Stark reviewed gene: CEP290: Rating: GREEN; Mode of pathogenicity: None; Publications: 18327255, 20690115, 16682973, 16682970, 17564967, 16909394, 17564974; Phenotypes: Bardet-Biedl syndrome 14, MIM# 615991, Joubert syndrome 5 610188, Leber congenital amaurosis 10, MIM# 611755, Meckel syndrome 4, MIM# 611134, Senior-Loken syndrome 6, MIM# 610189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8141 CEP164 Zornitza Stark Publications for gene: CEP164 were set to
Mendeliome v0.8139 CEP164 Zornitza Stark reviewed gene: CEP164: Rating: GREEN; Mode of pathogenicity: None; Publications: 34132027, 34013113, 32055034, 27708425, 22863007; Phenotypes: Bardet-Biedl syndrome, Nephronophthisis 15, MIM# 614845, Oro-facio-digital syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8138 CEP120 Zornitza Stark Publications for gene: CEP120 were set to
Mendeliome v0.8136 CEP120 Zornitza Stark reviewed gene: CEP120: Rating: GREEN; Mode of pathogenicity: None; Publications: 27208211, 33486889, 29847808, 25361962, 27208211; Phenotypes: Joubert syndrome 31, MIM# 617761, Short-rib thoracic dysplasia 13 with or without polydactyly, MIM# 616300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8135 CEP104 Zornitza Stark Publications for gene: CEP104 were set to
Mendeliome v0.8133 CEP104 Zornitza Stark reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 26477546; Phenotypes: Joubert syndrome 25, MIM# 616781, MONDO:0014770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8132 C5orf42 Zornitza Stark Publications for gene: C5orf42 were set to
Mendeliome v0.8130 C5orf42 Zornitza Stark edited their review of gene: C5orf42: Changed publications: 22425360, 24178751
Mendeliome v0.8130 C5orf42 Zornitza Stark edited their review of gene: C5orf42: Added comment: Well established gene-disease association.

New gene name is CPLANE1.; Changed publications: 22425360
Mendeliome v0.8129 C21orf2 Zornitza Stark Publications for gene: C21orf2 were set to
Mendeliome v0.8127 C21orf2 Zornitza Stark reviewed gene: C21orf2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26974433, 27548899, 28422394, 26294103, 23105016, 27548899; Phenotypes: Spondylometaphyseal dysplasia, axial, MIM# 602271, Retinal dystrophy with macular staphyloma, MIM# 617547; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8126 BBS9 Zornitza Stark Publications for gene: BBS9 were set to
Mendeliome v0.8124 BBS9 Zornitza Stark reviewed gene: BBS9: Rating: GREEN; Mode of pathogenicity: None; Publications: 16380913, 22353939, 32686083, 32037757; Phenotypes: Bardet-Biedl syndrome 9, MIM#615986, MONDO:0014437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8123 BBS7 Zornitza Stark Publications for gene: BBS7 were set to
Mendeliome v0.8121 BBS7 Zornitza Stark reviewed gene: BBS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 12567324, 21937992, 19797195; Phenotypes: Bardet-Biedl syndrome 7, MIM# 615984, MONDO:0014435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8120 BBS5 Zornitza Stark Publications for gene: BBS5 were set to
Mendeliome v0.8118 BBS5 Zornitza Stark reviewed gene: BBS5: Rating: GREEN; Mode of pathogenicity: None; Publications: 19252258, 15137946, 10053027, 15637713; Phenotypes: Bardet-Biedl syndrome 5, MIM#615983, MONDO:0014434; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8117 BBS4 Zornitza Stark Publications for gene: BBS4 were set to
Mendeliome v0.8115 BBS4 Zornitza Stark reviewed gene: BBS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12016587, 11381270; Phenotypes: Bardet-Biedl syndrome 4, MIM#615982, MONDO:0014433; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8114 ARL6 Zornitza Stark Publications for gene: ARL6 were set to
Mendeliome v0.8112 ARL6 Zornitza Stark reviewed gene: ARL6: Rating: GREEN; Mode of pathogenicity: None; Publications: 15258860, 32361989, 31888296, 25402481, 31736247, 19858128; Phenotypes: Bardet-Biedl syndrome 3, MIM# 600151, Retinitis pigmentosa 55, MIM# 613575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8110 SLCO2A1 Zornitza Stark Publications for gene: SLCO2A1 were set to
Mendeliome v0.8108 SLCO2A1 Zornitza Stark edited their review of gene: SLCO2A1: Changed publications: 23509104, 27134495, 33852188, 22331663, 27134495
Mendeliome v0.8108 SLCO2A1 Zornitza Stark reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23509104, 27134495, 33852188, 22331663, 27134495]; Phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8107 NDUFB11 Zornitza Stark Publications for gene: NDUFB11 were set to 28050600; 27488349; 30423443; 27488349
Mendeliome v0.8106 NDUFB11 Zornitza Stark reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 27488349; Phenotypes: X-linked sideroblastic anaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8105 PPP2R1A Zornitza Stark Publications for gene: PPP2R1A were set to
Mendeliome v0.8103 PPP2R1A Zornitza Stark reviewed gene: PPP2R1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal dominant 36, MIM#616362, Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8102 ARHGEF10 Bryony Thompson Added comment: Comment on list classification: ClinGen gene-disease clinical validity classification is limited for this gene.
Mendeliome v0.8100 PPP2R1A Elena Savva reviewed gene: PPP2R1A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 26168268, 33106617; Phenotypes: Mental retardation, autosomal dominant 36 MIM#616362; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.8100 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271
Mendeliome v0.8099 CLPB Zornitza Stark Publications for gene: CLPB were set to
Mendeliome v0.8097 CLPB Zornitza Stark reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25597510, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8096 SYK Zornitza Stark reviewed gene: SYK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency-82 with systemic inflammation (IMD82) , MIM#619381; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8094 PON1 Zornitza Stark reviewed gene: PON1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Coronary artery disease, susceptibility to}; Mode of inheritance: None
Mendeliome v0.8093 ABCB4 Zornitza Stark Publications for gene: ABCB4 were set to
Mendeliome v0.8090 OAS1 Zornitza Stark Publications for gene: OAS1 were set to
Mendeliome v0.8087 OAS1 Zornitza Stark reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34145065, 29455859; Phenotypes: Autoinflammatory immunodeficiency, infantile-onset pulmonary alveolar proteinosis, hypogammaglobulinaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8086 SLIT3 Zornitza Stark gene: SLIT3 was added
gene: SLIT3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLIT3 were set to 33933663
Phenotypes for gene: SLIT3 were set to Congenital diaphragmatic hernia
Review for gene: SLIT3 was set to AMBER
Added comment: Two affected individuals, single family, supportive mouse model.
Sources: Literature
Mendeliome v0.8081 TINF2 Zornitza Stark Publications for gene: TINF2 were set to
Mendeliome v0.8079 TINF2 Zornitza Stark edited their review of gene: TINF2: Added comment: RS is a severe variant of DKC with early bone marrow failure and retinopathy. Well established gene-disease associations.; Changed publications: 18252230, 21477109, 18979121, 18669893, 21199492, 33097095; Changed phenotypes: Dyskeratosis congenita, autosomal dominant 3, MIM# 613990, Revesz syndrome, MIM# 268130
Mendeliome v0.8078 POPDC3 Zornitza Stark gene: POPDC3 was added
gene: POPDC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POPDC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POPDC3 were set to 31610034
Phenotypes for gene: POPDC3 were set to Muscular dystrophy, limb-girdle, autosomal recessive 26, MIM# 618848
Review for gene: POPDC3 was set to GREEN
Added comment: 5 affected individuals from 3 unrelated families reported, supportive animal model data.
Sources: Literature
Mendeliome v0.8076 ACD Zornitza Stark Publications for gene: ACD were set to
Mendeliome v0.8073 ACD Zornitza Stark reviewed gene: ACD: Rating: RED; Mode of pathogenicity: None; Publications: 25205116, 25233904; Phenotypes: Dyskeratosis congenita, MIM# 616553; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8072 USB1 Zornitza Stark Publications for gene: USB1 were set to 25044170; 27612988
Mendeliome v0.8071 USB1 Zornitza Stark reviewed gene: USB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20004881, 20503306, 34004352, 33624217, 33111394, 32936385, 32620997, 31522452; Phenotypes: Poikiloderma with neutropaenia, MIM# 604173, MONDO:0011405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8070 WRAP53 Zornitza Stark Publications for gene: WRAP53 were set to
Mendeliome v0.8068 WRAP53 Zornitza Stark reviewed gene: WRAP53: Rating: GREEN; Mode of pathogenicity: None; Publications: 21205863, 32303682, 29514627; Phenotypes: Dyskeratosis congenita, autosomal recessive 3, MIM# 613988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8067 EP300 Zornitza Stark Publications for gene: EP300 were set to
Mendeliome v0.8065 EP300 Elena Savva reviewed gene: EP300: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29460469, 24381114; Phenotypes: Rubinstein-Taybi syndrome 2 MIM#613684, Menke-Hennekam syndrome 2 MIM#618333, Colorectal cancer, somatic MIM#114500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.8064 PARN Zornitza Stark Publications for gene: PARN were set to
Mendeliome v0.8062 PARN Zornitza Stark reviewed gene: PARN: Rating: GREEN; Mode of pathogenicity: None; Publications: 25893599, 26342108, 25848748; Phenotypes: Dyskeratosis congenita, autosomal recessive 6, MIM# 616353, Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, MIM# 616371; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8061 KLF1 Zornitza Stark Publications for gene: KLF1 were set to
Mendeliome v0.8059 KLF1 Zornitza Stark reviewed gene: KLF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21055716, 33339573, 32815883, 32221653, 32032242, 31818881; Phenotypes: Dyserythropoietic anaemia, congenital, type IV, MIM# 613673, MONDO:0013355; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8059 SPAG17 Zornitza Stark gene: SPAG17 was added
gene: SPAG17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPAG17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPAG17 were set to 28548327
Phenotypes for gene: SPAG17 were set to Spermatogenic failure 55, MIM#619380
Review for gene: SPAG17 was set to RED
Added comment: Single family reported with two affected brothers, homozygous missense variant.
Sources: Literature
Mendeliome v0.8058 CATIP Zornitza Stark Marked gene: CATIP as ready
Mendeliome v0.8058 CATIP Zornitza Stark Gene: catip has been classified as Red List (Low Evidence).
Mendeliome v0.8058 CATIP Zornitza Stark gene: CATIP was added
gene: CATIP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CATIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CATIP were set to 32503832
Phenotypes for gene: CATIP were set to Spermatogenic failure 54, MIM# 619379
Review for gene: CATIP was set to RED
Added comment: Homozygous missense variant reported in a single consanguineous family with 4 affecteds. Limited functional data.
Sources: Expert list
Mendeliome v0.8056 NCDN Zornitza Stark reviewed gene: NCDN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with infantile epileptic spasms (NEDIES), MIM#619373; Mode of inheritance: None
Mendeliome v0.8055 HAX1 Zornitza Stark Publications for gene: HAX1 were set to
Mendeliome v0.8053 HAX1 Zornitza Stark reviewed gene: HAX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17187068, 18611981, 19036076; Phenotypes: Neutropaenia, severe congenital 3, autosomal recessive, MIM# 610738, Kostmann syndrome MONDO:0012548; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8052 NFS1 Zornitza Stark Publications for gene: NFS1 were set to 24498631
Mendeliome v0.8048 ARCN1 Zornitza Stark Publications for gene: ARCN1 were set to
Mendeliome v0.8046 ARCN1 Zornitza Stark reviewed gene: ARCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476655, 33154040; Phenotypes: Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8045 NBEAL2 Zornitza Stark Publications for gene: NBEAL2 were set to
Mendeliome v0.8043 NBEAL2 Zornitza Stark reviewed gene: NBEAL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21765412, 21765411, 21765413; Phenotypes: Gray platelet syndrome, MIM# 139090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8042 GFI1 Zornitza Stark Publications for gene: GFI1 were set to
Mendeliome v0.8040 GFI1 Zornitza Stark reviewed gene: GFI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12778173, 20560965, 11810106, 22684987; Phenotypes: Neutropaenia, severe congenital 2, autosomal dominant, MIM# 613107; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8039 SLC13A5 Zornitza Stark Publications for gene: SLC13A5 were set to
Mendeliome v0.8037 SLC13A5 Zornitza Stark reviewed gene: SLC13A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24995870, 26384929; Phenotypes: Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905, MONDO:0014392; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8036 GATA2 Zornitza Stark Publications for gene: GATA2 were set to
Mendeliome v0.8034 GATA2 Zornitza Stark reviewed gene: GATA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21670465, 21242295, 21892158; Phenotypes: Immunodeficiency 21, MIM# 614172, GATA2 deficiency with susceptibility to MDS/AML MONDO:0042982, Emberger syndrome, MIM# 614038, Deafness-lymphoedema-leukaemia syndrome MONDO:0013540; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8032 GATA1 Zornitza Stark reviewed gene: GATA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thrombocytopaenia, X-linked, with or without dyserythropoietic anaemia, MIM# 300367; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8031 ELANE Zornitza Stark Publications for gene: ELANE were set to
Mendeliome v0.8029 ELANE Zornitza Stark reviewed gene: ELANE: Rating: GREEN; Mode of pathogenicity: None; Publications: 19036076; Phenotypes: Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8028 EFL1 Zornitza Stark Publications for gene: EFL1 were set to
Mendeliome v0.8026 EFL1 Zornitza Stark reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28331068, 31151987; Phenotypes: Shwachman-Diamond syndrome 2, MIM# 617941; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8025 CXCR4 Zornitza Stark Publications for gene: CXCR4 were set to
Mendeliome v0.8023 CXCR4 Zornitza Stark reviewed gene: CXCR4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12692554; Phenotypes: WHIM syndrome, MIM# 193670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8023 CTC1 Zornitza Stark Phenotypes for gene: CTC1 were changed from to Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199
Mendeliome v0.8022 CTC1 Zornitza Stark Publications for gene: CTC1 were set to
Mendeliome v0.8020 CTC1 Zornitza Stark reviewed gene: CTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22267198, 22387016; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8019 ANKRD26 Zornitza Stark Publications for gene: ANKRD26 were set to
Mendeliome v0.8017 ANKRD26 Zornitza Stark reviewed gene: ANKRD26: Rating: GREEN; Mode of pathogenicity: None; Publications: 21211618; Phenotypes: Thrombocytopaenia 2, MIM# 188000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8016 AK2 Zornitza Stark Publications for gene: AK2 were set to
Mendeliome v0.8014 AK2 Zornitza Stark reviewed gene: AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19043416; Phenotypes: Reticular dysgenesis, MIM# 267500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8013 ADA2 Zornitza Stark Publications for gene: ADA2 were set to
Mendeliome v0.8011 ADA2 Zornitza Stark reviewed gene: ADA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24552284, 24552285, 33791889; Phenotypes: Vasculitis, autoinflammation, immunodeficiency, and haematologic defects syndrome, MIM# 615688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8010 IFT74 Zornitza Stark Publications for gene: IFT74 were set to 27486776; 32144365
Mendeliome v0.8009 IFT74 Zornitza Stark edited their review of gene: IFT74: Added comment: PMID 33531668: Identified IFT74 as a JBTS-associated gene in 3 unrelated families through WES. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants.; Changed publications: 27486776, 32144365, 33531668; Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 617119, Joubert syndrome
Mendeliome v0.8008 RFX4 Zornitza Stark gene: RFX4 was added
gene: RFX4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX4 were set to 33658631
Phenotypes for gene: RFX4 were set to ID, ASD, ADHD
Review for gene: RFX4 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8006 RFX3 Zornitza Stark gene: RFX3 was added
gene: RFX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX3 were set to 33658631
Phenotypes for gene: RFX3 were set to ID, ASD, ADHD
Review for gene: RFX3 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8004 RFX7 Zornitza Stark gene: RFX7 was added
gene: RFX7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX7 were set to 33658631
Phenotypes for gene: RFX7 were set to ID, ASD, ADHD
Review for gene: RFX7 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Mendeliome v0.8002 SEMA3F Zornitza Stark gene: SEMA3F was added
gene: SEMA3F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEMA3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3F were set to 33495532
Phenotypes for gene: SEMA3F were set to Hypogonadotropic hypogonadism
Review for gene: SEMA3F was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 10 individuals from 7 families with heterozygous SEMA3F missense variants. In 4 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Provide unequivocal human embryonic data showing the expression of SEMA3F along the developing human GnRH migratory pathway. SEMA3Fs harboring the P452T, T29M, and T724M missense variants showed impaired SEMA3F secretion in whole cell lysates.
Sources: Literature
Mendeliome v0.8000 PLXNA3 Zornitza Stark gene: PLXNA3 was added
gene: PLXNA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLXNA3 were set to 33495532
Phenotypes for gene: PLXNA3 were set to Hypogonadotropic hypogonadism
Review for gene: PLXNA3 was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 7 individuals from 5 families with hemizygous PLXNA3 missense variants. In 2 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Data provided with evidence that PLXNA3, a key component of the SEMA3F holoreceptor complex,31 is expressed by the human GnRH and olfactory/vomeronasal systems. S646P variant showed PLXNA3 localization exclusively in the ER, indicating that the variant S646P disrupts cell surface localization of PLXNA3.
Sources: Literature
Mendeliome v0.7998 DLG4 Zornitza Stark Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719
Mendeliome v0.7997 DLG4 Zornitza Stark edited their review of gene: DLG4: Added comment: PMID 33597769: 53 patients (42 previously unpublished) with DLG4 variants. The clinical picture predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder.; Changed publications: 27479843, 25123844, 19617690, 29460436, 23020937, 28135719, 33597769; Changed phenotypes: Intellectual developmental disorder 62, MIM# 618793
Mendeliome v0.7996 GNAI1 Zornitza Stark Publications for gene: GNAI1 were set to
Mendeliome v0.7994 GNAI1 Zornitza Stark reviewed gene: GNAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 33473207; Phenotypes: Intellectual disability, seizures, hypotonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7994 SURF1 Elena Savva reviewed gene: SURF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24027061; Phenotypes: Charcot-Marie-Tooth disease, type 4K MIM#616684, Mitochondrial complex IV deficiency, nuclear type 1 MIM#220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.7993 FARSA Zornitza Stark edited their review of gene: FARSA: Added comment: Schuch et al. (2021) report 3 unrelated individuals with bi-allelic variants in FARSA. Identified through WES and variants segregated with disease. Functional evidence was obtained with reduced FARS1 enzyme activity levels in fibroblasts or EBV-transformed lymphoblastoid cell lines (EBV-LCLs) of patients. Common to all was a chronic interstitial lung disease starting early in life and characterized by bilateral ground-glass opacification on HR-CT, and cholesterol pneumonitis in lung histology. Additional abnormalities in other organ systems include liver disease, neurological manifestations, and growth restriction.; Changed rating: GREEN; Changed publications: 31355908, 33598926; Changed phenotypes: Rajab interstitial lung disease with brain calcifications 2, MIM# 619013
Mendeliome v0.7992 LAMA5 Bryony Thompson Publications for gene: LAMA5 were set to
Mendeliome v0.7990 LAMA5 Bryony Thompson reviewed gene: LAMA5: Rating: AMBER; Mode of pathogenicity: None; Publications: 33242826, 29534211, 16790509, 30589377, 28735299, 30631761; Phenotypes: bent bone dysplasia, nephrotic syndrome, Presynaptic congenital myasthenic syndrome, multisystem syndrome, developmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7989 ZNF81 Zornitza Stark Publications for gene: ZNF81 were set to
Mendeliome v0.7986 ZNF81 Zornitza Stark reviewed gene: ZNF81: Rating: RED; Mode of pathogenicity: None; Publications: 15121780; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7986 RELN Ee Ming Wong edited their review of gene: RELN: Added comment: - Six affected individuals carrying missense variants in RELN including
1. Two individuals with compound heterozygous variants
- One of the variants has 26 homozygotes in gnomAD and therefore pathogenicity of this variant is in question
- LoF demonstrated for three of the variants (reduced RELN secretion), except for p.Y1821H which demonstrated an apparently increased RELN secretion (GoF)
2. Two brothers carrying the maternally inherited variant (mother apparently healthy)
- LoF demonstrated for these variants
3. Two individuals de novo for RELN variants
- Dominant negative demonstrated for these variants where secretion of WT-RELN was impaired when co-transfected with mutant constructs in HEK293T cells; Changed rating: AMBER; Changed publications: Riva et al bioRxiv (pre-print, not peer-reviewed); Changed phenotypes: Pachygyria, Polymicrogyria, Heterotopia; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7985 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[(66_517)]
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 7-60
Pathogenic repeat range: >=61-500
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Mendeliome v0.7984 NOTCH2NL Bryony Thompson Added comment: Comment on list classification: STR is the only reported cause of disease for this gene. It has been added as an STR under NIID.
Mendeliome v0.7980 CNTNAP1 Zornitza Stark Publications for gene: CNTNAP1 were set to
Mendeliome v0.7978 CNTNAP1 Zornitza Stark reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28374019, 29511323, 27668699; Phenotypes: Hypomyelinating neuropathy, congenital, 3, MIM#618186, Lethal congenital contracture syndrome 7, MIM# 616286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7977 GLDN Zornitza Stark Publications for gene: GLDN were set to
Mendeliome v0.7975 GLDN Zornitza Stark reviewed gene: GLDN: Rating: GREEN; Mode of pathogenicity: None; Publications: 27616481, 32812332, 28726266; Phenotypes: Lethal congenital contracture syndrome 11, MIM# 617194, MONDO:0014965; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7974 ZBTB42 Zornitza Stark gene: ZBTB42 was added
gene: ZBTB42 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZBTB42 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB42 were set to 25055871
Phenotypes for gene: ZBTB42 were set to Lethal congenital contracture syndrome 6, MIM# 616248
Review for gene: ZBTB42 was set to AMBER
Added comment: Homozygous missense variant reported in a family with three stillbirths and a phenotype consistent with LCCS. Supportive zebrafish model.
Sources: Expert Review
Mendeliome v0.7972 MYBPC1 Zornitza Stark Publications for gene: MYBPC1 were set to
Mendeliome v0.7970 MYBPC1 Zornitza Stark reviewed gene: MYBPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20045868, 22610851, 23873045, 26661508, 31264822, 31025394; Phenotypes: Arthrogryposis, distal, type 1B 614335, Lethal congenital contracture syndrome 4, MIM# 614915, Myopathy, congenital, with tremor MIM#618524; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7969 ERBB3 Zornitza Stark Publications for gene: ERBB3 were set to 17701904; 31752936
Mendeliome v0.7967 TRPM6 Kristin Rigbye reviewed gene: TRPM6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 1, intestinal (MIM#602014), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7966 MUSK Zornitza Stark Publications for gene: MUSK were set to
Mendeliome v0.7964 MUSK Zornitza Stark reviewed gene: MUSK: Rating: GREEN; Mode of pathogenicity: None; Publications: 25537362, 25612909, 8653786, 31750350, 15496425, 19949040, 20371544, 32253145; Phenotypes: Fetal akinesia deformation sequence 1, MIM# 208150, MONDO:0100101, Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency, MIM# 616325, MONDO:0014587; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7963 DOK7 Zornitza Stark Publications for gene: DOK7 were set to
Mendeliome v0.7961 DOK7 Zornitza Stark reviewed gene: DOK7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16917026, 18626973, 20147321, 16794080, 31453852, 29395672, 32360404, 19261599, 31880392; Phenotypes: Myasthenic syndrome, congenital, 10, MIM# 254300, Fetal akinesia deformation sequence 3, MIM# 618389; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7960 TPM2 Zornitza Stark Publications for gene: TPM2 were set to
Mendeliome v0.7958 TPM2 Zornitza Stark reviewed gene: TPM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32092148, 27726070, 32092148, 24692096; Phenotypes: Arthrogryposis, distal, type 1A 108120, Arthrogryposis, distal, type 2B4 108120, CAP myopathy 2 609285, Nemaline myopathy 4, autosomal dominant 609285, Multiple pterygium syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7957 CHRNG Zornitza Stark Publications for gene: CHRNG were set to
Mendeliome v0.7955 CHRNG Zornitza Stark reviewed gene: CHRNG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826520, 16826531, 22167768; Phenotypes: Escobar syndrome, MIM# 265000, Multiple pterygium syndrome, lethal type, MIM# 253290, MONDO:0009926, MONDO:0009668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7954 CD207 Zornitza Stark Publications for gene: CD207 were set to
Mendeliome v0.7951 CD207 Zornitza Stark reviewed gene: CD207: Rating: RED; Mode of pathogenicity: None; Publications: 15816828; Phenotypes: Birbeck granule deficiency, MIM# 613393; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7951 KIF17 Zornitza Stark gene: KIF17 was added
gene: KIF17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF17 were set to 33922911; 30458707; 28341548
Phenotypes for gene: KIF17 were set to Microphthalmia; Coloboma
Review for gene: KIF17 was set to RED
Added comment: Two siblings reported with MAC spectrum and homozygous missense variant in this gene. Some pre-existing data linking KIF17 to eye development.
Sources: Literature
Mendeliome v0.7949 SASH3 Zornitza Stark gene: SASH3 was added
gene: SASH3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SASH3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SASH3 were set to 33876203
Phenotypes for gene: SASH3 were set to Combined immunodeficiency; immune dysregulation
Review for gene: SASH3 was set to GREEN
Added comment: Four unrelated males reported presenting with combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopaenias. One missense variant, rest were nonsense.
Sources: Literature
Mendeliome v0.7948 FOXP1 Zornitza Stark Publications for gene: FOXP1 were set to
Mendeliome v0.7946 FOXP1 Zornitza Stark edited their review of gene: FOXP1: Changed publications: 26633542, 28741757, 34109629
Mendeliome v0.7946 FOXP1 Zornitza Stark reviewed gene: FOXP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26633542, 28741757; Phenotypes: Mental retardation with language impairment and with or without autistic features 613670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7946 PARP6 Zornitza Stark Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Mendeliome v0.7945 PARP6 Zornitza Stark edited their review of gene: PARP6: Changed publications: 34067418
Mendeliome v0.7945 DNAH2 Zornitza Stark edited their review of gene: DNAH2: Added comment: PMID 32732226: compound het variants identified in a fetus with hydrops and complex congenital heart disease detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex congenital heart disease, hypotrophic splenium, and common mesentery.; Changed publications: 30811583, 32732226; Changed phenotypes: Spermatogenic failure 45, MIM# 619094, Heterotaxy
Mendeliome v0.7945 MYBPC2 Zornitza Stark gene: MYBPC2 was added
gene: MYBPC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYBPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBPC2 were set to 32732226
Phenotypes for gene: MYBPC2 were set to Fetal akinesia; Hydrops; Hygroma; Multiple pterygium
Review for gene: MYBPC2 was set to RED
Added comment: Novel candidate gene identified in a fetus with fetal akinesia detected by ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, hygroma, multiple pterygium. A homozygous variant (c.3394G>A/ p.Glu1132Lys) in MYBPC2 was found by exome sequencing with concordant segregation among one affected sib and two unaffected sibs.
Sources: Literature
Mendeliome v0.7944 SCN7A Zornitza Stark gene: SCN7A was added
gene: SCN7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCN7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN7A were set to 32732226
Phenotypes for gene: SCN7A were set to Holoprosencephaly
Review for gene: SCN7A was set to RED
Added comment: Novel candidate gene identified in a fetus with holoprosencephaly detected by ultrasound. Autopsy showed multiple congenital abnormalities including IUGR, microcephaly, bilateral, ablepharon, corpus callosum agenesis, myelomeningocele, tracheal atresia, absent nipples, unilateral simian crease, and hypoplastic phalanges. Compound heterozygous variants including a truncating variant were found by exome sequencing with concordant segregation.
Sources: Literature
Mendeliome v0.7943 SPTBN5 Zornitza Stark gene: SPTBN5 was added
gene: SPTBN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTBN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN5 were set to 32732226; 28007035
Phenotypes for gene: SPTBN5 were set to Sacral agenesis; congenital anomalies
Review for gene: SPTBN5 was set to RED
Added comment: Identified as a candidate gene in a sacral agenesis cohort.

PMID 32732226: compound het variants identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis.
Sources: Literature
Mendeliome v0.7941 WDR91 Zornitza Stark Publications for gene: WDR91 were set to
Mendeliome v0.7938 WDR91 Zornitza Stark commented on gene: WDR91: PMID 32732226: Novel candidate gene identified in a fetus with hygroma and hydrocephaly detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma, macrocephaly, abnormal ears, unilateral simian crease, hydrocephaly, cerebellar hypoplasia, and interventricular communication. A homozygous truncating variant was found by exome sequencing with concordant segregation among 4 affected fetus, 2 healthy sibs and both parents. Mouse models support role in brain development.
Mendeliome v0.7938 WDR91 Zornitza Stark reviewed gene: WDR91: Rating: AMBER; Mode of pathogenicity: None; Publications: 34028500, 28860274, 32732226; Phenotypes: Hydrocephalus, cerebellar hypoplasia, hygroma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7938 PLEKHN1 Zornitza Stark gene: PLEKHN1 was added
gene: PLEKHN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEKHN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHN1 were set to 33884296
Phenotypes for gene: PLEKHN1 were set to Sensory Neuropathy
Review for gene: PLEKHN1 was set to RED
Added comment: Hom missense variant in single patient with severely reduced/absent pain and temperature sensation
Sources: Literature
Mendeliome v0.7937 ZNF3 Zornitza Stark gene: ZNF3 was added
gene: ZNF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF3 were set to 32732226
Phenotypes for gene: ZNF3 were set to Hydrocephalus; cleft palate; microphthalmia
Review for gene: ZNF3 was set to RED
Added comment: Novel candidate gene identified in a fetus with hydrocephaly and facial cleft detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including a median cleft palate, partial maxillar agenesis, bilateral severe microphthalmia, arhinencephaly, partial thalamic fusion. A homozygous truncating variant (c.396A>G/ p.*132Trpext*69) in ZNF3 was found by exome sequencing.
Sources: Literature
Mendeliome v0.7936 SMPDL3A Seb Lunke gene: SMPDL3A was added
gene: SMPDL3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMPDL3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPDL3A were set to 33884296
Phenotypes for gene: SMPDL3A were set to Sensory Neuropathy
Added comment: Hom missense variant in twin sisters with deverely reduced pain and temperature sensation
Sources: Literature
Mendeliome v0.7935 WRAP73 Zornitza Stark gene: WRAP73 was added
gene: WRAP73 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WRAP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WRAP73 were set to 33693649
Phenotypes for gene: WRAP73 were set to Microsperophakia
Review for gene: WRAP73 was set to AMBER
Added comment: Two Indian families with same homozygous missense, (p.Pro383Leu) and supportive functional data (zebrafish model).
Sources: Literature
Mendeliome v0.7933 EIF2AK2 Zornitza Stark edited their review of gene: EIF2AK2: Changed publications: 33236446, 33866603
Mendeliome v0.7933 EIF2AK2 Zornitza Stark Publications for gene: EIF2AK2 were set to 32197074
Mendeliome v0.7932 EIF2AK2 Zornitza Stark edited their review of gene: EIF2AK2: Added comment: Four unrelated families reported with dystonia, recurrent variant, (p.Gly130Arg); Changed publications: 32197074, 33866603; Changed phenotypes: Intellectual disability, white matter abnormalities, ataxia, regression with febrile illness, Dystonia
Mendeliome v0.7931 SLC37A4 Zornitza Stark Publications for gene: SLC37A4 were set to
Mendeliome v0.7929 SLC37A4 Zornitza Stark reviewed gene: SLC37A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33964207, 9675154, 9758626; Phenotypes: Glycogen storage disease Ib 232220, Glycogen storage disease Ic 232240, Congenital disorder of glycosylation; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7928 TUBA1A Zornitza Stark Publications for gene: TUBA1A were set to
Mendeliome v0.7926 TUBA1A Zornitza Stark reviewed gene: TUBA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lissencephaly 3, MIM# 611603; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7925 COL9A3 Zornitza Stark Publications for gene: COL9A3 were set to 30450842; 31090205; 24273071; 10090888; 15551337; 33078831; 15917166
Mendeliome v0.7923 BCAS3 Zornitza Stark Publications for gene: BCAS3 were set to
Mendeliome v0.7919 SRCAP Zornitza Stark Publications for gene: SRCAP were set to
Mendeliome v0.7917 SRCAP Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Floating-Harbor syndrome MIM#136140, Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7916 ADAMTSL2 Zornitza Stark Publications for gene: ADAMTSL2 were set to
Mendeliome v0.7914 ADAMTSL2 Zornitza Stark reviewed gene: ADAMTSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33369194, 26879370, 21415077; Phenotypes: Geleophysic dysplasia 1, MIM# 231050, Dermatosparaxic Ehlers Danlos syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7912 HS3ST6 Zornitza Stark gene: HS3ST6 was added
gene: HS3ST6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HS3ST6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HS3ST6 were set to 33508266
Phenotypes for gene: HS3ST6 were set to Hereditary angioedema-8 (HAE8), MIM#619367
Review for gene: HS3ST6 was set to RED
Added comment: Three affected individuals from a single family reported, missense variant, no functional data.
Sources: Expert list
Mendeliome v0.7911 MYOF Zornitza Stark gene: MYOF was added
gene: MYOF was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MYOF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYOF were set to 32542751
Phenotypes for gene: MYOF were set to Hereditary angioedema-7 (HAE7), MIM#619366
Review for gene: MYOF was set to RED
Added comment: Three individuals from one family reported, onset of recurrent episodic swelling of the face, lips, and oral mucosa was in the second decade. Variant was also present in another unaffected family member. Some functional data.
Sources: Expert list
Mendeliome v0.7909 KNG1 Zornitza Stark Publications for gene: KNG1 were set to
Mendeliome v0.7906 KNG1 Zornitza Stark reviewed gene: KNG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31087670, 33114181; Phenotypes: Hereditary angioedema-6 (HAE6), MIM#619363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7905 ANGPT1 Zornitza Stark reviewed gene: ANGPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary angioedema-5 (HAE5), MIM#619361; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7905 PLG Zornitza Stark edited their review of gene: PLG: Changed publications: 28795768, 29548426, 29987869, 9242524, 10233898, 21174000, 21174000
Mendeliome v0.7904 PLG Zornitza Stark Publications for gene: PLG were set to
Mendeliome v0.7902 PLG Zornitza Stark reviewed gene: PLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 28795768, 29548426, 29987869, 9242524, 10233898; Phenotypes: Hereditary angioedema-4 (HAE4), MIM#619360, Plasminogen deficiency, type I, MIM# 217090; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7901 POU4F1 Zornitza Stark reviewed gene: POU4F1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS) , MIM#619352; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7900 PRKD1 Zornitza Stark Publications for gene: PRKD1 were set to 27479907; 32817298
Mendeliome v0.7897 PIGF Zornitza Stark reviewed gene: PIGF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome, MIM# 619356; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7897 PRKD1 Zornitza Stark edited their review of gene: PRKD1: Added comment: Additional publications supporting association with bi-allelic disease:

PMID: 33919081: Three sisters with pulmonary stenosis, truncus arteriosis, and atrial septal defect were homozygous for c.265-1G>T. Their asymptomatic father was also homozygous, however he had two affected sisters (not genotyped), raising the possibility that PRKD1 may undergo autosomal recessive inheritance mode with gender limitation. PMID: 25713110: Two sisters with truncus arteriosis were homozygous for R618X.; Changed publications: 27479907, 32817298, 25713110, 33919081; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7896 ATXN2L Seb Lunke gene: ATXN2L was added
gene: ATXN2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATXN2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATXN2L were set to 33283965; 33057194
Phenotypes for gene: ATXN2L were set to macrocephaly; intellectual disability
Review for gene: ATXN2L was set to AMBER
Added comment: Sources: Literature
Mendeliome v0.7891 RELN Ee Ming Wong reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25648840; Phenotypes: Myoclonus dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.7891 TUBA1A Kristin Rigbye reviewed gene: TUBA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30677308; Phenotypes: Congenital fibrosis of the extraocular muscles; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7891 PGM2L1 Chern Lim reviewed gene: PGM2L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33979636; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.7891 LTBP1 Chern Lim gene: LTBP1 was added
gene: LTBP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to cutis laxa syndrome
Review for gene: LTBP1 was set to GREEN
gene: LTBP1 was marked as current diagnostic
Added comment: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature
Mendeliome v0.7891 SLC30A5 Melanie Marty gene: SLC30A5 was added
gene: SLC30A5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A5 were set to 33547425; 12095919
Phenotypes for gene: SLC30A5 were set to Perinatal lethal cardiomyopathy
Review for gene: SLC30A5 was set to AMBER
Added comment: Four affected children from two unrelated families with cardiomyopathy, hydrops fetalis, or cystic hygroma that all deceased perinatally. 2 different homozygous PTCs variants found. Knockout of SLC30A5 in mouse models showed reduced body growth and reduced bone density. About 60% of the mice died due to bradyarrhythmia.
Sources: Literature
Mendeliome v0.7891 SRCAP Paul De Fazio reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Floating-Harbor syndrome MIM#136140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.7891 COL9A3 Kristin Rigbye reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33633367; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy, AD, MIM# 600969, Stickler syndrome, AR, Deafness, AD, Peripheral vitreoretinal degeneration and retinal detachment, AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7891 BCAS3 Paul De Fazio reviewed gene: BCAS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34022130; Phenotypes: Syndromic neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.7891 CADM3 Teresa Zhao gene: CADM3 was added
gene: CADM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CADM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CADM3 were set to PMID: 33889941
Phenotypes for gene: CADM3 were set to Charcot-Marie-Tooth disease
Review for gene: CADM3 was set to AMBER
Added comment: Three families reported with the same missense variant in CADM3 p.Tyr172Cys (one family de novo), with mice work to show reduced expression of the mutant protein in axons and abnormal axonal organization.
Sources: Literature
Mendeliome v0.7891 ANGPTL8 Dean Phelan gene: ANGPTL8 was added
gene: ANGPTL8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANGPTL8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPTL8 were set to PMID: 33909604
Phenotypes for gene: ANGPTL8 were set to Low serum triglycerides; Coronary artery disease
Review for gene: ANGPTL8 was set to RED
Added comment: PMID: 33909604 - Population studies showed PTV are associated with both lipid levels and coronary artery disease.
Sources: Literature
Mendeliome v0.7891 PGM2L1 Chern Lim gene: PGM2L1 was added
gene: PGM2L1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGM2L1 were set to 33979636
Phenotypes for gene: PGM2L1 were set to severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris
Review for gene: PGM2L1 was set to GREEN
gene: PGM2L1 was marked as current diagnostic
Added comment: PMID: 33979636:
- Hom/chet PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals.
- Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect.
Sources: Literature
Mendeliome v0.7890 KCNB1 Zornitza Stark Publications for gene: KCNB1 were set to
Mendeliome v0.7888 KCNB1 Zornitza Stark reviewed gene: KCNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31600826, 31513310; Phenotypes: Epileptic encephalopathy, early infantile, 26, MIM# 616056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7887 SYT1 Zornitza Stark Publications for gene: SYT1 were set to
Mendeliome v0.7885 SYT1 Zornitza Stark reviewed gene: SYT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30107533; Phenotypes: Baker-Gordon syndrome, MIM# 618218, MONDO:0033864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7884 UBTF Zornitza Stark Publications for gene: UBTF were set to
Mendeliome v0.7882 UBTF Zornitza Stark reviewed gene: UBTF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777933, 29300972; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7880 SLC9A6 Zornitza Stark Publications for gene: SLC9A6 were set to
Mendeliome v0.7878 SLC9A6 Zornitza Stark reviewed gene: SLC9A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18342287, 19377476, 25044251, 33278113, 32569089, 31879735; Phenotypes: Mental retardation, X-linked syndromic, Christianson type, MIM# 300243, MONDO:0010278; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7877 RPL3L Zornitza Stark reviewed gene: RPL3L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 2D, MIM# 619371, Neonatal dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7877 SHANK3 Zornitza Stark Publications for gene: SHANK3 were set to 30842224
Mendeliome v0.7876 SHANK3 Zornitza Stark reviewed gene: SHANK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16284256, 17173049, 20186804, 22892527; Phenotypes: Phelan-McDermid syndrome, MIM# 606232; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7874 SATB2 Zornitza Stark Publications for gene: SATB2 were set to
Mendeliome v0.7872 SATB2 Zornitza Stark reviewed gene: SATB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29023086, 28151491, 32446642; Phenotypes: Glass syndrome, MIM# 612313, MONDO:0100147; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7871 MEF2C Zornitza Stark Publications for gene: MEF2C were set to
Mendeliome v0.7870 MEF2C Zornitza Stark reviewed gene: MEF2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 19876902, 19471318, 19592390, 19592390, 20513142, 34055696, 34022131; Phenotypes: Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MIM# 613443, MONDO:0013266 Edit; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7869 MBD5 Zornitza Stark Publications for gene: MBD5 were set to
Mendeliome v0.7867 MBD5 Zornitza Stark reviewed gene: MBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 18812405, 21981781, 23708187, 22726846, 33912662; Phenotypes: Mental retardation, autosomal dominant 1, MIM# 156200, MONDO:0007974; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7866 IQSEC2 Zornitza Stark Publications for gene: IQSEC2 were set to 31415821; 20473311; 30842726
Mendeliome v0.7865 IQSEC2 Zornitza Stark reviewed gene: IQSEC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33368194, 20473311, 23674175; Phenotypes: Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656, Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7864 EEF1A2 Zornitza Stark Publications for gene: EEF1A2 were set to 32160274
Mendeliome v0.7863 EEF1A2 Zornitza Stark reviewed gene: EEF1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24697219, 32196822, 32160274, 32062104, 31893083; Phenotypes: Mental retardation, autosomal dominant 38, MIM# 616393, MONDO:0014617, Developmental and epileptic encephalopathy 33, MIM# 616409, MONDO:0014625; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7862 MASP1 Zornitza Stark Publications for gene: MASP1 were set to
Mendeliome v0.7860 MASP1 Zornitza Stark reviewed gene: MASP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26789649, 21258343, 21035106; Phenotypes: 3MC syndrome 1, MIM# 257920, MONDO:0009770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7859 BRPF1 Zornitza Stark Publications for gene: BRPF1 were set to
Mendeliome v0.7857 BRPF1 Zornitza Stark reviewed gene: BRPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27939640, 27939639; Phenotypes: Intellectual developmental disorder with dysmorphic facies and ptosis, MIM# 617333, MONDO:0015022; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7856 TRAF7 Zornitza Stark Publications for gene: TRAF7 were set to
Mendeliome v0.7854 TRAF7 Zornitza Stark reviewed gene: TRAF7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32376980; Phenotypes: Cardiac, facial, and digital anomalies with developmental delay, MIM# 618164; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7853 UBE3B Zornitza Stark Publications for gene: UBE3B were set to
Mendeliome v0.7851 UBE3B Zornitza Stark reviewed gene: UBE3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 23200864, 23200864, 34012380, 32949109; Phenotypes: Kaufman oculocerebrofacial syndrome, MIM# 244450, MONDO:0009485; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7851 HSPG2 Zornitza Stark Publications for gene: HSPG2 were set to 16927315
Mendeliome v0.7850 HSPG2 Zornitza Stark reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11101850, 16927315, 11279527; Phenotypes: Schwartz-Jampel syndrome, type 1, MIM# 255800, MONDO:0009717, Dyssegmental dysplasia, Silverman-Handmaker type, MIM# 224410, MONDO:0009140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7849 HLA-DRB1 Zornitza Stark reviewed gene: HLA-DRB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7848 HLA-DRA Zornitza Stark reviewed gene: HLA-DRA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7847 HLA-C Zornitza Stark reviewed gene: HLA-C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7846 HLA-B Zornitza Stark reviewed gene: HLA-B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7845 HLA-A Zornitza Stark reviewed gene: HLA-A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7844 TAF6 Zornitza Stark Publications for gene: TAF6 were set to
Mendeliome v0.7842 TAF6 Zornitza Stark reviewed gene: TAF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 25574841, 32030742; Phenotypes: Alazami-Yuan syndrome, MIM# 617126; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7840 SLC24A5 Zornitza Stark Publications for gene: SLC24A5 were set to
Mendeliome v0.7838 SLC24A5 Zornitza Stark reviewed gene: SLC24A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23364476, 23985994, 26491832; Phenotypes: Albinism, oculocutaneous, type VI, MIM# 113750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7837 SLC45A2 Zornitza Stark Publications for gene: SLC45A2 were set to
Mendeliome v0.7835 SLC45A2 Zornitza Stark reviewed gene: SLC45A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11574907, 14722913, 14961451; Phenotypes: Albinism, oculocutaneous, type IV, MIM# 606574, MONDO:0011683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7833 TYR Zornitza Stark reviewed gene: TYR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Albinism, oculocutaneous, type IA, MIM# 203100, MONDO:0008745, Albinism, oculocutaneous, type IB, MIM# 606952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7832 TYRP1 Zornitza Stark Publications for gene: TYRP1 were set to
Mendeliome v0.7830 TYRP1 Zornitza Stark reviewed gene: TYRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9345097; Phenotypes: Albinism, oculocutaneous, type III, MIM# 203290, MONDO:0008747; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7829 MC1R Zornitza Stark Publications for gene: MC1R were set to
Mendeliome v0.7826 MC1R Zornitza Stark reviewed gene: MC1R: Rating: AMBER; Mode of pathogenicity: None; Publications: 12876664; Phenotypes: {Albinism, oculocutaneous, type II, modifier of}, MIM# 203200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7825 LRMDA Zornitza Stark Publications for gene: LRMDA were set to
Mendeliome v0.7823 LRMDA Zornitza Stark reviewed gene: LRMDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 23395477; Phenotypes: Albinism, oculocutaneous, type VII, MIM# 615179, MONDO:0014070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7822 SERPINF2 Zornitza Stark Publications for gene: SERPINF2 were set to
Mendeliome v0.7820 SERPINF2 Zornitza Stark reviewed gene: SERPINF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 2572590, 10583218, 31441040, 31282989, 29656168; Phenotypes: Alpha-2-plasmin inhibitor deficiency, MIM# 262850; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7819 SERPINE1 Zornitza Stark Publications for gene: SERPINE1 were set to
Mendeliome v0.7817 SERPINE1 Zornitza Stark reviewed gene: SERPINE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9207454, 15650551; Phenotypes: Plasminogen activator inhibitor-1 deficiency, MIM# 613329; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.7816 TBXA2R Zornitza Stark Publications for gene: TBXA2R were set to
Mendeliome v0.7813 TBXA2R Zornitza Stark reviewed gene: TBXA2R: Rating: AMBER; Mode of pathogenicity: None; Publications: 7929844, 19828703, 22517902; Phenotypes: {Bleeding disorder, platelet-type, 13, susceptibility to}, MIM# 614009; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7812 P2RY12 Zornitza Stark Publications for gene: P2RY12 were set to
Mendeliome v0.7810 P2RY12 Zornitza Stark reviewed gene: P2RY12: Rating: GREEN; Mode of pathogenicity: None; Publications: 11196645, 12578987, 29117459, 19237732; Phenotypes: Bleeding disorder, platelet-type, 8, MIM# 609821, MONDO:0012354; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7809 MCFD2 Zornitza Stark Publications for gene: MCFD2 were set to
Mendeliome v0.7807 MCFD2 Zornitza Stark reviewed gene: MCFD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12717434, 16304051, 18391077; Phenotypes: Factor V and factor VIII, combined deficiency of, MIM# 613625, MONDO:0013331; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7806 LMAN1 Zornitza Stark Publications for gene: LMAN1 were set to
Mendeliome v0.7804 LMAN1 Zornitza Stark reviewed gene: LMAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9546392, 16304051; Phenotypes: Combined factor V and VIII deficiency, MIM# 227300, MONDO:0009206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7803 ITGA2B Zornitza Stark Publications for gene: ITGA2B were set to
Mendeliome v0.7801 ITGA2B Zornitza Stark reviewed gene: ITGA2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 1638023, 21454453, 8282784, 16463284; Phenotypes: Bleeding disorder, platelet-type, 16, MIM# 187800, MONDO:000855, Glanzmann thrombasthaenia 1, MIM# 273800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7800 LMOD1 Zornitza Stark Publications for gene: LMOD1 were set to
Mendeliome v0.7797 LMOD1 Zornitza Stark reviewed gene: LMOD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28292896; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome 3, MIM# 619362; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7796 POU4F1 Bryony Thompson gene: POU4F1 was added
gene: POU4F1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POU4F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU4F1 were set to 33783914; 8876243
Phenotypes for gene: POU4F1 were set to Ataxia; intention tremor; hypotonia
Review for gene: POU4F1 was set to GREEN
Added comment: 4 unrelated probands presenting with paediatric onset ataxia, intention tremor, and hypotonia, with de novo loss of function variants, and supporting null mouse model.
Sources: Literature
Mendeliome v0.7794 HPS6 Zornitza Stark Publications for gene: HPS6 were set to
Mendeliome v0.7792 HPS6 Zornitza Stark reviewed gene: HPS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 12548288, 17041891, 19843503; Phenotypes: Hermansky-Pudlak syndrome 6, MIM# 614075, MONDO:0013558; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7792 HPS4 Zornitza Stark Publications for gene: HPS4 were set to
Mendeliome v0.7789 HPS4 Zornitza Stark reviewed gene: HPS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11836498, 12664304; Phenotypes: Hermansky-Pudlak syndrome 4, MIM# 614073, MONDO:0013556; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7788 HPS3 Zornitza Stark Publications for gene: HPS3 were set to
Mendeliome v0.7786 HPS3 Zornitza Stark reviewed gene: HPS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11455388, 31880485, 31621111, 30990103; Phenotypes: Hermansky-Pudlak syndrome 3, MIM# 614072, MONDO:0013555; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7785 HPS1 Zornitza Stark Publications for gene: HPS1 were set to
Mendeliome v0.7783 HPS1 Zornitza Stark reviewed gene: HPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9497254; Phenotypes: Hermansky-Pudlak syndrome 1, MIM# 203300, MONDO:0008748; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7782 GP9 Zornitza Stark Publications for gene: GP9 were set to
Mendeliome v0.7780 GP9 Zornitza Stark reviewed gene: GP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 8049428, 33553065, 32030720, 31484196; Phenotypes: Bernard-Soulier syndrome, type C, MIM# 231200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7779 GP6 Zornitza Stark Publications for gene: GP6 were set to
Mendeliome v0.7777 GP6 Zornitza Stark reviewed gene: GP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 19549989, 19552682, 23815599; Phenotypes: Bleeding disorder, platelet-type, 11, MIM# 614201, MONDO:0013623; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7776 GP1BB Zornitza Stark Publications for gene: GP1BB were set to
Mendeliome v0.7774 GP1BB Zornitza Stark reviewed gene: GP1BB: Rating: GREEN; Mode of pathogenicity: None; Publications: 8703016, 9116284, 10887115, 33813986, 33657022, 33216977, 31997307, 1730088, 11222377; Phenotypes: Bernard-Soulier syndrome, type B, MIM# 231200, Macrothrombocytopaenia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7773 CREB3L3 Zornitza Stark reviewed gene: CREB3L3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypertriglyceridaemia-2, MIM#619324; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7773 PSMC3 Zornitza Stark Phenotypes for gene: PSMC3 were changed from Deafness; cataract to Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v0.7772 PSMC3 Zornitza Stark edited their review of gene: PSMC3: Changed phenotypes: Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v0.7772 PSMC3 Zornitza Stark edited their review of gene: PSMC3: Changed phenotypes: Feafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v0.7770 SCNN1B Zornitza Stark reviewed gene: SCNN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Liddle syndrome 1, MIM# 177200, Pseudohypoaldosteronism, type I, MIM# 264350, Bronchiectasis with or without elevated sweat chloride 1 (MIM#211400); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7769 FGB Zornitza Stark Publications for gene: FGB were set to
Mendeliome v0.7767 FGB Zornitza Stark changed review comment from: Inherited disorders of fibrinogen affect either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenemia) of the circulating fibrinogen or both.

Afibrinogenaemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenaemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial haemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. First-trimester pregnancy loss is common. Both arterial and venous thromboembolic complications have been reported. Hypofibrinogenaemia is a milder disorder. Well established gene-disease association.; to: Inherited disorders of fibrinogen affect either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenemia) of the circulating fibrinogen or both.

Afibrinogenaemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenaemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial haemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. First-trimester pregnancy loss is common. Both arterial and venous thromboembolic complications have been reported. Hypofibrinogenaemia is a milder disorder.

Well established gene-disease association.
Mendeliome v0.7767 FGB Zornitza Stark reviewed gene: FGB: Rating: GREEN; Mode of pathogenicity: None; Publications: 12393540, 16195396; Phenotypes: Afibrinogenaemia, congenital, MIM# 202400, Hypofibrinogenaemia, congenital, MIM# 202400, Dysfibrinogenaemia, congenital, MIM# 616004; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7766 F9 Zornitza Stark Publications for gene: F9 were set to
Mendeliome v0.7764 F9 Zornitza Stark reviewed gene: F9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19846852, 34015304, 33656538; Phenotypes: Haemophilia B, MIM# 306900, Thrombophilia, X-linked, due to factor IX defect, MIM# 300807; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7763 F8 Zornitza Stark Publications for gene: F8 were set to
Mendeliome v0.7761 F8 Zornitza Stark reviewed gene: F8: Rating: GREEN; Mode of pathogenicity: None; Publications: 2986011, 3097553; Phenotypes: Haemophilia A, MIM# 306700, MONDO:0010602; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7760 F7 Zornitza Stark Publications for gene: F7 were set to
Mendeliome v0.7758 F7 Zornitza Stark reviewed gene: F7: Rating: GREEN; Mode of pathogenicity: None; Publications: 12181036; Phenotypes: Factor VII deficiency, MIM# 227500, MONDO:0009211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7756 F5 Zornitza Stark reviewed gene: F5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Factor V deficiency, MIM# 227400, MONDO:0009210, Thrombophilia due to activated protein C resistance, MIM# 188055, MONDO:0008560, {Thrombophilia, susceptibility to, due to factor V Leiden}, MIM# 188055; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7755 F13A1 Zornitza Stark Publications for gene: F13A1 were set to
Mendeliome v0.7753 F13A1 Zornitza Stark reviewed gene: F13A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1644910, 7727776, 10027709, 33802692, 32060721; Phenotypes: Factor XIIIA deficiency, MIM# 613225, MONDO:0013187; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7752 F10 Zornitza Stark Publications for gene: F10 were set to
Mendeliome v0.7750 F10 Zornitza Stark reviewed gene: F10: Rating: GREEN; Mode of pathogenicity: None; Publications: 2790181, 2567188, 10746568, 12028042; Phenotypes: Factor X deficiency, MIM# 227600, MONDO:0009212; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7749 MCM7 Arina Puzriakova gene: MCM7 was added
gene: MCM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM7 were set to 33654309; 34059554
Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability; Lipodystrophy; Adrenal insufficiency
Review for gene: MCM7 was set to AMBER
Added comment: MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. MCM7 is not associated with any phenotype in OMIM or G2P at present.
------
Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (see below). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families.

- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment.
Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.

- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Sources: Literature
Mendeliome v0.7748 DTNBP1 Zornitza Stark Publications for gene: DTNBP1 were set to
Mendeliome v0.7746 DTNBP1 Zornitza Stark reviewed gene: DTNBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12923531, 23364359, 28259707, 30990103; Phenotypes: Hermansky-Pudlak syndrome 7, MIM# 614076, MONDO:0013559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7745 BLOC1S3 Zornitza Stark Publications for gene: BLOC1S3 were set to
Mendeliome v0.7743 BLOC1S3 Zornitza Stark reviewed gene: BLOC1S3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16385460, 22709368, 32687635; Phenotypes: Hermansky-Pudlak syndrome 8, MIM# 614077, MONDO:0013560; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7742 AP3B1 Zornitza Stark Publications for gene: AP3B1 were set to
Mendeliome v0.7740 AP3B1 Zornitza Stark reviewed gene: AP3B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10024875, 11809908, 14566336; Phenotypes: Hermansky-Pudlak syndrome 2, MIM# 608233, MONDO:0011997; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7739 LHCGR Zornitza Stark Publications for gene: LHCGR were set to
Mendeliome v0.7737 NEB Zornitza Stark Publications for gene: NEB were set to 25205138
Mendeliome v0.7735 NEB Zornitza Stark reviewed gene: NEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 10051637, 22367672, 26578207, 33376055; Phenotypes: Arthrogryposis multiplex congenita 6, MIM# 619334; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7735 LHCGR Ain Roesley reviewed gene: LHCGR: Rating: GREEN; Mode of pathogenicity: None; Publications: 11041448; Phenotypes: Luteinizing hormone resistance, female, (MIM#238320), Leydig cell hypoplasia with pseudohermaphroditism, (MIM#238320), Leydig cell hypoplasia with hypergonadotropic hypogonadism, (MIM#238320), Precocious puberty, male, (MIM#176410); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7734 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy. 30 individuals from 22 unrelated families reported.
Sources: Literature
Mendeliome v0.7732 ANO6 Zornitza Stark Publications for gene: ANO6 were set to
Mendeliome v0.7730 ANO6 Zornitza Stark reviewed gene: ANO6: Rating: GREEN; Mode of pathogenicity: None; Publications: 21107324, 11895776, 27879994, 27634832; Phenotypes: Scott syndrome, MIM# 262890, MONDO:0009885; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7729 KLHL3 Zornitza Stark Publications for gene: KLHL3 were set to
Mendeliome v0.7727 KLHL3 Zornitza Stark reviewed gene: KLHL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22266938, 22406640, 24821705, 34022862, 32462939; Phenotypes: Pseudohypoaldosteronism, type IID, MIM# 614495; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7726 KCNJ5 Zornitza Stark gene: KCNJ5 was added
gene: KCNJ5 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KCNJ5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ5 were set to 21311022; 22203740; 24420545; 24574546
Phenotypes for gene: KCNJ5 were set to Hyperaldosteronism, familial, type III, MIM# 613677
Review for gene: KCNJ5 was set to GREEN
Added comment: Association with hyperaldosteronism: At least 5 unrelated families reported.

Association with Long QT: disputed.
Sources: Expert Review
Mendeliome v0.7724 HSD11B2 Zornitza Stark Publications for gene: HSD11B2 were set to
Mendeliome v0.7722 HSD11B2 Zornitza Stark reviewed gene: HSD11B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7670488, 9683587, 17314322; Phenotypes: Apparent mineralocorticoid excess, MIM# 218030, MONDO:0009025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7721 CLCN2 Zornitza Stark Publications for gene: CLCN2 were set to
Mendeliome v0.7719 CLCN2 Zornitza Stark reviewed gene: CLCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29403011, 29403012, 23707145; Phenotypes: Leukoencephalopathy with ataxia, MIM# 615651, Hyperaldosteronism, familial, type II, MIM# 605635; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7718 CACNA1D Zornitza Stark Publications for gene: CACNA1D were set to
Mendeliome v0.7716 CACNA1D Zornitza Stark reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 23913001, 32336187, 30698561, 21131953, 15357422, 22678062; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474, MONDO:0014200, Sinoatrial node dysfunction and deafness, MIM# 614896; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7715 CACNA1H Zornitza Stark Publications for gene: CACNA1H were set to
Mendeliome v0.7713 CACNA1H Zornitza Stark reviewed gene: CACNA1H: Rating: GREEN; Mode of pathogenicity: None; Publications: 27729216, 25907736, 31126930; Phenotypes: Hyperaldosteronism, familial, type IV MIM#617027, MONDO:0014875; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7712 COX16 Zornitza Stark reviewed gene: COX16: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 22, MIM# 619355; Mode of inheritance: None
Mendeliome v0.7711 IPO8 Zornitza Stark Publications for gene: IPO8 were set to
Mendeliome v0.7709 IPO8 Zornitza Stark edited their review of gene: IPO8: Changed rating: GREEN; Changed publications: 34010604
Mendeliome v0.7708 NFU1 Zornitza Stark Publications for gene: NFU1 were set to
Mendeliome v0.7706 NFU1 Zornitza Stark reviewed gene: NFU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21944046, 22077971, 32747156, 29441221; Phenotypes: Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7705 RAB11B Zornitza Stark Publications for gene: RAB11B were set to
Mendeliome v0.7703 RAB11B Zornitza Stark reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter 617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7702 UFSP2 Zornitza Stark Publications for gene: UFSP2 were set to
Mendeliome v0.7700 KLHL13 Zornitza Stark gene: KLHL13 was added
gene: KLHL13 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLHL13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: KLHL13 were set to 24627108
Phenotypes for gene: KLHL13 were set to HMSN
Review for gene: KLHL13 was set to RED
Added comment: Single family (two affected males) with an inherited peripheral neuropathy, no functional analysis.
Sources: Expert Review
Mendeliome v0.7698 PRX Zornitza Stark Publications for gene: PRX were set to
Mendeliome v0.7696 PRX Zornitza Stark reviewed gene: PRX: Rating: GREEN; Mode of pathogenicity: None; Publications: 11133365, 11157804, 15197604, 21079185, 22847150, 10839370, 32460404, 31523542, 31426691; Phenotypes: Charcot-Marie-Tooth disease, type 4F, MIM# 614895, Dejerine-Sottas disease, MIM# 145900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7695 PLEKHG5 Zornitza Stark Publications for gene: PLEKHG5 were set to
Mendeliome v0.7693 PLEKHG5 Zornitza Stark reviewed gene: PLEKHG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564964, 23777631, 23844677, 33492783, 33275839, 33220101, 23777631; Phenotypes: Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376, Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7692 NEFL Zornitza Stark Publications for gene: NEFL were set to
Mendeliome v0.7690 NEFL Zornitza Stark reviewed gene: NEFL: Rating: GREEN; Mode of pathogenicity: None; Publications: 10841809, 12393795, 14733962, 24887401, 25877835, 20039262, 12566280, 29191368, 28902413; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate G, MIM# 617882, Charcot-Marie-Tooth disease, type 1F, MIM# 607734, Charcot-Marie-Tooth disease, type 2E 607684; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7689 ADNP Zornitza Stark Publications for gene: ADNP were set to
Mendeliome v0.7687 ADNP Zornitza Stark reviewed gene: ADNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 24531329, 25057125, 25533962, 29724491; Phenotypes: Helsmoortel-van der Aa syndrome MIM#615873, MONDO:0014379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7687 ADNP Elena Savva reviewed gene: ADNP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29911927; Phenotypes: Helsmoortel-van der Aa syndrome MIM#615873; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7686 CHUK Zornitza Stark Publications for gene: CHUK were set to
Mendeliome v0.7683 CHUK Zornitza Stark reviewed gene: CHUK: Rating: AMBER; Mode of pathogenicity: None; Publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979; Phenotypes: Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339, Cocoon syndrome, MIM# 613630, AEC-like syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7682 TMEM251 Zornitza Stark reviewed gene: TMEM251: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dysostosis multiplex, Ain-Naz type 619345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7680 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PARP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Mendeliome v0.7678 MAPKBP1 Zornitza Stark Publications for gene: MAPKBP1 were set to
Mendeliome v0.7676 MAPKBP1 Zornitza Stark reviewed gene: MAPKBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28089251, 33623699, 32505465, 32055034; Phenotypes: Nephronophthisis 20, MIM# 617271, MONDO:0014997; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7674 DNAJB2 Zornitza Stark Publications for gene: DNAJB2 were set to
Mendeliome v0.7672 DNAJB2 Zornitza Stark reviewed gene: DNAJB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22522442, 25274842, 33369814, 22522442; Phenotypes: Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881, MONDO:0014866; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7671 ATP7A Zornitza Stark Publications for gene: ATP7A were set to 21221114
Mendeliome v0.7670 ATP7A Zornitza Stark reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20170900, 33137485, 31969342, 31558336; Phenotypes: Menkes disease MIM#309400, Occipital horn syndrome MIM#304150, Spinal muscular atrophy, distal, X-linked 3, MIM# 300489; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7670 UFSP2 Zornitza Stark edited their review of gene: UFSP2: Changed publications: 33473208, 26428751, 28892125, 32755715
Mendeliome v0.7670 UFSP2 Zornitza Stark reviewed gene: UFSP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33473208, 26428751, 28892125; Phenotypes: Neurodevelopmental disorder, Hip dysplasia, Beukes type, MIM#142669, Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7669 TRPV6 Zornitza Stark Publications for gene: TRPV6 were set to
Mendeliome v0.7667 TRPV6 Zornitza Stark reviewed gene: TRPV6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32383311, 31930989, 29861107; Phenotypes: Hyperparathyroidism, transient neonatal, MIM# 618188, Early onset chronic pancreatitis susceptibility; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7667 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; spastic paraparesis and bilateral cataracts to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Cataracts, spastic paraparesis, and speech delay, MIM#619338
Mendeliome v0.7666 FAR1 Zornitza Stark edited their review of gene: FAR1: Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, Cataracts, spastic paraparesis, and speech delay, MIM#619338
Mendeliome v0.7665 CLDN11 Zornitza Stark reviewed gene: CLDN11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomyelinating leukodystrophy-22, MIM#619328; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7664 BICRA Zornitza Stark reviewed gene: BICRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coffin-Siris syndrome-12, MIM#619325; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7663 RETREG1 Zornitza Stark Publications for gene: RETREG1 were set to
Mendeliome v0.7661 RETREG1 Zornitza Stark reviewed gene: RETREG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19838196, 24327336, 31737055, 31596031; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, MIM# 613115, MONDO:0013142; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7660 SBF1 Zornitza Stark Publications for gene: SBF1 were set to
Mendeliome v0.7658 SBF1 Zornitza Stark reviewed gene: SBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23749797, 23749797, 32444983, 30039846, 28005197; Phenotypes: Charcot-Marie-Tooth disease, type 4B3 , MIM#615284, MONDO:0014117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7657 SBF2 Zornitza Stark Publications for gene: SBF2 were set to
Mendeliome v0.7655 SBF2 Zornitza Stark reviewed gene: SBF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12554688, 15477569, 12687498, 15304601, 31772832, 31070812; Phenotypes: Charcot-Marie-Tooth disease, type 4B2 , MIM#604563; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7654 SCN10A Zornitza Stark Publications for gene: SCN10A were set to
Mendeliome v0.7652 SCN10A Zornitza Stark reviewed gene: SCN10A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23115331, 33775738, 30731422, 30554136; Phenotypes: Episodic pain syndrome, familial, 2, MIM# 615551; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7652 KCNA2 Elena Savva reviewed gene: KCNA2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33802230, 29050392; Phenotypes: Developmental and epileptic encephalopathy 32, MIM#616366; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7652 MYCN Kristin Rigbye reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21224895, 8470948; Phenotypes: Feingold syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7650 COL5A1 Zornitza Stark Publications for gene: COL5A1 were set to
Mendeliome v0.7648 COL5A1 Zornitza Stark reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 32938213; Phenotypes: Ehlers-Danlos syndrome, classic type, 1, MIM# 130000, Fibromuscular dysplasia, multifocal, MIM# 619329; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7646 KDM4B Zornitza Stark reviewed gene: KDM4B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 65, MIM# 619320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7645 DKC1 Zornitza Stark Publications for gene: DKC1 were set to
Mendeliome v0.7643 DKC1 Zornitza Stark reviewed gene: DKC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31269755, 26951492, 29081935, 25940403; Phenotypes: Dyskeratosis congenita, X-linked 305000, Hoyeraal-Hreidarsson Syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7642 THOC2 Zornitza Stark Publications for gene: THOC2 were set to
Mendeliome v0.7639 FGA Zornitza Stark Publications for gene: FGA were set to
Mendeliome v0.7637 THOC2 Paul De Fazio reviewed gene: THOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26166480, 32116545, 29851191, 32960281; Phenotypes: Mental retardation, X-linked 12/35 MIM#300957; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.7637 FGA Chern Lim reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31064749, 17295221, 19073821, 11739173; Phenotypes: Afibrinogenemia, congenital (MIM#202400), AR, Amyloidosis, familial visceral (MIM#105200), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.7636 GRHL2 Zornitza Stark Publications for gene: GRHL2 were set to
Mendeliome v0.7634 GRHL2 Zornitza Stark reviewed gene: GRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152456, 29499165; Phenotypes: Ectodermal dysplasia/short stature syndrome MIM#616029, Corneal dystrophy, posterior polymorphous, 4, MIM# 618031, Deafness, autosomal dominant 28, MIM# 608641; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7633 ST14 Zornitza Stark Publications for gene: ST14 were set to
Mendeliome v0.7631 ST14 Zornitza Stark reviewed gene: ST14: Rating: GREEN; Mode of pathogenicity: None; Publications: 18843291, 29611532, 17273967; Phenotypes: Ichthyosis, congenital, autosomal recessive 11 MIM#602400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7630 CPE Zornitza Stark gene: CPE was added
gene: CPE was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Review for gene: CPE was set to AMBER
Added comment: Four affected individuals from two unrelated families reported, bi-allelic LoF variants.
Sources: Expert Review
Mendeliome v0.7628 CELSR1 Zornitza Stark gene: CELSR1 was added
gene: CELSR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELSR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELSR1 were set to 31215153; 31403174; 26855770
Phenotypes for gene: CELSR1 were set to Lymphatic malformation 9, MIM# 619319
Review for gene: CELSR1 was set to GREEN
Added comment: 3 unrelated families reported.
Sources: Literature
Mendeliome v0.7625 SLCO1B1 Zornitza Stark Publications for gene: SLCO1B1 were set to
Mendeliome v0.7623 SLC2A4RG Melanie Marty reviewed gene: SLC2A4RG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.7623 SLCO1B1 Dean Phelan reviewed gene: SLCO1B1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 30250148, 24918167; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7622 SIAH1 Zornitza Stark reviewed gene: SIAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Buratti-Harel syndrome, MIM# 619314; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7621 SMARCA5 Zornitza Stark gene: SMARCA5 was added
gene: SMARCA5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to Neurodevelopmental disorder; microcephaly; dysmorphic features
Review for gene: SMARCA5 was set to GREEN
Added comment: 12 individuals reported with either de novo or appropriately segregating variants in this gene and mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Functional data supports gene-disease association.
Sources: Literature
Mendeliome v0.7618 FBXW7 Elena Savva reviewed gene: FBXW7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33057194; Phenotypes: FBXW7-related neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7617 LEMD2 Zornitza Stark reviewed gene: LEMD2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Marbach-Rustad progeroid syndrome, OMIM# 619322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7617 SEPT9 Zornitza Stark Publications for gene: SEPT9 were set to
Mendeliome v0.7615 SEPT9 Zornitza Stark edited their review of gene: SEPT9: Added comment: Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant form of recurrent focal neuropathy characterized clinically by acute, recurrent episodes of brachial plexus neuropathy with muscle weakness and atrophy preceded by severe pain in the affected arm. Multiple founder variants, including p.Arg88Trp. Also note intragenic duplication and 5'UTR variant reported, which may not be detectable by all NGS assays.; Changed publications: 16186812, 19451530, 19939853, 19139049
Mendeliome v0.7614 SLC5A7 Zornitza Stark Publications for gene: SLC5A7 were set to
Mendeliome v0.7612 SLC5A7 Zornitza Stark reviewed gene: SLC5A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 23141292, 15173594, 29782645, 29582019, 27569547, 29189923, 30172469; Phenotypes: Neuronopathy, distal hereditary motor, type VIIA, MIM# 158580, MONDO:0008024, Myasthenic syndrome, congenital, 20, presynaptic, MIM# 617143; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7610 NR3C2 Zornitza Stark Publications for gene: NR3C2 were set to
Mendeliome v0.7608 NR3C2 Zornitza Stark reviewed gene: NR3C2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9662404, 11134129, 11344206, 12788847, 16972228; Phenotypes: Pseudohypoaldosteronism type I, autosomal dominant, MIM# 177735, MONDO:0008329; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7607 SCNN1A Zornitza Stark Publications for gene: SCNN1A were set to
Mendeliome v0.7605 SCNN1A Zornitza Stark reviewed gene: SCNN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31301676, 28710092, 19462466, 19017867; Phenotypes: Liddle syndrome 3 618126, MIM# AD, MONDO:0029132, Bronchiectasis with or without elevated sweat chloride 2, MIM# 613021 AD, MONDO:0013087, Pseudohypoaldosteronism, type I, MIM# 264350 AR, MIM#0009917; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7604 SPTLC1 Zornitza Stark Publications for gene: SPTLC1 were set to
Mendeliome v0.7601 SPTLC2 Zornitza Stark Publications for gene: SPTLC2 were set to
Mendeliome v0.7599 ZPR1 Zornitza Stark gene: ZPR1 was added
gene: ZPR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies 619321
Review for gene: ZPR1 was set to RED
Added comment: 3 families reported with growth restriction, hypoplastic kidneys, alopecia, and distinctive facies (GKAF). All were Hispanic families from the middle Rio Grande Valley. Homozygous missense identified in one family, p. Ile196Thr. Others unavailable for testing, founder effect postulated.
Sources: Literature
Mendeliome v0.7597 SPEN Zornitza Stark Publications for gene: SPEN were set to 33057194
Mendeliome v0.7596 SPEN Zornitza Stark reviewed gene: SPEN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Radio-Tartaglia syndrome, MIM# 619312; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7595 AFF3 Zornitza Stark Publications for gene: AFF3 were set to
Mendeliome v0.7593 AFF3 Zornitza Stark reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31388108, 33961779; Phenotypes: KINSSHIP syndrome, MIM# 619297; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7592 KDR Zornitza Stark Publications for gene: KDR were set to
Mendeliome v0.7590 KDR Zornitza Stark reviewed gene: KDR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31980491, 29650961, 18931684; Phenotypes: Pulmonary hypertension, Haemangioma, capillary infantile, somatic 602089; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7589 TRIM2 Zornitza Stark Publications for gene: TRIM2 were set to
Mendeliome v0.7587 TRIM2 Zornitza Stark reviewed gene: TRIM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23562820, 25893792, 18687884, 32815244, 32205255, 25893792; Phenotypes: Charcot-Marie-Tooth disease, type 2R, MIM# 615490, MONDO:0014208; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7586 RAB7A Zornitza Stark Publications for gene: RAB7A were set to
Mendeliome v0.7584 RAB7A Zornitza Stark reviewed gene: RAB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 12545426, 17060578, 32326241, 29130394, 25614874; Phenotypes: Charcot-Marie-Tooth disease, type 2B, MIM# 600882, MONDO:0010949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7583 PRDM12 Zornitza Stark Publications for gene: PRDM12 were set to
Mendeliome v0.7581 PRDM12 Zornitza Stark reviewed gene: PRDM12: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005867, 33789102, 33010785, 32828702; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VIII, MIM# 616488, MONDO:0014662; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7580 FIP1L1 Zornitza Stark reviewed gene: FIP1L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7578 THBS2 Zornitza Stark reviewed gene: THBS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Lumbar disc herniation, susceptibility to} 603932; Mode of inheritance: None
Mendeliome v0.7577 ADIPOQ Zornitza Stark Publications for gene: ADIPOQ were set to
Mendeliome v0.7574 INTU Zornitza Stark Publications for gene: INTU were set to
Mendeliome v0.7572 ADIPOQ Chern Lim reviewed gene: ADIPOQ: Rating: RED; Mode of pathogenicity: None; Publications: 10918532, 32685557, 33075772, 30574262; Phenotypes: Adiponectin deficiency MIM#612556; Mode of inheritance: None
Mendeliome v0.7572 INTU Elena Savva reviewed gene: INTU: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27158779, 29451301, 20067783; Phenotypes: ?Orofaciodigital syndrome XVII MIM#617926, ?Short-rib thoracic dysplasia 20 with polydactyly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7571 NGF Zornitza Stark Publications for gene: NGF were set to
Mendeliome v0.7569 NGF Zornitza Stark reviewed gene: NGF: Rating: GREEN; Mode of pathogenicity: None; Publications: 14976160, 20978020, 33884296, 32693191, 31685654, 30296891; Phenotypes: Neuropathy, hereditary sensory and autonomic, type V, MIM# 608654, MONDO:0012092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7568 SPEG Zornitza Stark Publications for gene: SPEG were set to 25087613; 31625632; 30412272; 30157964; 29614691; 29474540; 28624463; 26578207; 25087613
Mendeliome v0.7567 SPEG Zornitza Stark edited their review of gene: SPEG: Added comment: PMIDs 32925938;33794647: Reports of early onset isolated DCM, as well as cardiomyopathy in the context of skeletal myopathy.; Changed publications: 25087613, 31625632, 30412272, 30157964, 29614691, 29474540, 28624463, 26578207, 25087613, 32925938, 33794647; Changed phenotypes: Centronuclear myopathy 5, MIM# 615959, Dilated cardiomyopathy
Mendeliome v0.7566 NDUFB3 Zornitza Stark Publications for gene: NDUFB3 were set to
Mendeliome v0.7564 NDUFB3 Zornitza Stark reviewed gene: NDUFB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27091925; Phenotypes: Mitochondrial complex I deficiency, nuclear type 25, MIM# 618246, MONDO:0032629; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7564 NDUFB3 Elena Savva reviewed gene: NDUFB3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22499348; Phenotypes: Mitochondrial complex I deficiency, nuclear type 25, MIM#618246; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7560 CAPN15 Zornitza Stark Publications for gene: CAPN15 were set to 32885237
Mendeliome v0.7559 CAPN15 Zornitza Stark reviewed gene: CAPN15: Rating: GREEN; Mode of pathogenicity: None; Publications: 33410501; Phenotypes: Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318, microphthalmia HP:0000568, coloboma HP:0000589; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7557 SPI1 Zornitza Stark gene: SPI1 was added
gene: SPI1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPI1 were set to 33951726
Phenotypes for gene: SPI1 were set to Agammaglobulinaemia
Review for gene: SPI1 was set to GREEN
Added comment: Six unrelated individuals reported, four with de novo variants, two unphased. Some functional data.
Sources: Literature
Mendeliome v0.7555 NDRG1 Zornitza Stark Publications for gene: NDRG1 were set to
Mendeliome v0.7553 NDRG1 Zornitza Stark reviewed gene: NDRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10831399, 24136616, 33334662, 29724652, 29174527, 28776325; Phenotypes: Charcot Marie Tooth disease, type 4D, 601455, MONDO:0011085, Auditory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7552 MTMR2 Zornitza Stark Publications for gene: MTMR2 were set to 10802647; 16249189; 33653949; 32586600; 32488727; 31680794
Mendeliome v0.7552 MTMR2 Zornitza Stark Publications for gene: MTMR2 were set to
Mendeliome v0.7550 MTMR2 Zornitza Stark reviewed gene: MTMR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10802647, 16249189, 33653949, 32586600, 32488727, 31680794; Phenotypes: Charcot-Marie-Tooth disease, type 4B1, 601382, MONDO:0011066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7549 TMEM222 Zornitza Stark gene: TMEM222 was added
gene: TMEM222 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants. The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17.
Sources: Literature
Mendeliome v0.7547 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability; Epilepsy
Review for gene: CHD5 was set to GREEN
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Mendeliome v0.7545 MME Zornitza Stark Publications for gene: MME were set to
Mendeliome v0.7543 MME Zornitza Stark reviewed gene: MME: Rating: GREEN; Mode of pathogenicity: None; Publications: 26991897, 27588448, 33144514, 31429185, 27583304; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2T, MIM# 617017, MONDO:0014866, Spinocerebellar ataxia 43 MIM#617018; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7541 FBXO31 Zornitza Stark changed review comment from: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Sources: Expert list; to: AR intellectual disability: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Sources: Expert list
Mendeliome v0.7541 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP.; Changed rating: GREEN; Changed publications: 24623383, 33675180, 32989326; Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Spastic-dystonic cerebral palsy, de novo dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7540 RCAN1 Zornitza Stark gene: RCAN1 was added
gene: RCAN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RCAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RCAN1 were set to 33863784
Phenotypes for gene: RCAN1 were set to FSGS; proteinuria
Review for gene: RCAN1 was set to AMBER
Added comment: Two families reported, some functional data.
Sources: Literature
Mendeliome v0.7537 ZNFX1 Zornitza Stark gene: ZNFX1 was added
gene: ZNFX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNFX1 were set to 33872655; 33876776
Phenotypes for gene: ZNFX1 were set to Multisystem inflammation; susceptibility to viral infections
Review for gene: ZNFX1 was set to GREEN
Added comment: 15 individuals from 8 families reported with multi-system inflammation and susceptibility to viral infections.

In addition, four indviduals from two unrelated kindreds reported with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis.
Sources: Literature
Mendeliome v0.7535 STXBP3 Zornitza Stark gene: STXBP3 was added
gene: STXBP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STXBP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STXBP3 were set to 33891011
Phenotypes for gene: STXBP3 were set to Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation
Review for gene: STXBP3 was set to GREEN
Added comment: 10 individuals from 5 families reported.
Sources: Literature
Mendeliome v0.7533 IL21R Zornitza Stark Publications for gene: IL21R were set to
Mendeliome v0.7531 IL21R Zornitza Stark reviewed gene: IL21R: Rating: GREEN; Mode of pathogenicity: None; Publications: 33929673; Phenotypes: Immunodeficiency 56, MIM# 615207; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7527 VPS41 Zornitza Stark Publications for gene: VPS41 were set to 32808683
Mendeliome v0.7525 ANKRD17 Zornitza Stark Publications for gene: ANKRD17 were set to
Mendeliome v0.7520 LRSAM1 Zornitza Stark Publications for gene: LRSAM1 were set to
Mendeliome v0.7518 LRSAM1 Zornitza Stark reviewed gene: LRSAM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20865121, 22012984, 22781092, 27686364, 33568173, 33414056, 30996334; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2P, MIM# 614436, MONDO:0013753; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7517 LITAF Zornitza Stark Publications for gene: LITAF were set to
Mendeliome v0.7515 LITAF Zornitza Stark reviewed gene: LITAF: Rating: GREEN; Mode of pathogenicity: None; Publications: 12525712, 19541485, 23359569, 32665875, 28211240; Phenotypes: Charcot-Marie-Tooth disease, type 1C, MIM# 601098, MONDO:0010995; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7514 SLC3A1 Zornitza Stark Publications for gene: SLC3A1 were set to
Mendeliome v0.7512 SLC3A1 Zornitza Stark reviewed gene: SLC3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cystinuria, MIM# 220100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7511 LSM7 Bryony Thompson gene: LSM7 was added
gene: LSM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to DOI:https://doi.org/10.1016/j.xhgg.2021.100034
Phenotypes for gene: LSM7 were set to Leukodystrophy; foetal death
Review for gene: LSM7 was set to AMBER
Added comment: Homozygous variant (p.Asp41Asn) identified in a child with leukodystrophy and a homozygous variant (p.Arg69Pro) identified in an individual that died in utero. In vitro and in vivo (zebrafish) assays supporting pathogenicity of the 2 variants.
Sources: Literature
Mendeliome v0.7509 PTPN4 Bryony Thompson gene: PTPN4 was added
gene: PTPN4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability; developmental delay
Review for gene: PTPN4 was set to GREEN
Added comment: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Mendeliome v0.7508 SLC3A1 Michelle Torres reviewed gene: SLC3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25964309; Phenotypes: Cystinuria (MIM#220100) AD, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7508 WFS1 Zornitza Stark Publications for gene: WFS1 were set to 25211237
Mendeliome v0.7506 POLR3K Zornitza Stark gene: POLR3K was added
gene: POLR3K was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Hypomyelinating leukodystrophy-21, MIM#619310
Review for gene: POLR3K was set to AMBER
Added comment: Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes. Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life.
Sources: Expert Review
Mendeliome v0.7505 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: Wolfram syndrome 1, OMIM:222300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7504 SAG Zornitza Stark Publications for gene: SAG were set to
Mendeliome v0.7502 SAG Zornitza Stark reviewed gene: SAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 7670478, 9565049, 15234147, 28549094, 33047631; Phenotypes: Oguchi disease-1, MIM# 258100, Retinitis pigmentosa 47, MIM# 613758; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7501 YWHAG Zornitza Stark Publications for gene: YWHAG were set to
Mendeliome v0.7499 IL6ST Zornitza Stark Publications for gene: IL6ST were set to 28747427; 30309848; 12370259; 16041381; 31914175; 32207811
Mendeliome v0.7497 OCRL Zornitza Stark Publications for gene: OCRL were set to
Mendeliome v0.7495 OCRL Zornitza Stark reviewed gene: OCRL: Rating: GREEN; Mode of pathogenicity: None; Publications: 15627218, 9199559; Phenotypes: Dent disease 2, MIM# 300555, Lowe syndrome , MIM#309000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7494 APOL1 Zornitza Stark Publications for gene: APOL1 were set to 29470556; 20647424; 24206458; 20635188
Mendeliome v0.7493 PDGFRB Zornitza Stark Phenotypes for gene: PDGFRB were changed from Premature aging syndrome, Penttinen type, 601812 to Basal ganglia calcification, idiopathic, 4, MIM# 615007; Kosaki overgrowth syndrome, MIM# 616592; Myeloproliferative disorder with eosinophilia, MIM# 131440; Myofibromatosis, infantile, 1, MIM# 228550; Premature ageing syndrome, Penttinen type, MIM# 601812
Mendeliome v0.7492 PDGFRB Zornitza Stark Publications for gene: PDGFRB were set to 30573803; 26279204
Mendeliome v0.7491 PDGFRB Zornitza Stark reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Basal ganglia calcification, idiopathic, 4, MIM# 615007, Kosaki overgrowth syndrome, MIM# 616592, Myeloproliferative disorder with eosinophilia, MIM# 131440, Myofibromatosis, infantile, 1, MIM# 228550, Premature ageing syndrome, Penttinen type, MIM# 601812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7491 YWHAG Ain Roesley reviewed gene: YWHAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 33393734, 33590706, 31926053, 33767733; Phenotypes: Developmental and epileptic encephalopathy 56, (MIMI#617665); Mode of inheritance: None
Mendeliome v0.7490 NEK1 Zornitza Stark Publications for gene: NEK1 were set to
Mendeliome v0.7488 NEK1 Zornitza Stark reviewed gene: NEK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21211617, 22499340, 25492405, 28123176; Phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520, Amyotrophic lateral sclerosis, susceptibility to, 24, MIM# 617892; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7488 IL6ST Eleanor Williams reviewed gene: IL6ST: Rating: ; Mode of pathogenicity: None; Publications: 33517393; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7488 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: Lowe syndrome, OMIM:309000; Mode of inheritance: None
Mendeliome v0.7488 APOL1 Eleanor Williams reviewed gene: APOL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33517446; Phenotypes: {Focal Segmental Glomerulosclerosis 4, Susceptibility to} OMIM:612551, {End-stage renal disease, nondiabetic, susceptibility to} OMIM:612551; Mode of inheritance: None
Mendeliome v0.7488 PDGFRB Eleanor Williams reviewed gene: PDGFRB: Rating: ; Mode of pathogenicity: None; Publications: 33450762; Phenotypes: Ocular pterygium-digital keloid dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7488 NEK1 Eleanor Williams reviewed gene: NEK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33445179; Phenotypes: {Amyotrophic lateral sclerosis, susceptibility to, 24}, OMIM:617892; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7487 INF2 Zornitza Stark Publications for gene: INF2 were set to
Mendeliome v0.7485 INF2 Zornitza Stark reviewed gene: INF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22187985, 30680856, 25943269, 20023659; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate E, MIM# 614455, Glomerulosclerosis, focal segmental, 5, MIM# 613237; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7485 MED25 Zornitza Stark Phenotypes for gene: MED25 were changed from to Basel-Vanagait-Smirin-Yosef syndrome, MIM# 616449; Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643
Mendeliome v0.7484 MED25 Zornitza Stark Publications for gene: MED25 were set to
Mendeliome v0.7482 MED25 Zornitza Stark reviewed gene: MED25: Rating: GREEN; Mode of pathogenicity: None; Publications: 25792360, 32816121; Phenotypes: Basel-Vanagait-Smirin-Yosef syndrome, MIM# 616449, Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7481 HSPB1 Zornitza Stark Publications for gene: HSPB1 were set to
Mendeliome v0.7479 HSPB1 Zornitza Stark reviewed gene: HSPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21785432, 15122254, 18832141, 32639100, 32334137; Phenotypes: Charcot Marie Tooth disease, axonal, type 2F, 606595, MONDO:0011687, Neuropathy, distal hereditary motor, type IIB, 608634, MONDO:0012080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7478 HINT1 Zornitza Stark Publications for gene: HINT1 were set to
Mendeliome v0.7476 HINT1 Zornitza Stark reviewed gene: HINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22961002, 33663550, 33404983, 31848916; Phenotypes: Neuromyotonia and axonal neuropathy, autosomal recessive, MIM# 137200, Gamstorp-Wohlfart syndrome, MONDO:0007646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7475 GNB4 Zornitza Stark Publications for gene: GNB4 were set to
Mendeliome v0.7473 GNB4 Zornitza Stark reviewed gene: GNB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23434117, 28642160, 27908631; Phenotypes: Charcot-Marie-Tooth disease, dominant intermediate F, MIM# 615185, MONDO:0014074; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7472 GJB1 Zornitza Stark Publications for gene: GJB1 were set to
Mendeliome v0.7470 NEPRO Chern Lim gene: NEPRO was added
gene: NEPRO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853
Review for gene: NEPRO was set to AMBER
Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant.

PMID 31250547: 1 family with homozygous novel missense

All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies.
Sources: Literature
Mendeliome v0.7470 GJB1 Zornitza Stark reviewed gene: GJB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8266101, 17100997, 17353473, 31842800; Phenotypes: Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM# 302800, MONDO:0010549, reversible posterior leukoencephalopathy; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7469 FGD4 Zornitza Stark Publications for gene: FGD4 were set to
Mendeliome v0.7467 FGD4 Zornitza Stark reviewed gene: FGD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564959, 31152969, 28847448, 28543957; Phenotypes: Charcot Marie Tooth disease, type 4H, 609311, MONDO:0012250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7466 COX6A1 Zornitza Stark Publications for gene: COX6A1 were set to
Mendeliome v0.7464 COX6A1 Zornitza Stark reviewed gene: COX6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152455, 26302975, 25152455; Phenotypes: Charcot Marie Tooth disease, recessive intermediate D, MIM# 616039, MONDO:0014467; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7464 JAG2 Belinda Chong gene: JAG2 was added
gene: JAG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAG2 were set to PMID: 33861953
Phenotypes for gene: JAG2 were set to muscular dystrophy
Review for gene: JAG2 was set to GREEN
Added comment: Whole-exome sequencing identified 13 families with rare homozygous or compound heterozygous JAG2 variants. Bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy.
Sources: Literature
Mendeliome v0.7464 ANKRD17 Paul De Fazio reviewed gene: ANKRD17: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909992; Phenotypes: Intellectual disability, speech delay, and dysmorphism; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.7464 VPS41 Kristin Rigbye changed review comment from: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function."; to: "Five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function."

"Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay. Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation. Likewise, nystagmus was commonly described. In addition, all affected individuals displayed intellectual disability and speech delay. Two siblings further presented with therapy-resistant epilepsy. No major dysmorphic features were found. In two individuals, retinal pigment alterations were noticed. Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals while in one case (Subject 9) bilateral hyperintensities at the nucleus caudatus area were noted. No hearing or vision problems were noted and in cases where nerve conduction studies were performed, these were normal. Transmission electron microscopy (TEM) on peripheral blood lymphocytes from Subject 2 and lymphoblastoid cells from Subject 3 revealed more multilayered vesicles compared to control cells."
Mendeliome v0.7464 SIN3B Elena Savva gene: SIN3B was added
gene: SIN3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIN3B were set to PMID: 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability/autism spectrum disorder
Review for gene: SIN3B was set to GREEN
Added comment: PMID: 33811806
- 9 affected patients, all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
- CNVs encompassing the gene have been found
Sources: Literature
Mendeliome v0.7464 DPYSL5 Michelle Torres gene: DPYSL5 was added
gene: DPYSL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Review for gene: DPYSL5 was set to GREEN
Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development
Sources: Literature
Mendeliome v0.7464 VPS41 Kristin Rigbye reviewed gene: VPS41: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33764426; Phenotypes: Progressive neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7464 SCD Elena Savva gene: SCD was added
gene: SCD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCD were set to PMID: 33690217; 10899171
Phenotypes for gene: SCD were set to Adrenoleukodystrophy
Review for gene: SCD was set to RED
Added comment: PMID: 33690217 zebrafish K/O mimics the motor phenotype of ALD zebrafish

PMID: 10899171 null mouse was deficient in hepatic cholesterol esters and triglycerides despite the presence of normal activities of acyl-CoA, very low levels of triglycerides
Sources: Literature
Mendeliome v0.7461 BICD2 Zornitza Stark Publications for gene: BICD2 were set to
Mendeliome v0.7459 BICD2 Zornitza Stark reviewed gene: BICD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23664116, 23664119, 23664120, 27751653, 28635954, 30054298, 29528393; Phenotypes: Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290, MONDO:0014121, Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7456 KCNQ5 Zornitza Stark Publications for gene: KCNQ5 were set to
Mendeliome v0.7454 KCNQ5 Zornitza Stark reviewed gene: KCNQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 28669405, 30359776; Phenotypes: Mental retardation, autosomal dominant 46, MIM# 617601; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7453 KCNK9 Zornitza Stark Publications for gene: KCNK9 were set to
Mendeliome v0.7451 KCNK9 Zornitza Stark reviewed gene: KCNK9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28333430, 27151206, 24980697, 18678320; Phenotypes: Birk-Barel syndrome, MIM# 612292, MONDO:0012856; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.7451 KCNK9 Ain Roesley reviewed gene: KCNK9: Rating: GREEN; Mode of pathogenicity: None; Publications: 18678320, 27151206; Phenotypes: Birk-Barel syndrome (MIM#612292); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.7449 ATL1 Zornitza Stark Publications for gene: ATL1 were set to
Mendeliome v0.7447 ATL1 Zornitza Stark reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21194679, 24604904, 22340599, 16401858, 16537571, 17657515, 28396731, 24473461, 26888483; Phenotypes: Neuropathy, hereditary sensory, type ID , MIM#613708, MONDO:0013381; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7446 COQ2 Zornitza Stark Publications for gene: COQ2 were set to
Mendeliome v0.7444 COQ2 Zornitza Stark reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16400613, 17332895, 17855635; Phenotypes: Coenzyme Q10 deficiency, primary, 1, MIM# 607426, MONDO:0011829; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7443 COA6 Zornitza Stark Publications for gene: COA6 were set to
Mendeliome v0.7441 COA6 Zornitza Stark reviewed gene: COA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24549041, 25339201, 31851937, 26160915; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 13, MIM# 616501, Cardioencephalomyopathy, fatal infantile, MONDO:0014668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7440 CARS2 Zornitza Stark Publications for gene: CARS2 were set to
Mendeliome v0.7438 CARS2 Zornitza Stark reviewed gene: CARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25361775, 25787132, 30139652; Phenotypes: Combined oxidative phosphorylation deficiency 27, MIM# 616672, MONDO:0014728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7435 SLX4 Zornitza Stark Publications for gene: SLX4 were set to
Mendeliome v0.7433 SLX4 Zornitza Stark reviewed gene: SLX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21240275, 21240277; Phenotypes: Fanconi anaemia, complementation group P, MIM# 613951, MONDO:0013499; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7433 NLRP2 Zornitza Stark Publications for gene: NLRP2 were set to 30877238
Mendeliome v0.7432 NLRP2 Sarah Leigh reviewed gene: NLRP2: Rating: ; Mode of pathogenicity: None; Publications: 19300480, 29574422, 33090377; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.7431 SGCE Zornitza Stark Publications for gene: SGCE were set to
Mendeliome v0.7429 SGCE Zornitza Stark reviewed gene: SGCE: Rating: GREEN; Mode of pathogenicity: None; Publications: 11528394, 12821748, 16227522; Phenotypes: Dystonia-11, myoclonic, MIM# 159900, MONDO:0008044; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.7428 PRKRA Zornitza Stark Publications for gene: PRKRA were set to
Mendeliome v0.7426 PRKRA Zornitza Stark reviewed gene: PRKRA: Rating: GREEN; Mode of pathogenicity: None; Publications: 18243799, 25142429, 29279192; Phenotypes: Dystonia 16, MIM# 612067, MONDO:0012789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7425 KMT2B Zornitza Stark Publications for gene: KMT2B were set to
Mendeliome v0.7423 KMT2B Zornitza Stark reviewed gene: KMT2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 27839873, 27992417; Phenotypes: Dystonia 28, childhood-onset 617284, MONDO:0015004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7422 CIZ1 Zornitza Stark Publications for gene: CIZ1 were set to
Mendeliome v0.7419 CIZ1 Zornitza Stark reviewed gene: CIZ1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27163549, 29154038, 22447717; Phenotypes: Dystonia 23 MIM#614860; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7418 NPAS2 Zornitza Stark Publications for gene: NPAS2 were set to
Mendeliome v0.7415 NPAS2 Alison Compton changed review comment from: The brothers with NOA from consanguineous Turkish family, homozygous NM_002518.3(NPAS2) c.1363C>G; p.(Pro455Ala) variant identified. Heterozygous in mother, and fertile brother and sister. Not present in 1000 Genomes, EVS or gnomAD. Predicted to be “benign” by Polyphen2, and "neutral" by both SIFT and Mutation taster. Not predicted to in a functional domain. Not listed as a disease-gene in OMIM, no other 'pathogenic' or 'likely pathogenic' variants listed in ClinVar. Paper did not include any functional work.; to: Three brothers with NOA from consanguineous Turkish family, homozygous NM_002518.3(NPAS2) c.1363C>G; p.(Pro455Ala) variant identified. Found to be heterozygous in mother, and fertile brother and sister. Not present in 1000 Genomes, EVS or gnomAD. Predicted to be “benign” by Polyphen2, and "neutral" by both SIFT and Mutation taster. Not predicted to be within a functional domain. Gene not listed as a disease-gene in OMIM, no other 'pathogenic' or 'likely pathogenic' variants listed in ClinVar. Publication did not include any functional work as support.
Mendeliome v0.7414 PNKD Zornitza Stark Publications for gene: PNKD were set to
Mendeliome v0.7412 PNKD Zornitza Stark reviewed gene: PNKD: Rating: GREEN; Mode of pathogenicity: None; Publications: 15262732, 15496428, 15824259, 19124534, 21487022; Phenotypes: Paroxysmal nonkinesigenic dyskinesia 1, MIM# 118800, MONDO:0007326; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7412 NPAS2 Alison Compton reviewed gene: NPAS2: Rating: RED; Mode of pathogenicity: Other; Publications: 25956372; Phenotypes: Non-obstructive azoospermia; Mode of inheritance: Unknown
Mendeliome v0.7411 MECR Zornitza Stark Publications for gene: MECR were set to
Mendeliome v0.7409 MECR Zornitza Stark reviewed gene: MECR: Rating: GREEN; Mode of pathogenicity: None; Publications: 27817865, 33401012, 31137067, 31070877; Phenotypes: Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282, MONDO:0015003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7408 HPCA Zornitza Stark Publications for gene: HPCA were set to
Mendeliome v0.7406 HPCA Zornitza Stark reviewed gene: HPCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25799108, 30991467, 30145809; Phenotypes: Dystonia 2, torsion, autosomal recessive, MIM# 224500, MONDO:0009141; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7405 GNAL Zornitza Stark Publications for gene: GNAL were set to
Mendeliome v0.7403 GNAL Zornitza Stark reviewed gene: GNAL: Rating: GREEN; Mode of pathogenicity: None; Publications: 23222958, 33175450, 32180288; Phenotypes: Dystonia 25, MIM# 615073, MONDO:0014033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7402 ADCY5 Zornitza Stark Publications for gene: ADCY5 were set to
Mendeliome v0.7400 ADCY5 Zornitza Stark reviewed gene: ADCY5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22782511, 24700542, 33051786, 32647899, 33704598; Phenotypes: Dyskinesia, familial, with facial myokymia, MIM# 606703, MONDO:0011707; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7399 XPNPEP3 Zornitza Stark edited their review of gene: XPNPEP3: Added comment: PMID 20179356: two families with 5 individuals reported. Functional data, including animal models, supportive evidence for involvement in ciliary function.

PMID 32660933: Additional case reported.; Changed rating: GREEN; Changed publications: 20179356, 32660933
Mendeliome v0.7398 THAP1 Zornitza Stark Publications for gene: THAP1 were set to
Mendeliome v0.7396 THAP1 Zornitza Stark reviewed gene: THAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21793105, 22377579; Phenotypes: Dystonia 6, torsion, 602629, MONDO:0011264; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7396 EIF4G1 Bryony Thompson Publications for gene: EIF4G1 were set to 21907011; 23408866; 25368108
Mendeliome v0.7394 CHST11 Zornitza Stark gene: CHST11 was added
gene: CHST11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CHST11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHST11 were set to 26436107; 29514872
Phenotypes for gene: CHST11 were set to Osteochondrodysplasia, brachydactyly, and overlapping malformed digits, MIM# 618167
Review for gene: CHST11 was set to AMBER
Added comment: Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum.

Two unrelated families reported, note one had a homozygous deletion. One family had 10 affected individuals.
Sources: Expert Review
Mendeliome v0.7391 PSMB8 Zornitza Stark Publications for gene: PSMB8 were set to
Mendeliome v0.7389 PSMB8 Zornitza Stark reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21129723, 21881205, 21852578, 21953331; Phenotypes: Proteasome-associated autoinflammatory syndrome 1, MIM# 256040, MONDO:0054698; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7389 EFEMP1 Zornitza Stark Publications for gene: EFEMP1 were set to 32006683; 31792352
Mendeliome v0.7388 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Added comment: PMID 33807164: third unrelated family reported with CTD phenotype, single affected individual with bi-alllelic LoF variant, cutis laxa and multiple herniations.; Changed publications: 32006683, 31792352, 33807164
Mendeliome v0.7387 PPARG Zornitza Stark Publications for gene: PPARG were set to
Mendeliome v0.7385 PPARG Zornitza Stark reviewed gene: PPARG: Rating: GREEN; Mode of pathogenicity: None; Publications: 10622252, 12453919, 11788685, 31863320; Phenotypes: Lipodystrophy, familial partial, type 3, MIM# 604367, MONDO:0011448; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7384 POLD1 Zornitza Stark Publications for gene: POLD1 were set to
Mendeliome v0.7382 POLD1 Zornitza Stark reviewed gene: POLD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23770608, 33618333, 33369179, 32826474, 30023403, 29199204, 28791128; Phenotypes: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381, MONDO:0014157; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7381 PLIN1 Zornitza Stark Publications for gene: PLIN1 were set to
Mendeliome v0.7378 PLIN1 Zornitza Stark reviewed gene: PLIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21345103, 31504636, 30020498, 25114292; Phenotypes: Lipodystrophy, familial partial, type 4, MIM# 613877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7377 PCYT1A Zornitza Stark Publications for gene: PCYT1A were set to
Mendeliome v0.7375 PCYT1A Zornitza Stark reviewed gene: PCYT1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24387990, 24387991, 24889630; Phenotypes: Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940, Congenital lipodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7375 KCNJ6 Zornitza Stark Publications for gene: KCNJ6 were set to 25620207
Mendeliome v0.7374 KCNJ6 Zornitza Stark edited their review of gene: KCNJ6: Changed publications: 25620207, 29852244
Mendeliome v0.7373 KCNJ6 Zornitza Stark Publications for gene: KCNJ6 were set to
Mendeliome v0.7371 KCNJ6 Zornitza Stark reviewed gene: KCNJ6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25620207; Phenotypes: Keppen-Lubinsky syndrome, MIM# 614098, MONDO:0013572; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7370 EIF4G1 Zornitza Stark Publications for gene: EIF4G1 were set to
Mendeliome v0.7367 EIF4G1 Zornitza Stark reviewed gene: EIF4G1: Rating: RED; Mode of pathogenicity: None; Publications: 21907011, 23408866, 25368108; Phenotypes: {Parkinson disease 18} 614251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7366 CIDEC Zornitza Stark Publications for gene: CIDEC were set to
Mendeliome v0.7363 CIDEC Zornitza Stark reviewed gene: CIDEC: Rating: RED; Mode of pathogenicity: None; Publications: 20049731; Phenotypes: Lipodystrophy, familial partial, type 5, MIM# 615238; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7363 SAG Teresa Zhao reviewed gene: SAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 22419846, 9452120; Phenotypes: Oguchi disease-1 (MIM#258100), AR, Retinitis pigmentosa 47 (MIM#613758); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7362 LIG3 Zornitza Stark gene: LIG3 was added
gene: LIG3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy
Review for gene: LIG3 was set to GREEN
Added comment: Three unrelated families and functional data.
Sources: Literature
Mendeliome v0.7360 HNRNPDL Bryony Thompson gene: HNRNPDL was added
gene: HNRNPDL was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HNRNPDL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPDL were set to 24647604; 31267206; 31995753; 32407983; 32904822; 32367994
Phenotypes for gene: HNRNPDL were set to Muscular dystrophy, limb-girdle, autosomal dominant 3 MIM#609115
Review for gene: HNRNPDL was set to GREEN
gene: HNRNPDL was marked as current diagnostic
Added comment: At least 5 families reported with either D378H/N, and supporting functional assays demonstrating that these variants affect protein function. No other pathogenic variants have been reported. A VUS has been reported (along with another SETX variant) in an individual with a multi-system disorder, including a metabolic myopathy.
Sources: Expert list
Mendeliome v0.7358 JMJD1C Zornitza Stark gene: JMJD1C was added
gene: JMJD1C was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JMJD1C were set to 26181491; 32996679
Phenotypes for gene: JMJD1C were set to Intellectual disability
Review for gene: JMJD1C was set to GREEN
Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity.

Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679).

Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype.
Sources: Expert Review
Mendeliome v0.7356 CAVIN1 Zornitza Stark Publications for gene: CAVIN1 were set to
Mendeliome v0.7354 CAVIN1 Zornitza Stark reviewed gene: CAVIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19726876, 20300641, 20684003, 18840361; Phenotypes: Lipodystrophy, congenital generalized, type 4, MIM# 613327, MONDO:0013225; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7353 CAV1 Zornitza Stark Publications for gene: CAV1 were set to
Mendeliome v0.7351 CAV1 Zornitza Stark reviewed gene: CAV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18237401, 25898808, 11739396, 18211975, 27717241, 26176221, 33836561, 33776068, 32502478, 22474227, 28768485; Phenotypes: Lipodystrophy, familial partial, type 7, autosomal dominant MIM# 606721, Lipodystrophy, congenital generalized, type 3, autosomal recessive, MIM# 612526; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7350 AFF4 Zornitza Stark Publications for gene: AFF4 were set to
Mendeliome v0.7348 AFF4 Zornitza Stark reviewed gene: AFF4: Rating: GREEN; Mode of pathogenicity: Other; Publications: 25730767, 33248856, 31630891, 31058441; Phenotypes: CHOPS syndrome, MIM#616368, MONDO:0014609; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7346 GCGR Zornitza Stark gene: GCGR was added
gene: GCGR was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GCGR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GCGR were set to 19657311; 25695890; 27933176; 30032256; 30294546
Phenotypes for gene: GCGR were set to Mahvash disease, MIM# 619290
Review for gene: GCGR was set to GREEN
Added comment: Mahvash disease (MVAH) is caused by inactivating mutations in the glucagon receptor, leading to alpha-cell hyperplasia of the pancreas, hyperglucagonaemia without glucagonoma syndrome, and occasional hypoglycaemia. The disease may lead to glucagonomas and/or primitive neuroectodermal tumours.

More than 5 unrelated families reported.
Sources: Expert list
Mendeliome v0.7344 VPS4A Zornitza Stark reviewed gene: VPS4A: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: CIMDAG syndrome MIM# 619273; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7344 MED27 Zornitza Stark Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286
Mendeliome v0.7343 MED27 Zornitza Stark reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, MIM# 619286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7342 ABCB6 Zornitza Stark Publications for gene: ABCB6 were set to
Mendeliome v0.7340 ABCB6 Zornitza Stark reviewed gene: ABCB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23180570; Phenotypes: Pseudohyperkalemia, familial, 2, due to red cell leak, MIM# 609153, Microphthalmia, isolated, with coloboma 7, MIM# 614497, Dyschromatosis universalis hereditaria 3, MIM# 615402; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7339 PRDM15 Zornitza Stark gene: PRDM15 was added
gene: PRDM15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM15 were set to 31950080
Phenotypes for gene: PRDM15 were set to Steroid resistant nephrotic syndrome; Holoprosencephaly
Review for gene: PRDM15 was set to AMBER
Added comment: Four consanguineous families reported with same homozygous variant, C844Y, shown to be LoF. Syndromic SRNS including HPE, brain malformations, polydactyly, congenital heart disease. Mouse model, extensive functional data focused on the brain phenotype. Two additional homozygous missense identified with isolated SRNS.
Sources: Literature
Mendeliome v0.7337 ZIC2 Zornitza Stark Publications for gene: ZIC2 were set to
Mendeliome v0.7335 ZIC2 Zornitza Stark reviewed gene: ZIC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9771712, 11285244; Phenotypes: Holoprosencephaly 5, MIM# 609637, MONDO:0012322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7334 TGIF1 Zornitza Stark Publications for gene: TGIF1 were set to
Mendeliome v0.7332 TGIF1 Zornitza Stark reviewed gene: TGIF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10835638, 16323008; Phenotypes: Holoprosencephaly 4, MIM# 142946, MONDO:0007734; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7331 SIX3 Zornitza Stark Publications for gene: SIX3 were set to
Mendeliome v0.7329 SIX3 Zornitza Stark reviewed gene: SIX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10369266, 16323008, 19346217; Phenotypes: Holoprosencephaly 2, MIM# 157170, MONDO:0007999; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7328 DISP1 Zornitza Stark Publications for gene: DISP1 were set to
Mendeliome v0.7325 DISP1 Zornitza Stark reviewed gene: DISP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19184110, 26748417, 23542665; Phenotypes: Holoprosencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7324 TBX3 Zornitza Stark Publications for gene: TBX3 were set to
Mendeliome v0.7322 TBX3 Zornitza Stark reviewed gene: TBX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9207801, 19938096, 28145909; Phenotypes: Ulnar-mammary syndrome, MIM# 181450, MONDO:0008411; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7320 SALL1 Zornitza Stark reviewed gene: SALL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Townes-Brocks syndrome 1, MIM#107480, MONDO:0054581; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7316 HELLS Zornitza Stark Publications for gene: HELLS were set to
Mendeliome v0.7314 HELLS Zornitza Stark reviewed gene: HELLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 26216346; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911, MONDO:0014829; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7313 ZBTB24 Zornitza Stark Publications for gene: ZBTB24 were set to
Mendeliome v0.7311 ZBTB24 Zornitza Stark reviewed gene: ZBTB24: Rating: GREEN; Mode of pathogenicity: None; Publications: 21596365, 21906047, 23486536; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 2, MIM# 614069, MONDO:0013553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7310 CDCA7 Zornitza Stark Publications for gene: CDCA7 were set to
Mendeliome v0.7308 CDCA7 Zornitza Stark reviewed gene: CDCA7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26216346; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 3, MIM# 616910, MONDO:0014828; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7307 XRCC4 Zornitza Stark reviewed gene: XRCC4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Short stature, microcephaly, and endocrine dysfunction, MIM# 616541, MONDO:0014686; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7306 XPC Zornitza Stark Publications for gene: XPC were set to
Mendeliome v0.7304 XPC Zornitza Stark reviewed gene: XPC: Rating: GREEN; Mode of pathogenicity: None; Publications: 10447254; Phenotypes: Xeroderma pigmentosum, group C, MIM# 278720, MONDO:0010211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7303 XPA Zornitza Stark Publications for gene: XPA were set to
Mendeliome v0.7301 XPA Zornitza Stark reviewed gene: XPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 2234061, 1372102; Phenotypes: Xeroderma pigmentosum, group A , MIM#278700, MONDO:0010210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7300 RMI2 Zornitza Stark Publications for gene: RMI2 were set to
Mendeliome v0.7297 RMI2 Zornitza Stark reviewed gene: RMI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27977684; Phenotypes: Bloom-like syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7296 RAD51 Zornitza Stark Publications for gene: RAD51 were set to
Mendeliome v0.7294 RAD51 Zornitza Stark reviewed gene: RAD51: Rating: GREEN; Mode of pathogenicity: None; Publications: 26253028, 26681308, 30907510; Phenotypes: Fanconi anaemia, complementation group R, MIM# 617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7293 POLH Zornitza Stark Publications for gene: POLH were set to
Mendeliome v0.7291 POLH Zornitza Stark reviewed gene: POLH: Rating: GREEN; Mode of pathogenicity: None; Publications: 10385124, 10398605; Phenotypes: Xeroderma pigmentosum, variant type, MIM# 278750, MONDO:0010214; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7290 NEUROD2 Zornitza Stark Publications for gene: NEUROD2 were set to 30323019
Mendeliome v0.7289 NEUROD2 Zornitza Stark edited their review of gene: NEUROD2: Added comment: Additional two individuals reported with de novo variants and predominantly ID phenotype.; Changed publications: 33438828, 30323019; Changed phenotypes: Epileptic encephalopathy, early infantile, 72, MIM# 618374
Mendeliome v0.7288 MRE11 Zornitza Stark Publications for gene: MRE11 were set to
Mendeliome v0.7286 MRE11 Zornitza Stark reviewed gene: MRE11: Rating: GREEN; Mode of pathogenicity: None; Publications: 10612394, 11371508, 15269180, 22863007, 24332946, 21227757; Phenotypes: Ataxia-telangiectasia-like disorder 1, MIM# 604391, MONDO:0024557; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7285 MPLKIP Zornitza Stark Publications for gene: MPLKIP were set to
Mendeliome v0.7283 MPLKIP Zornitza Stark reviewed gene: MPLKIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 15645389, 16977596; Phenotypes: Trichothiodystrophy 4, nonphotosensitive, MIM# 234050, MONDO:0021013; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7282 PIK3CD Zornitza Stark Publications for gene: PIK3CD were set to
Mendeliome v0.7280 PIK3CD Zornitza Stark reviewed gene: PIK3CD: Rating: GREEN; Mode of pathogenicity: None; Publications: 30040974, 30336224, 29180244, 16984281, 24136356, 24165795, 24610295; Phenotypes: Immunodeficiency 14B, autosomal recessive, MIM# 619281, Immunodeficiency 14A, autosomal dominant, MIM# 615513; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7279 GTF2H5 Zornitza Stark Publications for gene: GTF2H5 were set to
Mendeliome v0.7277 GTF2H5 Zornitza Stark reviewed gene: GTF2H5: Rating: GREEN; Mode of pathogenicity: None; Publications: 15220921, 30359777, 24986372; Phenotypes: Trichothiodystrophy 3, photosensitive, MIM# 616395, MONDO:0014619; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7276 GTF2E2 Zornitza Stark Publications for gene: GTF2E2 were set to
Mendeliome v0.7273 GTF2E2 Zornitza Stark reviewed gene: GTF2E2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26996949; Phenotypes: Trichothiodystrophy 6, nonphotosensitive, MIM# 616943, MONDO:0014841; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7272 FANCL Zornitza Stark Publications for gene: FANCL were set to
Mendeliome v0.7270 FANCL Zornitza Stark reviewed gene: FANCL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19405097, 25754594, 33394227, 33224012; Phenotypes: Fanconi anemia, complementation group L, MIM# 614083, MONDO:0013566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7269 FANCI Zornitza Stark Publications for gene: FANCI were set to
Mendeliome v0.7267 FANCI Zornitza Stark reviewed gene: FANCI: Rating: GREEN; Mode of pathogenicity: None; Publications: 17452773; Phenotypes: Fanconi anemia, complementation group I, MIM# 609053, MONDO:0012186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7266 FANCG Zornitza Stark Publications for gene: FANCG were set to
Mendeliome v0.7264 FANCG Zornitza Stark reviewed gene: FANCG: Rating: GREEN; Mode of pathogenicity: None; Publications: 9806548, 12552564; Phenotypes: Fanconi anaemia, complementation group G, MIM# 614082, MONDO:0013565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7263 FANCF Zornitza Stark Publications for gene: FANCF were set to
Mendeliome v0.7261 FANCF Zornitza Stark reviewed gene: FANCF: Rating: GREEN; Mode of pathogenicity: None; Publications: 10615118, 31288759; Phenotypes: Fanconi anaemia, complementation group F 603467, MONDO:0011325; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7260 FANCE Zornitza Stark Publications for gene: FANCE were set to
Mendeliome v0.7258 FANCE Zornitza Stark reviewed gene: FANCE: Rating: GREEN; Mode of pathogenicity: None; Publications: 11001585, 31586946, 7662964, 9382107, 9147877, 10205272; Phenotypes: Fanconi anaemia, complementation group E, MIM# 600901, MONDO:0010953; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7257 MDM2 Zornitza Stark Publications for gene: MDM2 were set to
Mendeliome v0.7254 MDM2 Chern Lim reviewed gene: MDM2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28846075; Phenotypes: ?Lessel-Kubisch syndrome (MIM#618681); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7251 NDUFB11 Zornitza Stark Publications for gene: NDUFB11 were set to
Mendeliome v0.7249 NDUFB11 Kristin Rigbye reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 28050600, 27488349, 30423443, 27488349; Phenotypes: Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952), Mitochondrial complex I deficiency, nuclear type 30, XLR (MIM#301021); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7248 FANCC Zornitza Stark Publications for gene: FANCC were set to
Mendeliome v0.7246 FANCC Zornitza Stark reviewed gene: FANCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 31044565, 30792206, 28717661; Phenotypes: Fanconi anemia, complementation group C, MIM# 227645, MONDO:0009213; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7245 MFAP5 Zornitza Stark Publications for gene: MFAP5 were set to
Mendeliome v0.7242 MFAP5 Zornitza Stark reviewed gene: MFAP5: Rating: AMBER; Mode of pathogenicity: None; Publications: 25434006, 30763214, 33807627, 33514025, 29524629; Phenotypes: Aortic aneurysm, familial thoracic MIM# 616166; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7241 FANCB Zornitza Stark Publications for gene: FANCB were set to
Mendeliome v0.7239 FANCB Zornitza Stark reviewed gene: FANCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 15502827; Phenotypes: Fanconi anaemia, complementation group B, MIM# 300514, MONDO:0010351; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7238 SMG8 Zornitza Stark reviewed gene: SMG8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alzahrani-Kuwahara syndrome, MIM# 619268; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7237 FANCA Zornitza Stark Publications for gene: FANCA were set to
Mendeliome v0.7235 FANCA Zornitza Stark reviewed gene: FANCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 10094191; Phenotypes: Fanconi anaemia, complementation group A, MIM# 227650, MONDO:0009215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7234 ERCC8 Zornitza Stark Publications for gene: ERCC8 were set to
Mendeliome v0.7232 ERCC8 Zornitza Stark reviewed gene: ERCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 7664335, 19894250; Phenotypes: Cockayne syndrome, type A, MIM# 216400, MONDO:0019569, UV-sensitive syndrome 2, MIM# 614621, MONDO:0013829; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7232 GP1BA Zornitza Stark Publications for gene: GP1BA were set to
Mendeliome v0.7229 GP1BA Zornitza Stark reviewed gene: GP1BA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS), von Willebrand disease, platelet-type, (MIM#177820), AD (VWD), MONDO:0008332, Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS), MONDO:0007930; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7229 GP1BA Ain Roesley reviewed gene: GP1BA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24934643; Phenotypes: Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS), von Willebrand disease, platelet-type, (MIM#177820), AD (VWD), Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7229 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 7951246, 9096355, 9096355, 24700531, 33766032, 33219753; Phenotypes: Cerebrooculofacioskeletal syndrome 3, MIM# 616570, MONDO:0014696, Xeroderma pigmentosum, group G, MIM# 278780, MONDO:0010216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7229 ERCC5 Zornitza Stark Publications for gene: ERCC5 were set to 30838033; 24700531
Mendeliome v0.7226 ERCC4 Zornitza Stark Publications for gene: ERCC4 were set to
Mendeliome v0.7224 ERCC4 Zornitza Stark reviewed gene: ERCC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23623386, 8797827, 23623389, 17183314, 29105242; Phenotypes: Fanconi anemia, complementation group Q, MIM# 615272, MONDO:0014108, Xeroderma pigmentosum, group F, MIM# 278760, MONDO:0010215, XFE progeroid syndrome, MIM# 610965, MONDO:0012590; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7223 ERCC3 Zornitza Stark Publications for gene: ERCC3 were set to
Mendeliome v0.7221 ERCC3 Zornitza Stark reviewed gene: ERCC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 2167179, 10447254, 16947863, 9012405, 32557569, 27004399; Phenotypes: Trichothiodystrophy 2, photosensitive, MIM# 616390, Xeroderma pigmentosum, group B 61, MIM#0651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7219 SDHA Zornitza Stark Publications for gene: SDHA were set to
Mendeliome v0.7217 SDHA Zornitza Stark reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: None; Publications: 10976639, 27683074, 7550341, 22972948, 20551992, 21752896; Phenotypes: Mitochondrial complex II deficiency, nuclear type 1, MIM# 252011, Cardiomyopathy, dilated, 1GG, MIM# 613642, Neurodegeneration with ataxia and late-onset optic atrophy, MIM# 619259, Paragangliomas 5 , MIM#614165; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7217 SLC19A1 Zornitza Stark gene: SLC19A1 was added
gene: SLC19A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A1 were set to 32276275
Phenotypes for gene: SLC19A1 were set to Megaloblastic anemia, folate-responsive, MIM# 601775
Review for gene: SLC19A1 was set to RED
Added comment: Single individual reported with in-frame deletion, some functional data.
Sources: Expert list
Mendeliome v0.7215 ERCC2 Zornitza Stark Publications for gene: ERCC2 were set to
Mendeliome v0.7213 ERCC2 Zornitza Stark reviewed gene: ERCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7849702, 9758621, 11443545, 33733458; Phenotypes: Cerebrooculofacioskeletal syndrome 2, MIM# 610756, MONDO:0012553, Trichothiodystrophy 1, photosensitive, MIM# 601675, MONDO:0011125, Xeroderma pigmentosum, group D, MIM# 278730, MONDO:0010212; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7212 ERCC1 Zornitza Stark edited their review of gene: ERCC1: Changed publications: 17273966, 23623389, 32557569, 26085086, 33315086
Mendeliome v0.7211 NDUFA8 Zornitza Stark Publications for gene: NDUFA8 were set to 32385911
Mendeliome v0.7209 NDUFA8 Zornitza Stark edited their review of gene: NDUFA8: Changed rating: AMBER; Changed publications: 32385911, 33153867; Changed phenotypes: Mitochondrial complex I deficiency, nuclear type 37, MIM# 619272, Developmental delay, microcehaly, seizures
Mendeliome v0.7208 RORC Zornitza Stark Publications for gene: RORC were set to 26160376
Mendeliome v0.7205 KCNH1 Zornitza Stark Publications for gene: KCNH1 were set to
Mendeliome v0.7203 KCNH1 Zornitza Stark reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Temple-Baraitser syndrome, OMIM:611816, Zimmermann-Laband syndrome 1, OMIM:135500, Intellectual disability, Encephalopathy without features of TBS/ZLS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7202 GREB1L Zornitza Stark Publications for gene: GREB1L were set to 29100091
Mendeliome v0.7201 GREB1L Zornitza Stark edited their review of gene: GREB1L: Added comment: DFNA80 is characterized by nonsyndromic congenital deafness associated with absent or malformed cochleae and eighth cranial nerves. Four unrelated families reported, no comment on a renal phenotype. Note variants in this gene are also associated with renal agenesis.; Changed publications: 29100091, 29955957, 32585897; Changed phenotypes: Renal hypodysplasia/aplasia 3, OMIM# 617805, Deafness, autosomal dominant 80, MIM# 619274
Mendeliome v0.7199 EMC10 Zornitza Stark edited their review of gene: EMC10: Added comment: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).; Changed rating: GREEN; Changed publications: 32869858, 33531666; Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264
Mendeliome v0.7198 ITGB3 Zornitza Stark Publications for gene: ITGB3 were set to
Mendeliome v0.7196 ITGB3 Zornitza Stark reviewed gene: ITGB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18065693, 19336737, 20081061, 23253071; Phenotypes: Bleeding disorder, platelet-type, 24, MIM#619271, MONDO:0008552; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7196 KRT8 Seb Lunke reviewed gene: KRT8: Rating: RED; Mode of pathogenicity: None; Publications: 15235035, 11372009, 12724528; Phenotypes: CIRRHOSIS, FAMILIAL, MIM #215600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.7196 HDAC4 Bryony Thompson Publications for gene: HDAC4 were set to 24715439; 20691407; 31209962; https://doi.org/10.1016/j.xhgg.2020.100015
Mendeliome v0.7195 HDAC4 Bryony Thompson edited their review of gene: HDAC4: Changed publications: 33537682
Mendeliome v0.7195 TMEM218 Bryony Thompson Publications for gene: TMEM218 were set to https://doi.org/10.1016/j.xhgg.2020.100016; 25161209
Mendeliome v0.7194 TMEM218 Bryony Thompson edited their review of gene: TMEM218: Changed publications: 33791682, 25161209
Mendeliome v0.7193 ADCY6 Zornitza Stark Publications for gene: ADCY6 were set to 24319099; 26257172; 31846058
Mendeliome v0.7192 ADCY6 Zornitza Stark edited their review of gene: ADCY6: Changed publications: 24319099, 26257172, 31846058, 33820833
Mendeliome v0.7191 UNC50 Arina Puzriakova gene: UNC50 was added
gene: UNC50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC50 were set to 29016857; 33820833
Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita
Review for gene: UNC50 was set to AMBER
Added comment: UNC50 is currently not associated with any phenotype in OMIM (last edited on 02/01/2018) or Gene2Phenotype.

- PMID: 29016857 (2017) - Homozygosity mapping of disease loci combined with WES in a single male from a consanguineous family presenting with lethal AMC revealed a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4). Functional studies in C. elegans showed the variant caused loss of acetylcholine receptor expression in the muscle.

- PMID: 33820833 (2021) - Single individual reported with the same homozygous c.750_751del:p.Cys251Phefs*4 variant in UNC50 as previously described. The case was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and tetra ventricular dilation were detected prenatally.

-- Note: it isn't definitively clear whether these are different individuals. Both are singleton males born to consanguineous parents, with the same variant and similar phenotype. Also both infants died at 28 w.g. However, the 2021 paper (PMID:33820833) states their patient was selected from a cohort of cases without a molecular diagnosis and indicate the UNC50 gene had already previously been identified in relation to this phenotype, highlighting the earlier paper (PMID:29016857). There is also no mention of tetra ventricular dilation in the first case, so it is likely that these do represent distinct individuals. Additional cases needed to provide clarity.
Sources: Literature
Mendeliome v0.7191 PLCH1 Arina Puzriakova gene: PLCH1 was added
gene: PLCH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLCH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCH1 were set to 33820834
Phenotypes for gene: PLCH1 were set to Holoprosencephaly spectrum; Severe developmental delay; Brain malformations
Review for gene: PLCH1 was set to AMBER
Added comment: PLCH1 is currently not associated with any phenotype in OMIM (last edited on 16/06/2009) or Gene2Phenotype.

- PMID: 33820834 (2021) - Two sibling pairs from two unrelated families with a holoprosencephaly spectrum phenotype and different homozygous PLCH1 variants (c.2065C>T, p.Arg689* and c.4235delA, p.Cys1079ValfsTer16, respectively). One family presented with congenital hydrocephalus, epilepsy, significant developmental delay and a monoventricle or fused thalami; while sibs from the second family had alobar holoprosencephaly and cyclopia. 3/4 individuals also displayed a cleft palate and congenital heart disease.
Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome.
Sources: Literature
Mendeliome v0.7190 DDX11 Zornitza Stark Publications for gene: DDX11 were set to
Mendeliome v0.7188 DDX11 Zornitza Stark reviewed gene: DDX11: Rating: GREEN; Mode of pathogenicity: None; Publications: 20137776, 23033317, 30216658; Phenotypes: Warsaw breakage syndrome, MIM# 613398, MONDO:0013252; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7186 EXOSC1 Zornitza Stark gene: EXOSC1 was added
gene: EXOSC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOSC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC1 were set to 33463720
Phenotypes for gene: EXOSC1 were set to Pontocerebellar hypoplasia
Review for gene: EXOSC1 was set to RED
Added comment: An 8‐months‐old male with developmental delay, microcephaly, subtle dysmorphism, hypotonia, pontocerebellar hypoplasia and delayed myelination. Similarly affected elder sibling succumbed at the age of 4‐years 6‐months. Exome sequencing revealed a homozygous missense variant (c.104C >T, p.Ser35Leu) in EXOSC1. In silico mutagenesis revealed loss of a polar contact with neighbouring Leu37 residue. Quantitative real‐time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. Of note, bi‐allelic variants in other exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively.
Sources: Literature
Mendeliome v0.7185 CACNA1H Paul De Fazio edited their review of gene: CACNA1H: Changed publications: 27729216, 25907736, 31126930, 16754686, 32571372
Mendeliome v0.7185 CACNA1H Paul De Fazio reviewed gene: CACNA1H: Rating: GREEN; Mode of pathogenicity: None; Publications: 27729216, 25907736, 31126930; Phenotypes: Hyperaldosteronism, familial, type IV MIM#617027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.7184 MED12 Zornitza Stark Publications for gene: MED12 were set to 33244166; 32174975; 30006928; 27312080
Mendeliome v0.7183 MED12 Zornitza Stark reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33244166; Phenotypes: Hardikar syndrome, OMIM #612726; Mode of inheritance: Other
Mendeliome v0.7182 UBE4A Zornitza Stark gene: UBE4A was added
gene: UBE4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE4A were set to 33420346
Phenotypes for gene: UBE4A were set to Intellectual disability and global developmental delay
Review for gene: UBE4A was set to GREEN
Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.
Sources: Literature
Mendeliome v0.7180 MAPKAPK5 Zornitza Stark gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 3344202
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic
Review for gene: MAPKAPK5 was set to GREEN
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.
Sources: Literature
Mendeliome v0.7179 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; spastic paraparesis and bilateral cataracts
Mendeliome v0.7178 FAR1 Zornitza Stark Publications for gene: FAR1 were set to 25439727
Mendeliome v0.7175 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7174 GRIA3 Zornitza Stark Publications for gene: GRIA3 were set to
Mendeliome v0.7172 GRIA3 Zornitza Stark reviewed gene: GRIA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32977175, 17989220; Phenotypes: Intellectual developmental disorder, X-linked, syndromic, Wu type (MIM#300699); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7171 SLC17A5 Zornitza Stark Publications for gene: SLC17A5 were set to
Mendeliome v0.7169 SLC17A5 Zornitza Stark edited their review of gene: SLC17A5: Added comment: Sialic acid storage diseases are autosomal recessive neurodegenerative disorders that may present as a severe infantile form or a slowly progressive adult form, which is prevalent in Finland and referred to as Salla disease. p.Arg39Cys is a founder Finnish variant. Multiple families reported.; Changed publications: 10581036, 10947946; Changed phenotypes: Salla disease 604369, MONDO:0011449, Sialic acid storage disorder, infantile 269920, MONDO:0010027
Mendeliome v0.7168 SGSH Zornitza Stark Publications for gene: SGSH were set to
Mendeliome v0.7166 SGSH Zornitza Stark reviewed gene: SGSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7493035, 9158154, 9401012, 9554748; Phenotypes: Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900, MONDO:0009655; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7165 SMPD1 Zornitza Stark Publications for gene: SMPD1 were set to
Mendeliome v0.7163 SMPD1 Zornitza Stark reviewed gene: SMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32292456, 32280632, 28164782; Phenotypes: Niemann-Pick disease, type A, MIM# 257200, MONDO:0009756, Niemann-Pick disease, type B, MIM# 607616, MONDO:0011871; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7162 TPP1 Zornitza Stark Publications for gene: TPP1 were set to 31283065
Mendeliome v0.7161 TPP1 Zornitza Stark reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9295267, 18684116, 23418007, 26224725, 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2, MIM# 204500, MONDO:0008769, Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270, MONDO:0012235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7160 PSAP Zornitza Stark edited their review of gene: PSAP: Changed publications: 32201884, 10682309, 1371116, 15773042, 31061751, 30632081
Mendeliome v0.7159 PPT1 Zornitza Stark Publications for gene: PPT1 were set to
Mendeliome v0.7157 PPT1 Zornitza Stark reviewed gene: PPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7637805, 9425237, 9664077; Phenotypes: Ceroid lipofuscinosis, neuronal, 1, MIM# 256730, MONDO:0009744; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7156 NEU1 Zornitza Stark Publications for gene: NEU1 were set to
Mendeliome v0.7154 NEU1 Zornitza Stark reviewed gene: NEU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8985184, 9054950, 11063730; Phenotypes: Sialidosis, type I and type II, MIM# 256550, MONDO:0009738; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7152 NAGLU Zornitza Stark Publications for gene: NAGLU were set to
Mendeliome v0.7150 NAGLU Zornitza Stark reviewed gene: NAGLU: Rating: GREEN; Mode of pathogenicity: None; Publications: 25818867, 8650226; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920, Charcot-Marie-Tooth disease, axonal, type 2V MIM#616491; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7149 NAGA Zornitza Stark Publications for gene: NAGA were set to 1313741; 31468281
Mendeliome v0.7148 NAGA Zornitza Stark reviewed gene: NAGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11313741, 31468281, 15619430, 8782044; Phenotypes: Kanzaki disease, MIM# 609242, Schindler disease, type I and type II 609241, alpha-N-acetylgalactosaminidase deficiency MONDO:0017779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7147 MIA3 Zornitza Stark gene: MIA3 was added
gene: MIA3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to 32101163; 33778321
Phenotypes for gene: MIA3 were set to Ondontochondrodysplasia 2 with hearing loss and diabetes , MIM#619269
Review for gene: MIA3 was set to AMBER
Added comment: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability.

Four affected siblings reported. Mouse model has absence of bone mineralization.
Sources: Expert list
Mendeliome v0.7145 MFSD8 Zornitza Stark Publications for gene: MFSD8 were set to 31006324
Mendeliome v0.7144 MFSD8 Zornitza Stark reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564970, 19201763, 25227500; Phenotypes: Ceroid lipofuscinosis, neuronal, 7, MIM# 610951, MONDO:0012588, Macular dystrophy with central cone involvement, MIM# 616170, MONDO:0014515; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7142 MCOLN1 Zornitza Stark reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucolipidosis IV, MIM# 252650, MONDO:0009653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7140 MANBA Zornitza Stark reviewed gene: MANBA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mannosidosis, beta, MIM# 248510, MONDO:0009562; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7138 MAN2B1 Zornitza Stark reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mannosidosis, alpha-, types I and II, MIM# 248500, MONDO:0009561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7137 LIPA Zornitza Stark Publications for gene: LIPA were set to
Mendeliome v0.7135 LIPA Zornitza Stark reviewed gene: LIPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11487567; Phenotypes: Cholesteryl ester storage disease, MIM# 278000, Wolman disease, MIM# 278000, Lysosomal acid lipase deficiency, MONDO:0010204; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7135 LAMP2 Zornitza Stark changed review comment from: XLD. Vacuolar cardiomyopathy and myopathy. Gene encodes lysosome-associated membrane protein-2.; to: XLD. Gene encodes lysosome-associated membrane protein-2.

Danon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease) with 'normal acid maltase' or alpha-glucosidase, however, it may be more accurately classified as a lysosomal disorder.
Mendeliome v0.7133 LAMP2 Zornitza Stark reviewed gene: LAMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Danon disease, MIM# 300257, MONDO:0010281; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7132 IDUA Zornitza Stark reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis type 1, MONDO:0001586; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7131 IDS Zornitza Stark Publications for gene: IDS were set to
Mendeliome v0.7129 IDS Zornitza Stark reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9921913, 9762601, 8940265, 1901826; Phenotypes: Mucopolysaccharidosis II, MIM# 309900, MONDO:0010674, Hunter syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7128 ERBB2 Teresa Zhao reviewed gene: ERBB2: Rating: RED; Mode of pathogenicity: None; Publications: 33720042; Phenotypes: Hirschsprung disease (HSCR, aganglionic megacolon, MIM#142623); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7127 VWA1 Melanie Marty gene: VWA1 was added
gene: VWA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA1 were set to 33459760; 33693694; 33559681
Phenotypes for gene: VWA1 were set to Hereditary motor neuropathy
Review for gene: VWA1 was set to GREEN
Added comment: Six different truncating variants identified in 15 affected individuals from six families (biallelic inheritance). Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed.

An additional 17 individuals from 15 families with hereditary motor neuropathy were identified. A 10-bp repeat expansion at the end of exon 1 was observed in 14 families and was homozygous in 10 of them. This mutation, c.62_71dup [p.Gly25Argfs*74], leads to a frameshift that results in a reduction in VWA1 transcript levels via nonsense-mediated decay.
Sources: Literature
Mendeliome v0.7126 TSPOAP1 Tiong Tan Added comment: Comment on list classification: Need to add to HSP gene lists too - dystonia/HSP
Mendeliome v0.7124 GIPC1 Dean Phelan reviewed gene: GIPC1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33374016; Phenotypes: Oculopharyngodistal myopathy 2 (MIM#618940); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7121 TSPOAP1 Ain Roesley gene: TSPOAP1 was added
gene: TSPOAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TSPOAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPOAP1 were set to 33539324
Phenotypes for gene: TSPOAP1 were set to Dystonia, intellectual disability and cerebellar atrophy
Penetrance for gene: TSPOAP1 were set to unknown
Review for gene: TSPOAP1 was set to GREEN
Added comment: 7 affecteds from 3 families (1 consanguineous)
2x null, 1x missense

Affecteds with the null variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy while those with the missense p.(Gly1808Ser) presented with isolated adult-onset focal dystonia (mild cognitive impairment noted)

mice KO models were investigated
Sources: Literature
Mendeliome v0.7121 ERBB3 Teresa Zhao reviewed gene: ERBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33720042; Phenotypes: Hirschsprung disease (HSCR, aganglionic megacolon, MIM#142623; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7121 CLDN11 Melanie Marty gene: CLDN11 was added
gene: CLDN11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Hypomyelinating leukodystrophy
Review for gene: CLDN11 was set to GREEN
Added comment: In three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia, 2 different heterozygous de novo stop-loss variants were identified. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.
Sources: Literature
Mendeliome v0.7121 SYK Paul De Fazio gene: SYK was added
gene: SYK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SYK were set to 33782605
Phenotypes for gene: SYK were set to Immune dysregulation and systemic inflammation
Mode of pathogenicity for gene: SYK was set to Other
Review for gene: SYK was set to GREEN
gene: SYK was marked as current diagnostic
Added comment: 5 unrelated patients with monoallelic missense variants in SYK with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. 2 patients were confirmed de novo, others were undetermined. Variants exhibited a GoF effect in functional studies. A knock-in mouse model of a patient variant recapitulated aspects of the human disease.
Sources: Literature
Mendeliome v0.7121 NCDN Ain Roesley gene: NCDN was added
gene: NCDN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to neurodevelopmental delay, intellectual disability, and epilepsy
Penetrance for gene: NCDN were set to unknown
Review for gene: NCDN was set to GREEN
Added comment: 4x families all missense and de novo except for 1 consag family where 3 affecteds were homozygous and carrier parents unaffected

ID ranged from mild to severe
3/4 probands had seizures
only 3 affecteds had MRI done, with 1 delayed myelination

in vitro studies were done
Sources: Literature
Mendeliome v0.7120 SLC5A5 Zornitza Stark Publications for gene: SLC5A5 were set to
Mendeliome v0.7118 SLC5A5 Zornitza Stark reviewed gene: SLC5A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 9745458, 9171822, 33815280, 32319661; Phenotypes: Thyroid dyshormonogenesis 1, MIM# 274400, MONDO:0020716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7117 SLC45A1 Zornitza Stark Publications for gene: SLC45A1 were set to
Mendeliome v0.7114 SLC45A1 Zornitza Stark reviewed gene: SLC45A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28434495; Phenotypes: Intellectual developmental disorder with neuropsychiatric features, MIM# 617532; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7113 MESP1 Zornitza Stark gene: MESP1 was added
gene: MESP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MESP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MESP1 were set to 28677747; 28050627; 27185833; 26694203
Phenotypes for gene: MESP1 were set to Congenital heart disease
Review for gene: MESP1 was set to AMBER
Added comment: Rare/novel variants reported in at least 7 unrelated individuals with congenital heart disease, in-silicos conflicting, familial segregation only available for some (one de novo, three inherited, others unresolved). Functional data implicates gene in cardiac development.
Sources: Expert list
Mendeliome v0.7111 HYAL1 Zornitza Stark Publications for gene: HYAL1 were set to
Mendeliome v0.7108 HYAL1 Zornitza Stark reviewed gene: HYAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 10339581, 18344557, 21559944; Phenotypes: Mucopolysaccharidosis type IX, MIM# 601492, MONDO:0011093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7107 HGSNAT Zornitza Stark reviewed gene: HGSNAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 25859010; Phenotypes: Retinitis pigmentosa 73, MIM# 616544, MONDO:0014687; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7107 HGSNAT Zornitza Stark Publications for gene: HGSNAT were set to 19479962; 31228227; 20825431; 20583299
Mendeliome v0.7103 HEXB Zornitza Stark reviewed gene: HEXB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Sandhoff disease, infantile, juvenile, and adult forms, MIM# 268800, MONDO:0010006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7100 GUSB Zornitza Stark reviewed gene: GUSB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis VII, MIM# 253220, MONDO:0009662; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7099 GNS Zornitza Stark Publications for gene: GNS were set to
Mendeliome v0.7097 GNS Zornitza Stark reviewed gene: GNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12573255, 12624138, 31536183, 25851924; Phenotypes: Mucopolysaccharidosis type IIID, MIM# 252940, Sanfilippo syndrome type D, MONDO:0009658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7096 GNPTG Zornitza Stark Publications for gene: GNPTG were set to
Mendeliome v0.7094 GNPTG Zornitza Stark reviewed gene: GNPTG: Rating: GREEN; Mode of pathogenicity: None; Publications: 10712439, 19370764, 19659762, 33507475, 33023972, 32651481; Phenotypes: Mucolipidosis III gamma, MIM# 252605, MONDO:0009652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7093 CHD7 Zornitza Stark Publications for gene: CHD7 were set to
Mendeliome v0.7091 CHD7 Elena Savva reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26411921; Phenotypes: Hypogonadotropic hypogonadism 5 with or without anosmia MIM#612370, CHARGE syndrome MIM#214800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.7090 NDUFA12 Bryony Thompson Publications for gene: NDUFA12 were set to 21617257
Mendeliome v0.7088 NDUFA12 Bryony Thompson reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23 MIM#618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7088 ALDH1A2 Bryony Thompson Publications for gene: ALDH1A2 were set to
Mendeliome v0.7086 ALDH1A2 Bryony Thompson reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33565183, 10192400; Phenotypes: congenital heart defects, diaphragmatic eventration, pulmonary hypoplasia, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7086 FBN2 Zornitza Stark Publications for gene: FBN2 were set to 19473076; 11068201; 27007659; 24899048
Mendeliome v0.7084 FBN2 Zornitza Stark edited their review of gene: FBN2: Added comment: The association between mono-allelic variants in FBN2 and CCA is well established. Recent report of bi-allelic variants, Kloth (2021): biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O. Authors performed a lit review and identified an additional 2 homozygous patients (both missense variants) with - fetal akinesia, brain ischemia and neonatal death - severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy.

Evidence for association with Macular degeneration, early-onset MIM#616118 is limited. One family reported, plus some rare variants reported in cohort studies. The familial variant p.Glu1144Lys is present in 11 hets in gnomad and has benign in silicos. The second variant reported in the paper, p.Met1247Thr is present in >20 hets.; Changed rating: GREEN; Changed publications: 33571691; Changed phenotypes: Contractural arachnodactyly, congenital MIM#121050, Macular degeneration, early-onset MIM#616118; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7083 MMP20 Bryony Thompson Publications for gene: MMP20 were set to
Mendeliome v0.7081 MMP20 Bryony Thompson reviewed gene: MMP20: Rating: GREEN; Mode of pathogenicity: None; Publications: 15744043, 33600052; Phenotypes: Amelogenesis imperfecta, type IIA2 MIM#612529; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.7080 NDUFB7 Bryony Thompson gene: NDUFB7 was added
gene: NDUFB7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDUFB7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFB7 were set to 33502047; 27626371
Phenotypes for gene: NDUFB7 were set to Congenital lactic acidosis; hypertrophic cardiomyopathy
Review for gene: NDUFB7 was set to AMBER
Added comment: Single patient with a homozygous variant impacting RNA splicing (c.113-10C>G) with intrauterine growth restriction and anaemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome. Also, a supporting knockout cell line model demonstrating impaired complex I assembly.
Sources: Literature
Mendeliome v0.7077 CDH11 Zornitza Stark Publications for gene: CDH11 were set to
Mendeliome v0.7075 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7075 CELA3B Bryony Thompson gene: CELA3B was added
gene: CELA3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELA3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELA3B were set to 31369399; 33565216
Phenotypes for gene: CELA3B were set to Chronic pancreatitis
Mode of pathogenicity for gene: CELA3B was set to Other
Review for gene: CELA3B was set to AMBER
Added comment: PMID: 33565216 - p.Arg90Cys (c.268C>T) identified in a chronic pancreatitis (also diabetes and pancreatic adenocarcinoma present in some individuals) pedigree. Variant was present in 2 affected individuals and not present in 7 healthy relatives. Also, supporting in vitro functional assays demonstrating gain of function mechanism for R90C and R90L, and supporting mouse model.
PMID: 31369399 - p.Arg90Leu (c.269G>T) identified in 4 French chronic pancreatitis cases and 0 controls. However, there are 229 hets in gnomAD v2.1 with this variant.
Sources: Literature
Mendeliome v0.7073 SLC10A1 Zornitza Stark gene: SLC10A1 was added
gene: SLC10A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC10A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC10A1 were set to 24867799; 27882152; 28835676; 29290974; 31201272
Phenotypes for gene: SLC10A1 were set to Familial hypercholanemia-2, MIM#619256
Review for gene: SLC10A1 was set to GREEN
Added comment: IEM characterised by persistently increased plasma levels of conjugated bile salts apparent from infancy. Most patients are asymptomatic and have no liver dysfunction, although some neonates may have transient jaundice or transiently elevated liver enzymes. These abnormalities improve with age. The bile acid defect can result in impaired absorption of fat-soluble vitamins, including D and K, causing decreased bone mineral density or prolonged prothrobin time (PT). Some variants are recurrent (founder effect likely) but at least 3 different variants reported, mouse model.
Sources: Expert list
Mendeliome v0.7071 GALNS Zornitza Stark Publications for gene: GALNS were set to
Mendeliome v0.7069 GALNS Zornitza Stark reviewed gene: GALNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9298823; Phenotypes: Mucopolysaccharidosis IVA, MIM# 253000, MONDO:0009659; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7068 GALC Zornitza Stark Publications for gene: GALC were set to
Mendeliome v0.7066 GALC Zornitza Stark reviewed gene: GALC: Rating: GREEN; Mode of pathogenicity: None; Publications: 20886637; Phenotypes: Krabbe disease, MIM# 245200, MONDO:0009499; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7064 FUCA1 Zornitza Stark Publications for gene: FUCA1 were set to
Mendeliome v0.7062 FUCA1 Zornitza Stark reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10094192; Phenotypes: Fucosidosis, MIM# 230000, MONDO:0009254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7061 CTSD Zornitza Stark Publications for gene: CTSD were set to
Mendeliome v0.7059 CTSD Zornitza Stark reviewed gene: CTSD: Rating: GREEN; Mode of pathogenicity: None; Publications: 16685649, 16670177, 25298308, 33681191, 29284168, 27072142; Phenotypes: Ceroid lipofuscinosis, neuronal, 10, MIM# 610127, MONDO:0012414; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7057 CCDC88C Zornitza Stark Publications for gene: CCDC88C were set to 23042809; 21031079; 25062847; 30398676
Mendeliome v0.7056 CCDC88C Paul De Fazio reviewed gene: CCDC88C: Rating: GREEN; Mode of pathogenicity: None; Publications: 33602173; Phenotypes: Eearly-onset pure hereditary spastic paraplegia; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.7054 NMNAT1 Zornitza Stark Publications for gene: NMNAT1 were set to
Mendeliome v0.7053 NMNAT1 Zornitza Stark reviewed gene: NMNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32533184, 33668384, 22842230, 22842229; Phenotypes: Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260, Leber congenital amaurosis 9, MIM# 608553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7051 ZMPSTE24 Zornitza Stark Publications for gene: ZMPSTE24 were set to
Mendeliome v0.7049 ZMPSTE24 Zornitza Stark reviewed gene: ZMPSTE24: Rating: GREEN; Mode of pathogenicity: None; Publications: 11923874, 22718200, 29794150, 29208544, 12913070, 27410998, 27409638, 15937076, 16671095, 22718200, 29794150, 24169522; Phenotypes: Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612, MONDO:0012074, Restrictive dermopathy, lethal, MIM# 275210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7049 WDR35 Zornitza Stark reviewed gene: WDR35: Rating: GREEN; Mode of pathogenicity: None; Publications: 33421337, 29134781, 28870638, 26691894, 24027799, 21473986; Phenotypes: Cranioectodermal dysplasia 2, MIM#613610, MONDO:0013323, Short-rib thoracic dysplasia 7 with or without polydactyly, MIM#614091, MONDO:0013569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7047 EDN1 Zornitza Stark Publications for gene: EDN1 were set to
Mendeliome v0.7044 EDN1 Zornitza Stark reviewed gene: EDN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23315542, 23913798, 24268655; Phenotypes: Auriculocondylar syndrome 3, MIM# 615706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7043 CLN5 Zornitza Stark Publications for gene: CLN5 were set to
Mendeliome v0.7041 CLN5 Zornitza Stark reviewed gene: CLN5: Rating: GREEN; Mode of pathogenicity: None; Publications: 20157158; Phenotypes: Ceroid lipofuscinosis, neuronal, 5, MIM# 256731, MONDO:0009745; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7040 CLN3 Zornitza Stark Publications for gene: CLN3 were set to
Mendeliome v0.7038 CLN3 Zornitza Stark reviewed gene: CLN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 7553855; Phenotypes: Ceroid lipofuscinosis, neuronal, 3, MIM# 204200, MONDO:0008767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7037 ARSB Zornitza Stark Publications for gene: ARSB were set to
Mendeliome v0.7035 ARSB Zornitza Stark reviewed gene: ARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 11668612; Phenotypes: Mucopolysaccharidosis type VI (Maroteaux-Lamy), MIM# 253200, MONDO:0009661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7034 AGA Zornitza Stark Publications for gene: AGA were set to
Mendeliome v0.7032 AGA Zornitza Stark edited their review of gene: AGA: Added comment: Aspartylglucosaminuria (AGU) is a severe autosomal recessive lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. Multiple families and mouse model.; Changed publications: 1703489, 1904874, 8064811, 8946839; Changed phenotypes: Aspartylglucosaminuria, MIM# 208400, MONDO:0008830
Mendeliome v0.7031 ATCAY Zornitza Stark Publications for gene: ATCAY were set to
Mendeliome v0.7029 ATCAY Zornitza Stark edited their review of gene: ATCAY: Added comment: Report of a variant c.599_605del, p.Pro200Profs*20 (PMID 29449188), which is in addition to the previously reported linked variants in the Cayman population (c.965+3G > T & p.S301R)(PMID 29449188). Mouse and zebra fish models share phenotypic features with humans with Ataxia, cerebellar, Cayman type (OMIM:601238)(PMID 14556008; 26343454).; Changed rating: GREEN; Changed publications: 14556008, 29449188, 23226316, 26343454; Changed phenotypes: Ataxia, cerebellar, Cayman type, MIM# 601238, MONDO:0011025
Mendeliome v0.7029 COPB1 Zornitza Stark Phenotypes for gene: COPB1 were changed from Severe intellectual disability; variable microcephaly; cataracts to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Mendeliome v0.7028 COPB1 Zornitza Stark edited their review of gene: COPB1: Changed phenotypes: Baralle-Macken syndrome, MIM# 619255, Severe intellectual disability, variable microcephaly, cataracts
Mendeliome v0.7027 ARAP3 Zornitza Stark gene: ARAP3 was added
gene: ARAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARAP3 were set to 32908855
Phenotypes for gene: ARAP3 were set to Lymphoedema
Review for gene: ARAP3 was set to AMBER
Added comment: Three unrelated families reported with rare missense variants in this gene as part of a lymphoedema cohort. However, incomplete information regarding segregation and no supporting functional data.
Sources: Literature
Mendeliome v0.7026 RORC Zornitza Stark edited their review of gene: RORC: Added comment: Association with lymphoedema: Two individuals reported with LoF variants as part of a large cohort. Note gene is depleted for LoF in gnomad, and bi-allelic variants have been associated with immunodeficiency.; Changed publications: 26160376, 32960152; Changed phenotypes: Immunodeficiency 42, MIM# 616622, Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, MONDO:0014710, Lymphoedema; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.7025 RORC Zornitza Stark Publications for gene: RORC were set to
Mendeliome v0.7023 RORC Zornitza Stark reviewed gene: RORC: Rating: GREEN; Mode of pathogenicity: None; Publications: 26160376; Phenotypes: Immunodeficiency 42, MIM# 616622, Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, MONDO:0014710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7022 IL17RC Zornitza Stark Publications for gene: IL17RC were set to
Mendeliome v0.7020 IL17RC Zornitza Stark reviewed gene: IL17RC: Rating: GREEN; Mode of pathogenicity: None; Publications: 25918342; Phenotypes: Candidiasis, familial, 9, MIM# 616445, MONDO:0014642; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7020 IL17RA Zornitza Stark Publications for gene: IL17RA were set to
Mendeliome v0.7017 IL17RA Zornitza Stark reviewed gene: IL17RA: Rating: GREEN; Mode of pathogenicity: None; Publications: 21350122, 27930337; Phenotypes: Immunodeficiency 51, MIM# 613953; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7016 CARD9 Zornitza Stark Publications for gene: CARD9 were set to
Mendeliome v0.7014 CARD9 Zornitza Stark reviewed gene: CARD9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19864672, 23335372, 24131138, 33789983, 33558980, 33180249; Phenotypes: Candidiasis, familial, 2, autosomal recessive, MIM# 212050, Predisposition to invasive fungal disease, MONDO:0008905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7013 CYP24A1 Zornitza Stark Publications for gene: CYP24A1 were set to
Mendeliome v0.7011 CYP24A1 Zornitza Stark reviewed gene: CYP24A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21675912, 22047572, 33516786, 33186763, 32866123, 32743688; Phenotypes: Hypercalcaemia, infantile, 1, MIM# 143880, MONDO:0020739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.7010 AP2S1 Zornitza Stark Publications for gene: AP2S1 were set to 33057194
Mendeliome v0.7009 AP2S1 Zornitza Stark reviewed gene: AP2S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23222959, 33729479, 33168530, 3204769, 31723423, 29479578; Phenotypes: Hypocalciuric hypercalcemia, type III, MIM# 600740, MONDO:0010926; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.7008 ABCB7 Zornitza Stark Publications for gene: ABCB7 were set to
Mendeliome v0.7006 ABCB7 Zornitza Stark reviewed gene: ABCB7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10196363, 10196363, 33157103, 31772327, 31511561, 26242992; Phenotypes: Anaemia, sideroblastic, with ataxia, MIM# 301310; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.7004 PORCN Zornitza Stark reviewed gene: PORCN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Focal dermal hypoplasia, MIM# 305600; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.7004 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7003 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7003 PRIM1 Zornitza Stark changed review comment from: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature; to: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7003 PRIM1 Zornitza Stark gene: PRIM1 was added
gene: PRIM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to AMBER
Added comment: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Mendeliome v0.7001 ACTL9 Zornitza Stark reviewed gene: ACTL9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 53, MIM#619258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6999 MCM10 Zornitza Stark Publications for gene: MCM10 were set to 32865517
Mendeliome v0.6998 MCM10 Zornitza Stark edited their review of gene: MCM10: Added comment: PMID 33712616: second family reported, three affected sibs with restrictive cardiomyopathy and hypoplasia of the spleen and thymus. Functional data suggested that MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion.; Changed publications: 32865517, 33712616; Changed phenotypes: Susceptibility to CMV, Restrictive cardiomyopathy
Mendeliome v0.6997 CYBA Zornitza Stark Publications for gene: CYBA were set to
Mendeliome v0.6995 CYBA Zornitza Stark reviewed gene: CYBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 2770793; Phenotypes: Chronic granulomatous disease 4, autosomal recessive, MIM# 233690, MONDO:0009308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6994 COPB2 Zornitza Stark gene: COPB2 was added
gene: COPB2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COPB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to 29036432
Phenotypes for gene: COPB2 were set to Microcephaly 19, primary, autosomal recessive, MIM# 617800
Review for gene: COPB2 was set to RED
Added comment: Two sibs with homozygous missense variant in this gene, mice homozygous for this variant had normal brain size however. Mice compound het for null allele and missense variant had some brain features, suggesting the missense variant is hypomorphic.
Sources: Expert list
Mendeliome v0.6992 WDR62 Zornitza Stark Publications for gene: WDR62 were set to
Mendeliome v0.6990 WDR62 Zornitza Stark reviewed gene: WDR62: Rating: GREEN; Mode of pathogenicity: None; Publications: 20890279, 20729831, 20890278, 21496009, 21834044, 22775483, 32677750, 31788460; Phenotypes: Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317, MONDO:0011435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6989 TRMT10A Zornitza Stark Publications for gene: TRMT10A were set to
Mendeliome v0.6987 TRMT10A Zornitza Stark reviewed gene: TRMT10A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24204302, 25053765, 33448213, 33067246, 26535115, 26526202, 26297882; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033, MONDO:0000208; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6986 TRAIP Zornitza Stark Publications for gene: TRAIP were set to
Mendeliome v0.6984 TRAIP Zornitza Stark reviewed gene: TRAIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 26595769; Phenotypes: Seckel syndrome 9, MIM# 616777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6984 TOP3A Zornitza Stark Publications for gene: TOP3A were set to 30057030; 33631320
Mendeliome v0.6983 TOP3A Zornitza Stark edited their review of gene: TOP3A: Changed publications: 30057030, 33631320, 29290614
Mendeliome v0.6982 TOP3A Zornitza Stark Publications for gene: TOP3A were set to
Mendeliome v0.6980 TOP3A Zornitza Stark reviewed gene: TOP3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30057030, 33631320; Phenotypes: Microcephaly, growth restriction, and increased sister chromatid exchange 2, MIM# 618097, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, MIM#618098; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6979 STIL Zornitza Stark Publications for gene: STIL were set to
Mendeliome v0.6977 STIL Zornitza Stark reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19215732, 22989186, 25218063, 33132204, 32677750, 29230157; Phenotypes: Microcephaly 7, primary, autosomal recessive, MIM# 612703, MONDO:0012989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6976 RAD50 Zornitza Stark Publications for gene: RAD50 were set to 19409520; 32212377
Mendeliome v0.6975 RAD50 Arina Puzriakova reviewed gene: RAD50: Rating: GREEN; Mode of pathogenicity: None; Publications: 33378670; Phenotypes: Nijmegen breakage syndrome-like disorder, OMIM:613078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6974 STAMBP Zornitza Stark Publications for gene: STAMBP were set to
Mendeliome v0.6972 STAMBP Zornitza Stark reviewed gene: STAMBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23542699, 31638258, 29907875, 27531570, 25692795, 25266620; Phenotypes: Microcephaly-capillary malformation syndrome, MIM# 614261, MONDO:0013659; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6971 PCNT Zornitza Stark Publications for gene: PCNT were set to
Mendeliome v0.6969 PCNT Zornitza Stark reviewed gene: PCNT: Rating: GREEN; Mode of pathogenicity: None; Publications: 18174396, 12210304, 30922925, 33460028, 32557621, 32267100; Phenotypes: Microcephalic osteodysplastic primordial dwarfism, type II, MIM# 210720, MONDO:0008872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6968 NHEJ1 Zornitza Stark Publications for gene: NHEJ1 were set to
Mendeliome v0.6966 NHEJ1 Zornitza Stark reviewed gene: NHEJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6965 NBN Zornitza Stark Publications for gene: NBN were set to
Mendeliome v0.6963 NBN Zornitza Stark reviewed gene: NBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33488600, 33082212; Phenotypes: Nijmegen breakage syndrome, MIM# 251260, MONDO:0009623; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6963 MSMO1 Zornitza Stark Phenotypes for gene: MSMO1 were changed from to Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834; MONDO:0014793; Disorders of the metabolism of sterols
Mendeliome v0.6962 MSMO1 Zornitza Stark Publications for gene: MSMO1 were set to
Mendeliome v0.6960 MSMO1 Zornitza Stark reviewed gene: MSMO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21285510, 24144731, 28673550, 33161406; Phenotypes: Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834, MONDO:0014793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6959 MCPH1 Zornitza Stark Publications for gene: MCPH1 were set to
Mendeliome v0.6957 MCPH1 Zornitza Stark reviewed gene: MCPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12046007, 15199523, 16311745, 20978018, 32294449, 30351297, 29026105; Phenotypes: Microcephaly 1, primary, autosomal recessive, MIM# 251200, MONDO:0009617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6956 ATP1A3 Zornitza Stark Publications for gene: ATP1A3 were set to
Mendeliome v0.6954 ATP1A3 Zornitza Stark reviewed gene: ATP1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15260953, 22842232, 24468074, 33762331; Phenotypes: Alternating hemiplegia of childhood 2, MIM# 614820, CAPOS syndrome, MIM# 601338, Dystonia-12, MIM# 128235, Polymicrogyria; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6952 LARP7 Zornitza Stark Publications for gene: LARP7 were set to
Mendeliome v0.6950 LARP7 Zornitza Stark reviewed gene: LARP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22865833, 21937992, 30006060, 33569879; Phenotypes: Alazami syndrome, MIM# 615071, Microcephalic primordial dwarfism, Alazami type MONDO:0014031; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6949 KNL1 Zornitza Stark Publications for gene: KNL1 were set to
Mendeliome v0.6947 KNL1 Zornitza Stark reviewed gene: KNL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22983954, 26626498, 27149178, 30304678, 27784895; Phenotypes: Microcephaly 4, primary, autosomal recessive, MIM# 604321, MONDO:0011437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6945 BAAT Zornitza Stark Publications for gene: BAAT were set to
Mendeliome v0.6943 BAAT Zornitza Stark reviewed gene: BAAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 12704386, 23415802; Phenotypes: Bile acid conjugation defect 1, MIM# 619232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6942 KIF11 Zornitza Stark Publications for gene: KIF11 were set to
Mendeliome v0.6940 KIF11 Zornitza Stark reviewed gene: KIF11: Rating: GREEN; Mode of pathogenicity: None; Publications: 22284827, 25115524, 25124931, 27212378, 32730767, 31993640, 25996076; Phenotypes: Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950, MONDO:0007918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6939 IER3IP1 Zornitza Stark Publications for gene: IER3IP1 were set to
Mendeliome v0.6937 IER3IP1 Zornitza Stark reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21835305, 22991235, 24138066, 28711742; Phenotypes: Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231, Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6936 EFTUD2 Zornitza Stark Publications for gene: EFTUD2 were set to
Mendeliome v0.6934 EFTUD2 Zornitza Stark reviewed gene: EFTUD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305528, 23188108, 33601405, 33262786, 26507355; Phenotypes: Mandibulofacial dysostosis, Guion-Almeida type, MIM# 610536, Mandibulofacial dysostosis-microcephaly syndrome MONDO:0012516; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6933 CEP152 Zornitza Stark Publications for gene: CEP152 were set to
Mendeliome v0.6931 CEP152 Zornitza Stark reviewed gene: CEP152: Rating: GREEN; Mode of pathogenicity: None; Publications: 20598275, 22775483, 21131973, 23199753; Phenotypes: Microcephaly 9, primary, autosomal recessive, MIM# 614852, MONDO:0013923, Seckel syndrome 5, MIM# 613823, MONDO:0013443; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6930 GNPAT Zornitza Stark Publications for gene: GNPAT were set to
Mendeliome v0.6928 GNPAT Zornitza Stark reviewed gene: GNPAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536089, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 2, MIM# 222765, MONDO:0009112; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6926 CD4 Zornitza Stark Publications for gene: CD4 were set to
Mendeliome v0.6924 CD4 Zornitza Stark edited their review of gene: CD4: Changed rating: GREEN; Changed publications: 31781092, 33471124; Changed phenotypes: Immunodeficiency 79, MIM# 619238, Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts
Mendeliome v0.6923 TMEM231 Zornitza Stark Publications for gene: TMEM231 were set to
Mendeliome v0.6921 TMEM231 Zornitza Stark edited their review of gene: TMEM231: Changed rating: GREEN; Changed publications: 23012439, 23349226, 22179047, 30617574, 27449316, 31663672, 25869670; Changed phenotypes: Joubert syndrome 20, MIM# 614970, MONDO:0013994, Meckel syndrome 11, MIM# 615397, MONDO:0014164
Mendeliome v0.6920 TMEM216 Zornitza Stark Publications for gene: TMEM216 were set to
Mendeliome v0.6917 TMEM138 Zornitza Stark Publications for gene: TMEM138 were set to
Mendeliome v0.6915 TMEM138 Zornitza Stark edited their review of gene: TMEM138: Changed rating: GREEN; Changed publications: 22282472, 28102635, 27434533; Changed phenotypes: Joubert syndrome 16, MIM# 614465, MONDO:0013764
Mendeliome v0.6914 TCTN2 Zornitza Stark Publications for gene: TCTN2 were set to
Mendeliome v0.6912 TCTN2 Zornitza Stark edited their review of gene: TCTN2: Changed publications: 21462283, 21565611, 25118024, 21725307, 32139166, 25118024, 32655147, 33590725; Changed phenotypes: Joubert syndrome 24, MIM# 616654, MONDO:0014724, Meckel syndrome 8, MIM# 613885, MONDO:0013482
Mendeliome v0.6911 TCTN1 Zornitza Stark Publications for gene: TCTN1 were set to
Mendeliome v0.6909 SMCHD1 Zornitza Stark Publications for gene: SMCHD1 were set to 31600781
Mendeliome v0.6908 SMCHD1 Zornitza Stark edited their review of gene: SMCHD1: Added comment: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. Choanal atresia is a feature. More than 30 unrelated individuals reported. Caused by gain of function missense variants with the extended ATPase domain.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed publications: 28067909; Changed phenotypes: Bosma arhinia microphthalmia syndrome, MIM# 603457, Arhinia, choanal atresia, microphthalmia MONDO:0011323; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6905 TXNL4A Zornitza Stark Publications for gene: TXNL4A were set to
Mendeliome v0.6903 TXNL4A Zornitza Stark reviewed gene: TXNL4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25434003; Phenotypes: Burn-McKeown syndrome, MIM# 608572, Choanal atresia - deafness - cardiac defects - dysmorphism syndrome, MONDO:0012064; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6902 SPINT2 Zornitza Stark Publications for gene: SPINT2 were set to 24142340; 30445423
Mendeliome v0.6901 SPINT2 Zornitza Stark edited their review of gene: SPINT2: Changed publications: 19185281, 20009592, 24142340, 30445423; Changed phenotypes: Diarrhoea 3, secretory sodium, congenital, syndromic 270420, MONDO:0010036
Mendeliome v0.6900 FOXE1 Zornitza Stark Publications for gene: FOXE1 were set to
Mendeliome v0.6898 FOXE1 Zornitza Stark reviewed gene: FOXE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9697705, 12165566, 16882747, 24219130, 20484477; Phenotypes: Bamforth-Lazarus syndrome, MIM# 241850, MONDO:0009437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6897 MIB1 Zornitza Stark reviewed gene: MIB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30322850, 23314057; Phenotypes: Left ventricular noncompaction 7, MIM# 615092, cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6896 ANO3 Zornitza Stark Publications for gene: ANO3 were set to
Mendeliome v0.6894 ANO3 Zornitza Stark reviewed gene: ANO3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33388357; Phenotypes: Dystonia 24, MIM#615034, familial form of cranio-cervical dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6893 IPO8 Zornitza Stark gene: IPO8 was added
gene: IPO8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Review for gene: IPO8 was set to AMBER
Added comment: 12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Expert Review
Mendeliome v0.6892 DDB1 Zornitza Stark Publications for gene: DDB1 were set to
Mendeliome v0.6891 DDB1 Zornitza Stark edited their review of gene: DDB1: Added comment: 8 individuals with de novo missense variants and varying degrees of intellectual disability, hypotonia, and some malformations, brachydactyly and syndactyly. Functional evidence of abnormal DNA repair in patient lymphoblasts.; Changed publications: 33743206
Mendeliome v0.6890 FAM20C Zornitza Stark Publications for gene: FAM20C were set to
Mendeliome v0.6888 FAM20C Zornitza Stark reviewed gene: FAM20C: Rating: GREEN; Mode of pathogenicity: None; Publications: 19250384, 32299476, 20825432, 33676444, 32833257; Phenotypes: Raine syndrome, MIM# 259775, MONDO:0009821; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6887 POLR3A Zornitza Stark Publications for gene: POLR3A were set to
Mendeliome v0.6885 ANKS6 Zornitza Stark Publications for gene: ANKS6 were set to
Mendeliome v0.6883 ANKS6 Zornitza Stark reviewed gene: ANKS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23793029, 31678577, 31635528, 26039630, 24610927; Phenotypes: Nephronophthisis 16, MIM# 615382, MONDO:0014158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6882 GLIS2 Zornitza Stark Publications for gene: GLIS2 were set to 17618285; 23559409
Mendeliome v0.6881 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Changed publications: 17618285, 23559409, 31676329; Changed phenotypes: Nephronophthisis 7, OMIM#611498, MONDO:0012680
Mendeliome v0.6880 CLDN2 Zornitza Stark Publications for gene: CLDN2 were set to 29884332; 31163246
Mendeliome v0.6878 CLDN2 Zornitza Stark changed review comment from: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype. Likely polygenic susceptibility rather than Mendelian disorder.; to: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype. Likely polygenic susceptibility rather than Mendelian disorder.
Mendeliome v0.6878 CLDN2 Zornitza Stark edited their review of gene: CLDN2: Added comment: Azoospermia: single multigenerational family reported.; Changed publications: 29884332, 31163246, 31320686; Changed phenotypes: Susceptibility to pancreatitis, Azoospermia, obstructive, with nephrolithiasis, MIM# 301060; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6878 FLII Zornitza Stark Publications for gene: FLII were set to 32870709
Mendeliome v0.6876 POLR3A Elena Savva reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31637490; Phenotypes: Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism MIM#607694, Wiedemann-Rautenstrauch syndrome MIM#264090, POLR3A-related spastic ataxia; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6876 FLII Elena Savva reviewed gene: FLII: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32870709, 11971982, 32980309; Phenotypes: Dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6876 HSF2BP Zornitza Stark gene: HSF2BP was added
gene: HSF2BP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237
Phenotypes for gene: HSF2BP were set to Premature ovarian failure, OMIM#619245
Review for gene: HSF2BP was set to RED
Added comment: Single family reported where homozygous missense variant segregated with POF in three sisters.
Sources: Expert list
Mendeliome v0.6874 COL4A6 Zornitza Stark Publications for gene: COL4A6 were set to
Mendeliome v0.6870 RNF6 Zornitza Stark reviewed gene: RNF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.6870 COL4A6 Paul De Fazio reviewed gene: COL4A6: Rating: RED; Mode of pathogenicity: None; Publications: 23714752, 12784310; Phenotypes: ?Deafness, X-linked 6 MIM#300914; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v0.6869 MED12 Zornitza Stark Publications for gene: MED12 were set to
Mendeliome v0.6866 BMPR2 Zornitza Stark Publications for gene: BMPR2 were set to
Mendeliome v0.6863 MED12 Elena Savva reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33244166, 32174975, 30006928, 27312080; Phenotypes: Ohdo syndrome, X-linked MIM#300895, Lujan-Fryns syndrome MIM#309520, Opitz-Kaveggia syndrome MIM#305450; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6863 BMPR2 Elena Savva reviewed gene: BMPR2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33380512; Phenotypes: Pulmonary venoocclusive disease 1 MIM#265450, Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600, Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6862 ZNF711 Zornitza Stark Publications for gene: ZNF711 were set to
Mendeliome v0.6860 ZNF711 Zornitza Stark reviewed gene: ZNF711: Rating: GREEN; Mode of pathogenicity: None; Publications: 27993705, 19377476; Phenotypes: Mental retardation, X-linked 97, OMIM #300803; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.6859 SLC35A2 Zornitza Stark Publications for gene: SLC35A2 were set to
Mendeliome v0.6857 SLC35A2 Zornitza Stark reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561849, 24115232, 27743886, 25778940, 33407896; Phenotypes: Congenital disorder of glycosylation, type IIm (MIM #300896) 30817854, Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6854 MEF2A Zornitza Stark reviewed gene: MEF2A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Coronary artery disease, autosomal dominant, 1} 608320; Mode of inheritance: None
Mendeliome v0.6853 FN1 Zornitza Stark Publications for gene: FN1 were set to
Mendeliome v0.6851 IL37 Zornitza Stark gene: IL37 was added
gene: IL37 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Mendeliome v0.6850 PEX10 Teresa Zhao reviewed gene: PEX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 30640048; Phenotypes: Peroxisome biogenesis disorder 6A (Zellweger) (MIM#614870), Peroxisome biogenesis disorder 6B (MIM#614871); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6850 FN1 Ain Roesley reviewed gene: FN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100092; Phenotypes: Glomerulopathy with fibronectin deposits 2 (MIM#601894), Spondylometaphyseal dysplasia, corner fracture type (MIM#184255); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6849 CHRDL1 Zornitza Stark Publications for gene: CHRDL1 were set to
Mendeliome v0.6847 CHRDL1 Zornitza Stark reviewed gene: CHRDL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25093588; Phenotypes: Megalocornea OMIM# 309300; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6846 HDL2 Bryony Thompson STR: HDL2 was added
STR: HDL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: HDL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: HDL2 were set to 20301701
Phenotypes for STR: HDL2 were set to Huntington disease-like 2 MIM#606438
Review for STR: HDL2 was set to GREEN
STR: HDL2 was marked as clinically relevant
Added comment: NM_001271604.2:c.431CTG[X] or NM_020655.4:c.382+760CTG[X]
In an alternatively spliced exon, the repeat can be transcribed in both directions, leading to CUG (more common) or CAG (less common) repeat-containing transcripts. While a dominant RNA toxic effect may occur, the repeat expansion also reduces levels of the Junctophilin-3 protein
Normal: ≤28 repeats
Questionable significance: 29-39 repeats, mutable normal or reduced penetrance included
Full penetrance: ≥40 repeats
Sources: Expert list
Mendeliome v0.6845 JPH3 Bryony Thompson Added comment: Comment on list classification: See STRs for this panel
Mendeliome v0.6843 DM2 Bryony Thompson STR: DM2 was added
STR: DM2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM2 were set to 20301639; 29325606
Phenotypes for STR: DM2 were set to Myotonic dystrophy 2 MIM#602668
Review for STR: DM2 was set to GREEN
STR: DM2 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_003418.4:c.-14-833_-14-830[X]
Toxic gain of function RNA expected mechanism of disease
Normal: ≤30 uninterrupted CCTG repeats, 11-26 CCTG repeats with any GCTC or TCTG interruptions
Unknown significance (normal vs. mutable): 27-29 CCTG repeats
Mutable normal (premutation) alleles. ~30-~54 CCTG repeats
Unknown significance (premutation vs pathogenic): ~55-74 CCTG repeats
Pathogenic: ~75-11,000 CCTG repeats
Sources: Expert list
Mendeliome v0.6842 CNBP Bryony Thompson Added comment: Comment on list classification: Condition is caused by a CCTG expansion in intron 1. No reported SNVs or indels reported in association with disease. Present under STRs on this panel
Mendeliome v0.6840 DM1 Bryony Thompson STR: DM1 was added
STR: DM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM1 were set to 20301344; 29325606
Phenotypes for STR: DM1 were set to Myotonic dystrophy 1 MIM#160900
Review for STR: DM1 was set to GREEN
STR: DM1 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_001081560.2:c.*224_*226CTG[X]
RNA toxic gain of function is mechanism of disease
Premutation: 35-49 repeats, no clinical signs
Mild: 50-~150 repeats, age of onset 20-70 yrs, clinical signs - cataracts, mild myotonia
Classic: ~100-~1,000 repeats, age of onset 10-30 yrs, clinical signs - weakness, myotonia, cataracts, balding, cardiac arrhythmia
Congenital: >1,000 repeats, age of onset birth-10 yrs , clinical signs - infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adults
Sources: Expert list
Mendeliome v0.6839 DMPK Bryony Thompson Added comment: Comment on list classification: STR is the only cause of condition for this gene and is present in STRs for this panel.
Mendeliome v0.6837 SCA17 Bryony Thompson STR: SCA17 was added
STR: SCA17 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA17 were set to 20301611; 29325606
Phenotypes for STR: SCA17 were set to Spinocerebellar ataxia 17 MIM#607136
Review for STR: SCA17 was set to GREEN
STR: SCA17 was marked as clinically relevant
Added comment: NM_003194.4:c.172_174[X]
Mechanism of disease expected to be gain of function
Normal: ≤ 40 CAG/CAA repeats
Reduced-penetrance: 41-48 CAG/CAA repeats, individual may or may not develop symptoms.
Full-penetrance: ≥49 CAG/CAA repeats
Sources: Expert list
Mendeliome v0.6836 TBP Bryony Thompson Added comment: Comment on list classification: See STRs
Mendeliome v0.6834 SCA12 Bryony Thompson STR: SCA12 was added
STR: SCA12 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA12 were set to 29325606; 20301381
Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326
Review for STR: SCA12 was set to GREEN
STR: SCA12 was marked as clinically relevant
Added comment: NM_181675.3:c.27CAG[X]
Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase
Normal: ≤32 repeats
Reduced penetrance: ~40-66 repeats
Full penetrance: ≥66 repeats
Sources: Expert list
Mendeliome v0.6831 SCA36 Bryony Thompson STR: SCA36 was added
STR: SCA36 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA36 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA36 were set to 25101480
Phenotypes for STR: SCA36 were set to Spinocerebellar ataxia 36 MIM#614153
Review for STR: SCA36 was set to GREEN
STR: SCA36 was marked as clinically relevant
Added comment: NM_006392​.3:c.3+71GGCCTG[X]
Toxic RNA effect is suggested mechanism of disease
Normal: 3-14 repeats
Uncertain significance: 15-650 repeats
Pathogenic: ≥650 repeats
Sources: Expert list
Mendeliome v0.6830 NOP56 Bryony Thompson Added comment: Comment on list classification: A hexanucleotide (GGCCTG) repeat expansion in the first intron of the NOP56 gene is the only reported cause of disease. See STRS
Mendeliome v0.6828 SCA37 Bryony Thompson STR: SCA37 was added
STR: SCA37 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA37 were set to 28686858; 31145571
Phenotypes for STR: SCA37 were set to Spinocerebellar ataxia 37 MIM#615945
Review for STR: SCA37 was set to GREEN
STR: SCA37 was marked as clinically relevant
Added comment: NC_000001.10:g.57832716_57832797ins[(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90]
Located in a 5'UTR intron, flanked by (ATTTT)n on both sides
Non-pathogenic allele: (ATTTT)7–400
Pathogenic allele: [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90]
Sources: Expert list
Mendeliome v0.6825 SCA31 Bryony Thompson STR: SCA31 was added
STR: SCA31 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA31 were set to 19878914; 31755042
Phenotypes for STR: SCA31 were set to Spinocerebellar ataxia 31 MIM#117210
Review for STR: SCA31 was set to GREEN
STR: SCA31 was marked as clinically relevant
Added comment: Complex repeat insertion (TGGAA)n, (TAGAA)n, (TAAAA)n, (TAAAATAGAA)n, TGGAA is present only in affected cases. Sequencing showed that the insertion consisted of a preceding TCAC sequence, and 3 pentanucleotide repeat components (TGGAA)n, (TAGAA)n, and (TAAAA)n in all patients tested.
2.5-3.8 KB insertion is associated with disease and RNA toxicity expected to be mechanism of disease
Normal and pathogenic cut-offs are based on animal model experiments (PMID: 31755042)
Sources: Expert list
Mendeliome v0.6822 SCA7 Bryony Thompson STR: SCA7 was added
STR: SCA7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA7 were set to 29325606; 20301433
Phenotypes for STR: SCA7 were set to Spinocerebellar ataxia 7 MIM#164500
Review for STR: SCA7 was set to GREEN
STR: SCA7 was marked as clinically relevant
Added comment: NM_000333​.3:c.89_91AGC[X]
Gain of function mechanism of disease
Normal: ≤27 repeats
Mutable normal: 28-33 repeats, meiotically unstable, but not associated with an abnormal phenotype.
Pathogenic reduced penetrance: 34-36 repeats, when manifestations occur, they are more likely to be later onset and milder than average
Pathogenic full penetrance: 37-460 repeats
Sources: Expert list
Mendeliome v0.6819 SCA3 Bryony Thompson STR: SCA3 was added
STR: SCA3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA3 were set to 20301375; 29325606
Phenotypes for STR: SCA3 were set to Machado-Joseph disease MIM#109150; Spinocerebellar ataxia type 3
Review for STR: SCA3 was set to GREEN
STR: SCA3 was marked as clinically relevant
Added comment: NM_004993​.5:c.886_888CAG[X]
Toxic aggregation and mislocalization in neurons is mechanism of disease
Normal: ≤44 repeats, mostly <31 repeats
Intermediate: 45-59 repeats, some intermediate alleles are not associated with classic clinical features of SCA3
Pathogenic (full penetrance): ≥60 repeats
Sources: Expert list
Mendeliome v0.6816 SCA2 Bryony Thompson STR: SCA2 was added
STR: SCA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA2 were set to 29325606; 20301452
Phenotypes for STR: SCA2 were set to Spinocerebellar ataxia 2 MIM#183090
Review for STR: SCA2 was set to GREEN
STR: SCA2 was marked as clinically relevant
Added comment: NM_002973​.3:c.496_498CAG[X]
Toxic protein aggregation is mechanism of disease
Benign: ≤31 repeats (homozygous 31/31 repeats reported for recessive SCA2)
Uncertain: 32 repeats
ALS risk allele: 30-32 repeats
Reduced penetrance: 33-34 repeats, may not develop symptoms or only very late in life
Full penetrance: ≥35 repeats
Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size, but may enhance the meiotic stability of the repeat
Sources: Expert list
Mendeliome v0.6813 SCA10 Bryony Thompson STR: SCA10 was added
STR: SCA10 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA10 were set to 20301354
Phenotypes for STR: SCA10 were set to Spinocerebellar ataxia 10 MIM#603516
Review for STR: SCA10 was set to GREEN
STR: SCA10 was marked as clinically relevant
Added comment: NM_013236​.2:c.1430+54822ATTCT[X]
Toxic RNA gain-of-function mechanism of disease
Normal alleles: 10-32 ATTCT repeats
Alleles of questionable significance: 33-280 ATTCT repeats
Reduced-penetrance alleles: 33-850 repeats
Full-penetrance alleles: 800-4,500 ATTCT repeats
Sources: Expert list
Mendeliome v0.6810 INPP4A Zornitza Stark gene: INPP4A was added
gene: INPP4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Phenotypes for gene: INPP4A were set to Intellectual disability
Review for gene: INPP4A was set to AMBER
Added comment: Two families reported with bi-allelic variants and a neurological phenotype. Supportive mouse model and expression data.
Sources: Literature
Mendeliome v0.6808 SATB1 Zornitza Stark edited their review of gene: SATB1: Changed publications: 33513338
Mendeliome v0.6807 SATB1 Zornitza Stark Publications for gene: SATB1 were set to 33057194
Mendeliome v0.6805 SATB1 Zornitza Stark reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6804 MKS1 Zornitza Stark Publications for gene: MKS1 were set to
Mendeliome v0.6802 MKS1 Zornitza Stark reviewed gene: MKS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17377820, 24886560, 19776033, 33193692, 27570071, 27377014, 18327255, 24608809; Phenotypes: Joubert syndrome 28, MIM# 617121, MONDO:0014928, Meckel syndrome 1, MIM# 249000, MONDO:0009571, Bardet-Biedl syndrome 13, MIM# 615990, MONDO:0014441; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6801 FLII Zornitza Stark gene: FLII was added
gene: FLII was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLII were set to 32870709
Phenotypes for gene: FLII were set to Dilated cardiomyopathy
Review for gene: FLII was set to AMBER
Added comment: Two unrelated families reported with homozygous missense variants. Emerging evidence.
Sources: Literature
Mendeliome v0.6799 RHBDF1 Zornitza Stark gene: RHBDF1 was added
gene: RHBDF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RHBDF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHBDF1 were set to 32870709
Phenotypes for gene: RHBDF1 were set to Dilated cardiomyopathy
Review for gene: RHBDF1 was set to AMBER
Added comment: Three families reported with homozygous variants in this gene and onset of DCM in infancy/childhood. Two of the families had the same truncating variant, indicative of founder effect, and one family had a homozygous missense variant.
Sources: Literature
Mendeliome v0.6797 MYLK3 Zornitza Stark gene: MYLK3 was added
gene: MYLK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy
Review for gene: MYLK3 was set to AMBER
Added comment: Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Mendeliome v0.6795 NRAP Zornitza Stark gene: NRAP was added
gene: NRAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NRAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRAP were set to 33534821; 30384889; 28611399; 32870709
Phenotypes for gene: NRAP were set to Dilated cardiomyopathy
Review for gene: NRAP was set to GREEN
Added comment: Twenty unrelated families reported with childhood onset DCM.
Sources: Literature
Mendeliome v0.6793 MPEG1 Zornitza Stark gene: MPEG1 was added
gene: MPEG1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754
Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223
Review for gene: MPEG1 was set to GREEN
Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus.

Four individuals reported, functional data, including animal model.
Sources: Expert list
Mendeliome v0.6792 INPP5E Zornitza Stark Publications for gene: INPP5E were set to 19668216; 32139166; 29230161; 29052317; 27998989; 27401686
Mendeliome v0.6791 INPP5E Zornitza Stark edited their review of gene: INPP5E: Changed publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686, 19668215
Mendeliome v0.6790 INPP5E Zornitza Stark Publications for gene: INPP5E were set to
Mendeliome v0.6788 INPP5E Zornitza Stark reviewed gene: INPP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686; Phenotypes: Joubert syndrome 1, MIM# 213300, MONDO:0008944, Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156, MONDO:0012423; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6787 CSPP1 Zornitza Stark Publications for gene: CSPP1 were set to
Mendeliome v0.6785 CSPP1 Zornitza Stark reviewed gene: CSPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360808, 24360803, 24360807, 25997910; Phenotypes: Joubert syndrome 21, MIM# 615636, MONDO:0014288; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6784 CEP41 Zornitza Stark Publications for gene: CEP41 were set to
Mendeliome v0.6782 CEP41 Zornitza Stark reviewed gene: CEP41: Rating: GREEN; Mode of pathogenicity: None; Publications: 22246503; Phenotypes: Joubert syndrome 15, MIM# 614464; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6781 SCA1 Bryony Thompson STR: SCA1 was added
STR: SCA1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA1 were set to 29325606; 20301363
Phenotypes for STR: SCA1 were set to Spinocerebellar ataxia 1 MIM#164400
STR: SCA1 was marked as clinically relevant
Added comment: NM_000332.3:c.589_591CAG[X]
Toxic protein aggregation is mechanism of disease
Normal: ≤35 CAG repeats or 36-44 CAG repeats with CAT interruptions
Mutable normal (intermediate): 36-38 CAG repeats without CAT interruptions
Full-penetrance: ≥39 CAG repeats without CAT interruptions or ≥46 uninterrupted CAG repeats with CAT interruptions and additional CAGs
Sources: Expert list
Mendeliome v0.6779 RANBP2 Bryony Thompson reviewed gene: RANBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19118815, 25128471, 25522933, 32048120; Phenotypes: {Encephalopathy, acute, infection-induced, 3, susceptibility to} MIM#608033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6779 NCSTN Bryony Thompson reviewed gene: NCSTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20929727, 21412258, 32048120; Phenotypes: Acne inversa, familial, 1 MIM#142690; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6778 PSENEN Bryony Thompson Publications for gene: PSENEN were set to
Mendeliome v0.6776 PSENEN Bryony Thompson reviewed gene: PSENEN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20929727, 21412258, 27900998; Phenotypes: Acne inversa, familial, 2, with or without Dowling-Degos disease MIM#613736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6774 ESCO2 Zornitza Stark Publications for gene: ESCO2 were set to
Mendeliome v0.6772 ESCO2 Zornitza Stark reviewed gene: ESCO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32977150; Phenotypes: Juberg-Hayward syndrome, MIM# 216100, Roberts-SC phocomelia syndrome, MIM#268300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6772 RNF113A Bryony Thompson Publications for gene: RNF113A were set to 25612912; 31793730
Mendeliome v0.6771 RNF113A Bryony Thompson Added comment: Comment on list classification: Additional cases published
Mendeliome v0.6769 ALDH1L2 Naomi Baker gene: ALDH1L2 was added
gene: ALDH1L2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALDH1L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH1L2 were set to PMID: 31341639; 33168096
Phenotypes for gene: ALDH1L2 were set to pruritic ichthyosis, severe diffuse hypomyelination seen on MRI, and abnormal lipid peaks
Review for gene: ALDH1L2 was set to RED
Added comment: Individual reported with bialleleic ALDH1L2 variants (non-canonical splice and a frameshift mutation), who also has a de novo hemizygous RPS6KA3 frameshift mutation. Authors state that not all features of the individual could be explained by the RPS6KA3 variant, and that consideration of Coffin-Lowry sysndrome was only made after identification of the RPS6KA3 variant. Therefore individual has there is a blended phenotype of Coffin–Lowry syndrome and Sjögren–Larsson syndrome. From functional studies authors propose that the ALDH1L2 loss induces mitochondrial dysfunction due to reduced NADPH and increased oxidative stress (PMID: 31341639). Knockout mouse model was viable and did not show an apparent phenotype, however metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Authors therefore postulate that the role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous disease.
Sources: Literature
Mendeliome v0.6768 FAM57B Zornitza Stark gene: FAM57B was added
gene: FAM57B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM57B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM57B were set to 33077892
Phenotypes for gene: FAM57B were set to Cone–rod dystrophy; Maculopathy
Review for gene: FAM57B was set to GREEN
Added comment: 4 patients with cone-rod dystrophy or maculopathy from 3 families, with LOF pathogenic variants in TLCD3B (ceramide synthase gene). Ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. Variants segregated with disease. TLCD3B showed high expression in the adult retina with higher expression in the macular than in the peripheral region. Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina.
Sources: Literature
Mendeliome v0.6766 LRRC8A Bryony Thompson changed review comment from: A single case reported with a reciprocal translocation, t(9;20)(q33.2;q12), and demonstrated truncation of the LRRC8A gene. No other supporting evidence; to: A single case reported with a reciprocal translocation, t(9;20)(q33.2;q12), and demonstrated truncation of the LRRC8A gene. No other supporting evidence could be identified.
Mendeliome v0.6766 LRRC8A Bryony Thompson reviewed gene: LRRC8A: Rating: RED; Mode of pathogenicity: None; Publications: 14660746; Phenotypes: ?Agammaglobulinemia 5 MIM#613506; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6765 SIAE Bryony Thompson reviewed gene: SIAE: Rating: RED; Mode of pathogenicity: None; Publications: 20555325, 28900629, 22200769; Phenotypes: {Autoimmune disease, susceptibility to, 6} MIM#613551; Mode of inheritance: Unknown
Mendeliome v0.6763 TAOK2 Bryony Thompson gene: TAOK2 was added
gene: TAOK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAOK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TAOK2 were set to 28385331; 29467497
Phenotypes for gene: TAOK2 were set to Generalized verrucosis; abnormal T cell activation
Review for gene: TAOK2 was set to AMBER
Added comment: PMID: 28385331 - A single consanguineous family with generalized verrucosis and abnormal T cell activation, and a homozygous missense (p.R700C), with some assays on patient fibroblasts.
PMID: 29467497 - One of the several genes in the 16p11.2 microdeletion region associated with autism. Taok2 heterozygous and knockout mice had gene dosage-dependent impairments in cognition, anxiety, social interaction, brain size, and neural connectivity. 3 de novo variants and 3 predicted loss of function variants identified in 6 unrelated autism cases. 2 of the de novo variants have supporting functional assays, but 1 of them co-occurs in an individual with a CHD8 frameshift. 1 of the predicted loss of function variants was also identified in the unaffected father and sibling.
Sources: Literature
Mendeliome v0.6761 CC2D2A Zornitza Stark Publications for gene: CC2D2A were set to
Mendeliome v0.6759 CC2D2A Zornitza Stark reviewed gene: CC2D2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18387594, 18950740, 18513680, 18950740, 19574260, 21725307, 33486889; Phenotypes: Joubert syndrome 9, MIM# 612285, Meckel syndrome 6, MIM# 612284, COACH syndrome 2, MIM# 619111; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6757 INVS Zornitza Stark Publications for gene: INVS were set to
Mendeliome v0.6755 INVS Paul De Fazio reviewed gene: INVS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872123, 19177160; Phenotypes: Nephronophthisis 2, infantile, (MIM#602088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6754 ZCCHC8 Bryony Thompson gene: ZCCHC8 was added
gene: ZCCHC8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZCCHC8 were set to 31488579
Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis
Review for gene: ZCCHC8 was set to AMBER
Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model.
Sources: Literature
Mendeliome v0.6753 KDM5B Zornitza Stark reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, Intellectual disability and/or autism, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6752 KDM5B Zornitza Stark Publications for gene: KDM5B were set to
Mendeliome v0.6749 TPP2 Zornitza Stark Publications for gene: TPP2 were set to
Mendeliome v0.6747 TPP2 Zornitza Stark reviewed gene: TPP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25525876, 25414442, 33586135, 18362329; Phenotypes: Immunodeficiency 78 with autoimmunity and developmental delay, MIM# 619220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6745 DOCK7 Zornitza Stark Publications for gene: DOCK7 were set to
Mendeliome v0.6743 UBAP1 Zornitza Stark Publications for gene: UBAP1 were set to 31203368; 31696996
Mendeliome v0.6742 UBAP1 Zornitza Stark changed review comment from: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.; to: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.

PMID 32934340: additional 7 families. Median age of onset 10yrs.
Mendeliome v0.6742 UBAP1 Zornitza Stark edited their review of gene: UBAP1: Changed publications: 31696996, 32934340
Mendeliome v0.6741 RTN2 Zornitza Stark Publications for gene: RTN2 were set to
Mendeliome v0.6739 RTN2 Zornitza Stark reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22232211, 27165006; Phenotypes: Spastic paraplegia 12, autosomal dominant, 604805, MONDO:0011489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6739 KDM5B Elena Savva reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29276005, 30217758, 30409806; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, autosomal dominant autism spectrum disorder or intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6738 NIPA1 Zornitza Stark Publications for gene: NIPA1 were set to
Mendeliome v0.6736 NIPA1 Zornitza Stark reviewed gene: NIPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14508710, 15711826, 32500351, 25133278; Phenotypes: Spastic paraplegia 6, autosomal dominant, MIM# 600363, MONDO:0010878; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6736 DOCK7 Paul De Fazio reviewed gene: DOCK7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24814191, 30771731, 30807358; Phenotypes: Developmental and epileptic encephalopathy 23 MIM#615859; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6735 DDHD1 Zornitza Stark Publications for gene: DDHD1 were set to
Mendeliome v0.6733 DDHD1 Zornitza Stark reviewed gene: DDHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 28, autosomal recessive, 609340, MONDO:0012256; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6733 CPT1C Zornitza Stark Publications for gene: CPT1C were set to 25751282; 23973755
Mendeliome v0.6732 CPT1C Zornitza Stark reviewed gene: CPT1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 30564185; Phenotypes: Spastic paraplegia 73, autosomal dominant MIM#616282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6731 CAPN1 Zornitza Stark Publications for gene: CAPN1 were set to 27153400
Mendeliome v0.6728 AP5Z1 Zornitza Stark Publications for gene: AP5Z1 were set to
Mendeliome v0.6726 AP5Z1 Zornitza Stark reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26085577, 33543803, 27606357; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647, MONDO:0013342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6725 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature
Mendeliome v0.6722 SLC1A4 Zornitza Stark Publications for gene: SLC1A4 were set to
Mendeliome v0.6718 TFG Zornitza Stark reviewed gene: TFG: Rating: GREEN; Mode of pathogenicity: None; Publications: 30467354, 30157421, 28124177, 27601211, 27492651, 23479643, 25098539, 23553329, 22883144, 31449671, 31111683; Phenotypes: Hereditary motor and sensory neuropathy, Okinawa type, MIM# 604484, Spastic paraplegia 57, autosomal recessive, MIM# 615658; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6717 WDR45B Zornitza Stark Publications for gene: WDR45B were set to
Mendeliome v0.6715 WDR45B Zornitza Stark reviewed gene: WDR45B: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 28503735, 27431290; Phenotypes: Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, MIM# 617977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6714 REEP2 Zornitza Stark Publications for gene: REEP2 were set to
Mendeliome v0.6712 REEP2 Zornitza Stark reviewed gene: REEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33526816, 28491902, 24388663; Phenotypes: Spastic paraplegia 72, dominant and recessive, MIM# 615625, MONDO:0014282; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6711 NT5C2 Zornitza Stark Publications for gene: NT5C2 were set to
Mendeliome v0.6709 NT5C2 Zornitza Stark reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 32153630, 29123918, 28884889, 28327087; Phenotypes: Spastic paraplegia 45, autosomal recessive, MIM# 613162, MONDO:0013165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6708 HACE1 Zornitza Stark Publications for gene: HACE1 were set to
Mendeliome v0.6706 HACE1 Zornitza Stark reviewed gene: HACE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26424145, 26437029, 31321300; Phenotypes: Spastic paraplegia and psychomotor retardation with or without seizures, 616756, MONDO:0014764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6705 NKX6-2 Zornitza Stark Publications for gene: NKX6-2 were set to
Mendeliome v0.6703 NKX6-2 Zornitza Stark reviewed gene: NKX6-2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28575651, 15601927, 32246862, 32004679; Phenotypes: Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, MIM# 617560, MONDO:0033043; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6702 ARPC1B Zornitza Stark Publications for gene: ARPC1B were set to
Mendeliome v0.6700 ARPC1B Zornitza Stark reviewed gene: ARPC1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28368018, 33679784; Phenotypes: Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease 617718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6700 KIDINS220 Zornitza Stark Publications for gene: KIDINS220 were set to 33205811; 28934391; 22048169; 27005418
Mendeliome v0.6699 KIDINS220 Zornitza Stark edited their review of gene: KIDINS220: Added comment: Note additional family with severe prenatal phenotype and bi-allelic variants reported in PMID 32909676, so total of 3 unrelated families for bi-allelic fetal phenotype.; Changed publications: 27005418, 32909676
Mendeliome v0.6698 KDM5C Zornitza Stark Publications for gene: KDM5C were set to
Mendeliome v0.6696 KDM5C Zornitza Stark reviewed gene: KDM5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 15586325, 32279304; Phenotypes: Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534, MONDO:0010355; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6695 ENTPD1 Zornitza Stark Publications for gene: ENTPD1 were set to
Mendeliome v0.6693 ENTPD1 Zornitza Stark reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 30652007; Phenotypes: Spastic paraplegia 64, autosomal recessive MIM#615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6692 C12orf65 Zornitza Stark Publications for gene: C12orf65 were set to
Mendeliome v0.6690 C12orf65 Zornitza Stark reviewed gene: C12orf65: Rating: GREEN; Mode of pathogenicity: None; Publications: 23188110, 24080142, 24198383, 20598281, 32808965, 32478789, 28804760; Phenotypes: Spastic paraplegia 55, autosomal recessive, MIM#615035, Combined oxidative phosphorylation deficiency 7, MIM# 613559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6689 C19orf12 Zornitza Stark Publications for gene: C19orf12 were set to
Mendeliome v0.6687 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33688131, 21981780, 22508347, 23269600, 31804703, 30088953, 20039086; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM# 614298, Spastic paraplegia 43, autosomal recessive, MIM# 615043; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6686 CYP2U1 Zornitza Stark Publications for gene: CYP2U1 were set to
Mendeliome v0.6684 CYP2U1 Zornitza Stark edited their review of gene: CYP2U1: Added comment: SPG56 is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy. Onset is typically in the first decade. More than 5 unrelated families reported.; Changed rating: GREEN; Changed publications: 23176821, 32006740, 29034544
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6683 KLC4 Zornitza Stark gene: KLC4 was added
gene: KLC4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLC4 were set to 26423925
Phenotypes for gene: KLC4 were set to Complicated hereditary spastic paraplegia
Review for gene: KLC4 was set to RED
Added comment: Single family reported.
Sources: Expert Review
Mendeliome v0.6681 AP4M1 Zornitza Stark Publications for gene: AP4M1 were set to
Mendeliome v0.6679 AP4M1 Zornitza Stark reviewed gene: AP4M1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19559397, 21937992, 21937992, 32979048, 31915823, 29096665, 28464862, 25496299; Phenotypes: Spastic paraplegia 50, autosomal recessive, MIM# 612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6678 ADAMTS13 Zornitza Stark Publications for gene: ADAMTS13 were set to
Mendeliome v0.6676 ADAMTS13 Zornitza Stark reviewed gene: ADAMTS13: Rating: GREEN; Mode of pathogenicity: None; Publications: 11586351, 30312976; Phenotypes: Thrombotic thrombocytopenic purpura, hereditary, MIM# 274150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6675 AP4S1 Zornitza Stark Publications for gene: AP4S1 were set to
Mendeliome v0.6673 AP4S1 Zornitza Stark reviewed gene: AP4S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 25552650, 32979048, 32216065, 31915823, 30283821, 27444738; Phenotypes: Spastic paraplegia 52, autosomal recessive, MIM# 614067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6672 AIMP1 Zornitza Stark Publications for gene: AIMP1 were set to
Mendeliome v0.6670 AIMP1 Zornitza Stark reviewed gene: AIMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21092922, 24958424, 33402283, 32531460, 30486714, 30477741; Phenotypes: Leukodystrophy, hypomyelinating, 3, MIM# 260600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6670 UBA1 Zornitza Stark Publications for gene: UBA1 were set to 18179898; 32181232; 31932168; 29034082; 27699224; 26028276; 23518311; 33108101
Mendeliome v0.6669 UBA1 Zornitza Stark edited their review of gene: UBA1: Changed publications: 33690815; Changed phenotypes: VEXAS syndrome, somatic, MIM# 301054
Mendeliome v0.6667 WBP11 Zornitza Stark reviewed gene: WBP11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vertebral, cardiac, tracheoesophageal, renal, and limb defects, MIM# 619227; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6666 CC2D1A Zornitza Stark Publications for gene: CC2D1A were set to
Mendeliome v0.6664 CC2D1A Zornitza Stark reviewed gene: CC2D1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066123; Phenotypes: Autosomal recessive mental retardation, (MIM#608443); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6663 ZAP70 Zornitza Stark Publications for gene: ZAP70 were set to
Mendeliome v0.6660 ZAP70 Zornitza Stark reviewed gene: ZAP70: Rating: GREEN; Mode of pathogenicity: Other; Publications: 8124727, 8202712, 11412303, 26783323, 33628209, 33531381; Phenotypes: Immunodeficiency 48, MIM# 269840, Autoimmune disease, multisystem, infantile-onset, 2, MIM# 617006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6660 GDF5 Michelle Torres reviewed gene: GDF5: Rating: RED; Mode of pathogenicity: None; Publications: 8589725, 33333243; Phenotypes: ? Hunter-Thompson type acromesomelic dysplasia (MIM#201250) AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6659 CST3 Zornitza Stark Publications for gene: CST3 were set to
Mendeliome v0.6656 CST3 Zornitza Stark reviewed gene: CST3: Rating: AMBER; Mode of pathogenicity: None; Publications: 3495457; Phenotypes: Cerebral amyloid angiopathy, MIM# 105150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6655 NR3C1 Zornitza Stark Publications for gene: NR3C1 were set to
Mendeliome v0.6653 NR3C1 Zornitza Stark reviewed gene: NR3C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12754700, 1704018, 8445027, 31995340, 30158362; Phenotypes: Glucocorticoid resistance, OMIM # 615962; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6653 YY1AP1 Zornitza Stark Publications for gene: YY1AP1 were set to
Mendeliome v0.6652 YY1AP1 Zornitza Stark edited their review of gene: YY1AP1: Changed publications: 31633303, 30356112, 31270375, 22987684, 16691574, 27939641, 30556293
Mendeliome v0.6651 NOS3 Zornitza Stark Publications for gene: NOS3 were set to
Mendeliome v0.6649 NOS3 Zornitza Stark reviewed gene: NOS3: Rating: RED; Mode of pathogenicity: None; Publications: 24986538, 28084234, 33652340; Phenotypes: {Hypertension, susceptibility to}, MIM#145500, {Ischemic stroke, susceptibility to}, MIM# 601367, {Hypertension, pregnancy-induced}, MIM# 189800; Mode of inheritance: Unknown
Mendeliome v0.6648 CDT1 Zornitza Stark Publications for gene: CDT1 were set to
Mendeliome v0.6646 CDT1 Zornitza Stark reviewed gene: CDT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 21358631, 33338304, 22333897; Phenotypes: Meier-Gorlin syndrome 4, MIM# 613804, MONDO:0013431; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6645 CDK5RAP2 Zornitza Stark Publications for gene: CDK5RAP2 were set to
Mendeliome v0.6643 CDK5RAP2 Zornitza Stark reviewed gene: CDK5RAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15793586, 22887808, 23995685, 23726037, 27761245, 20460369, 32677750, 32015000; Phenotypes: Microcephaly 3, primary, autosomal recessive, MIM# 604804, MONDO:0011488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6642 UGT2B17 Ain Roesley reviewed gene: UGT2B17: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.6641 PLD1 Zornitza Stark Publications for gene: PLD1 were set to 27799408
Mendeliome v0.6639 PLD1 Zornitza Stark reviewed gene: PLD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27799408, 33645542; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6638 DONSON Zornitza Stark Publications for gene: DONSON were set to
Mendeliome v0.6636 DONSON Zornitza Stark reviewed gene: DONSON: Rating: GREEN; Mode of pathogenicity: None; Publications: 28191891, 28630177, 28191891; Phenotypes: Microcephaly, short stature, and limb abnormalities, MIM# 617604, Microcephaly-micromelia syndrome, MIM# 251230, MONDO:0009619; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6632 PGK1 Zornitza Stark Publications for gene: PGK1 were set to
Mendeliome v0.6630 PGK1 Zornitza Stark reviewed gene: PGK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 6933565, 1547346, 7577653, 9512313; Phenotypes: Phosphoglycerate kinase 1 deficiency, MIM# 300653; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.6629 PGM1 Zornitza Stark Publications for gene: PGM1 were set to
Mendeliome v0.6627 PGM1 Zornitza Stark reviewed gene: PGM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19625727, 24499211; Phenotypes: Congenital disorder of glycosylation, type It 614921, Glycogen storage disorder XIV; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6625 PHKA1 Zornitza Stark Publications for gene: PHKA1 were set to
Mendeliome v0.6623 PHKA1 Zornitza Stark reviewed gene: PHKA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7874115, 12825073, 9731190; Phenotypes: Muscle glycogenosis, MIM# 300559; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6622 PHKB Zornitza Stark Publications for gene: PHKB were set to
Mendeliome v0.6620 PHKB Zornitza Stark reviewed gene: PHKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 9215682, 25266922, 30659246; Phenotypes: Phosphorylase kinase deficiency of liver and muscle, autosomal recessive 261750, Glycogen storage disease IXb, MONDO:0009868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6619 PHKG2 Zornitza Stark Publications for gene: PHKG2 were set to
Mendeliome v0.6617 PHKG2 Zornitza Stark reviewed gene: PHKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8896567, 9384616, 10905889; Phenotypes: Glycogen storage disease IXc, MIM# 613027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6616 PYGL Zornitza Stark Publications for gene: PYGL were set to
Mendeliome v0.6614 PYGL Zornitza Stark reviewed gene: PYGL: Rating: GREEN; Mode of pathogenicity: None; Publications: 9529348, 9536091, 33505429, 32961316, 32892177; Phenotypes: Glycogen storage disease VI, MIM# 232700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6613 NHLRC1 Zornitza Stark Publications for gene: NHLRC1 were set to
Mendeliome v0.6611 NHLRC1 Zornitza Stark reviewed gene: NHLRC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21505799, 12958597; Phenotypes: Epilepsy, progressive myoclonic 2B (Lafora) 254780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6610 LDHA Zornitza Stark Publications for gene: LDHA were set to
Mendeliome v0.6608 LDHA Zornitza Stark reviewed gene: LDHA: Rating: GREEN; Mode of pathogenicity: None; Publications: 2334430, 1959923, 8327147; Phenotypes: Glycogen storage disease XI, MIM# 612933; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6606 RPL18 Zornitza Stark gene: RPL18 was added
gene: RPL18 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPL18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL18 were set to 28280134; 32075953
Phenotypes for gene: RPL18 were set to Diamond-Blackfan anemia 18, MIM# 618310
Review for gene: RPL18 was set to AMBER
Added comment: One family and a zebrafish model.
Sources: Expert list
Mendeliome v0.6605 RPS15A Zornitza Stark gene: RPS15A was added
gene: RPS15A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPS15A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS15A were set to 27909223
Phenotypes for gene: RPS15A were set to Diamond-Blackfan anemia 20, MIM# 618313
Review for gene: RPS15A was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.6604 RPL35 Zornitza Stark gene: RPL35 was added
gene: RPL35 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPL35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL35 were set to 28280134
Phenotypes for gene: RPL35 were set to Diamond-Blackfan anemia 19, MIM# 618312
Review for gene: RPL35 was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.6602 RPS7 Zornitza Stark Publications for gene: RPS7 were set to
Mendeliome v0.6600 RPS7 Zornitza Stark reviewed gene: RPS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 19061985, 23718193, 27882484, 32772263; Phenotypes: Diamond-Blackfan anemia 8, MIM# 612563, MONDO:0012939; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6599 RPS26 Zornitza Stark Publications for gene: RPS26 were set to
Mendeliome v0.6597 RPS26 Zornitza Stark reviewed gene: RPS26: Rating: GREEN; Mode of pathogenicity: None; Publications: 20116044, 23812780, 24942156; Phenotypes: Diamond-Blackfan anemia 10, MIM# 613309, MONDO:0013217; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6596 RPS24 Zornitza Stark Publications for gene: RPS24 were set to
Mendeliome v0.6594 RPS24 Zornitza Stark reviewed gene: RPS24: Rating: GREEN; Mode of pathogenicity: None; Publications: 17186470, 23812780, 25946618; Phenotypes: Diamond-blackfan anemia 3, MIM# 610629, MONDO:0012529; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6592 RPS19 Zornitza Stark Publications for gene: RPS19 were set to
Mendeliome v0.6590 RPS19 Zornitza Stark reviewed gene: RPS19: Rating: GREEN; Mode of pathogenicity: None; Publications: 9988267, 10590074; Phenotypes: Diamond-Blackfan anemia 1, MIM# 105650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6589 ACKR3 Zornitza Stark reviewed gene: ACKR3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Oculomotor-abducens synkinesis, MIM# 619215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6589 SIAH1 Arina Puzriakova gene: SIAH1 was added
gene: SIAH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Mendeliome v0.6587 RPL5 Zornitza Stark Publications for gene: RPL5 were set to
Mendeliome v0.6585 RPL5 Zornitza Stark reviewed gene: RPL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 19061985; Phenotypes: Diamond-Blackfan anemia 6, MIM# 612561, MONDO:0012937; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6584 RPL35A Zornitza Stark Publications for gene: RPL35A were set to
Mendeliome v0.6582 SYCP2L Arina Puzriakova gene: SYCP2L was added
gene: SYCP2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYCP2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCP2L were set to 32303603
Phenotypes for gene: SYCP2L were set to Premature ovarian insufficiency
Review for gene: SYCP2L was set to AMBER
Added comment: - PMID: 32303603 (2021) - Two unrelated individuals with premature ovarian insufficiency and homozygous variants (c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L.
In vitro assays revealed that mutant SYCP2L proteins induced mislocalisation and reduced expression. Sycp2l knockout mice exhibit accelerated reproductive ageing.
Sources: Literature
Mendeliome v0.6582 RPL35A Zornitza Stark reviewed gene: RPL35A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18535205, 32241839; Phenotypes: Diamond-Blackfan anemia 5, MIM# 612528; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6581 RPL27 Zornitza Stark Publications for gene: RPL27 were set to
Mendeliome v0.6578 RPL27 Zornitza Stark reviewed gene: RPL27: Rating: RED; Mode of pathogenicity: None; Publications: 25424902; Phenotypes: Diamond-Blackfan anemia 16, MIM# 617408; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6577 RPL11 Zornitza Stark Publications for gene: RPL11 were set to
Mendeliome v0.6575 RPL11 Zornitza Stark reviewed gene: RPL11: Rating: GREEN; Mode of pathogenicity: None; Publications: 19061985; Phenotypes: Diamond-Blackfan anemia 7, MIM# 612562, MONDO:0012938; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6573 TTC7A Zornitza Stark Publications for gene: TTC7A were set to 30553809; 28936210
Mendeliome v0.6572 TTC7A Zornitza Stark reviewed gene: TTC7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24417819, 24292712, 23830146, 29174094, 31743734; Phenotypes: Very Early Onset Inflammatory Bowel Disease (VEOIBD); Mode of inheritance: None
Mendeliome v0.6571 CLCN4 Zornitza Stark Publications for gene: CLCN4 were set to
Mendeliome v0.6569 CLCN4 Zornitza Stark reviewed gene: CLCN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27550844; Phenotypes: Raynaud-Claes syndrome, MIM#300114, intellectual disability, epilepsy, autistic features, mood disorders, cerebral white matter changes, progressive appendicular spasticity; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6567 EN1 Zornitza Stark changed review comment from: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature; to: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.

An additional fourth individual had cerebellar hypoplasia in addition to the skeletal phenotype, and a bi-allelic LoF variant.
Sources: Literature
Mendeliome v0.6566 EN1 Zornitza Stark gene: EN1 was added
gene: EN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EN1 were set to 33568816
Phenotypes for gene: EN1 were set to ENDOVE syndrome, limb-only type, MIM# 619217
Review for gene: EN1 was set to GREEN
Added comment: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature
Mendeliome v0.6563 EEF2 Zornitza Stark edited their review of gene: EEF2: Added comment: Phenotype reported in PMID 33355653 is distinct from the adult-onset SCA reported in PMID: 23001565. Evidence for association with SCA remains limited.; Changed rating: GREEN; Changed publications: 33355653; Changed phenotypes: Neurodevelopmental disorder, macrocephaly, hydrocephalus
Mendeliome v0.6561 EEF2 Zornitza Stark Publications for gene: EEF2 were set to 15732118; 23001565
Mendeliome v0.6558 MKRN3 Zornitza Stark Publications for gene: MKRN3 were set to
Mendeliome v0.6556 MKRN3 Zornitza Stark reviewed gene: MKRN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31687022, 31041429, 31636607, 32480405; Phenotypes: Precocious puberty, central, 2, MIM# 615346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6556 ACSL5 Zornitza Stark gene: ACSL5 was added
gene: ACSL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACSL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACSL5 were set to 33191500
Phenotypes for gene: ACSL5 were set to severe FTT (no OMIM #)
Review for gene: ACSL5 was set to RED
Added comment: 6 individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Autozygosity mapping and WES identified homozygous variant (c.1358C>A:p.(Thr453Lys) in ACSL5. Segregated with affected individuals. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss‐of‐function mutation without any remaining activity. Affected individuals were treated with total parenteral nutrition or medium‐chain triglyceride‐based formula restricted in long‐chain triglycerides. They responded well and follow up suggests that treatment is only required during early life.
Sources: Literature
Mendeliome v0.6554 GDF5 Zornitza Stark reviewed gene: GDF5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Type A1C brachydactyly (MIM#615072), Type A2 brachydactyly, (MIM#112600), Type C brachydactyly (MIM#113100), Grebe type chondrodysplasia (MIM#200700), Du Pan syndrome (MIM#228900), Multiple synostoses syndrome 2 (MIM#610017), Proximal Symphalangism 1B (MIM#615298); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6554 GDF5 Zornitza Stark Publications for gene: GDF5 were set to
Mendeliome v0.6552 EEF2 Eleanor Williams reviewed gene: EEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23001565, 33355653; Phenotypes: Spinocerebellar ataxia 26 MIM#609306; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6551 KIDINS220 Zornitza Stark Publications for gene: KIDINS220 were set to
Mendeliome v0.6549 KIDINS220 Zornitza Stark reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: None; Publications: 27005418; Phenotypes: Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6548 MYO15A Zornitza Stark Publications for gene: MYO15A were set to 27375115; 26226137; 23208854; 19309289; 9603735; 10915760
Mendeliome v0.6546 MYO3A Zornitza Stark Publications for gene: MYO3A were set to
Mendeliome v0.6544 MYO3A Zornitza Stark reviewed gene: MYO3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21165622, 26754646, 23990876; Phenotypes: Deafness, autosomal recessive 30, MIM# 607101; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6543 COL9A3 Zornitza Stark Publications for gene: COL9A3 were set to
Mendeliome v0.6541 COL9A3 Zornitza Stark reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30450842, 31090205, 24273071, 10090888, 15551337; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969, Stickler syndrome, Deafness; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6540 DLK1 Zornitza Stark gene: DLK1 was added
gene: DLK1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DLK1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: DLK1 were set to 28324015; 30462238
Phenotypes for gene: DLK1 were set to central precocious puberty
Review for gene: DLK1 was set to GREEN
Added comment: PMID: 30462238 "three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1". PMID: 28324015 single large family, only affected females, central precocious puberty all carrying paternally inherited LOF variant (del/dup of 5'UTR and exon 1) absent DLK1 expression in all affected. Unclear if males affected as none reported to date.
Sources: Expert Review
Mendeliome v0.6539 GDF5 Ain Roesley reviewed gene: GDF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33333243; Phenotypes: Type A1C brachydactyly (MIM#615072), Type A2 brachydactyly, (MIM#112600), Type C brachydactyly (MIM#113100), Grebe type chondrodysplasia (MIM#200700), Du Pan syndrome (MIM#228900), Multiple synostoses syndrome 2 (MIM#610017), Proximal Symphalangism 1B (MIM#615298); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6539 KIDINS220 Eleanor Williams reviewed gene: KIDINS220: Rating: AMBER; Mode of pathogenicity: None; Publications: 33205811, 28934391, 22048169; Phenotypes: cerebral ventriculomegaly, limb contractures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 MYO15A Eleanor Williams reviewed gene: MYO15A: Rating: ; Mode of pathogenicity: None; Publications: 33078831; Phenotypes: Deafness, autosomal recessive 3 OMIM:600316, autosomal recessive nonsyndromic deafness 3 MONDO:0010860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 MYO3A Eleanor Williams reviewed gene: MYO3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33078831, 26841241, 29880844; Phenotypes: Deafness, autosomal recessive 30 OMIM:607101, autosomal recessive nonsyndromic deafness 30 MONDO:0011774; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 COL9A3 Eleanor Williams reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33078831, 15917166; Phenotypes: autosomal recessive non-syndromic hearing impairment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6538 EIF5A Zornitza Stark gene: EIF5A was added
gene: EIF5A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: 7 unrelated individuals reported with de novo variants in this gene and variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism.
Sources: Literature
Mendeliome v0.6536 POLRMT Zornitza Stark gene: POLRMT was added
gene: POLRMT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 33602924
Phenotypes for gene: POLRMT were set to Mitochondrial disorder; intellectual disability; hypotonia
Review for gene: POLRMT was set to GREEN
Added comment: 8 individuals from 7 families reported. 5 families with bi-allelic variants and 2 with heterozygous variants. Affected individuals presented with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype.
Sources: Literature
Mendeliome v0.6534 PERP Zornitza Stark Publications for gene: PERP were set to 31898316
Mendeliome v0.6531 PERP Zornitza Stark edited their review of gene: PERP: Added comment: Four families reported with heterozygous variants and Olmsted syndrome-2 (OLMS2), which is characterised by mutilating hyperkeratotic skin lesions, primarily on the palms and soles, but also extending onto dorsal surfaces of the hands and feet and distal extremities. The lesions are progressive, becoming thicker with verrucous fissures on the palms and soles over time. In addition, affected individuals exhibit perioral hyperkeratosis, and may have lesions around other orifices as well, such as the nostrils, perineum, and anus. Most patients also have hyperkeratotic nails and light-colored woolly hair.

Two families reported with bi-allelic variants and Erythrokeratodermia variabilis et progressiva-7 (EKVP7), which is characterised by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet (transgrediens), as well as erythematous annular skin lesions. Pruritis, woolly hair, and dystrophic nails may also be present.; Changed rating: GREEN; Changed publications: 31898316, 30321533, 31361044; Changed phenotypes: Olmsted syndrome 2, MIM# 619208, Erythrokeratodermia variabilis et progressiva 7, MIM# 619209; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6529 KARS Zornitza Stark Publications for gene: KARS were set to
Mendeliome v0.6527 KARS Zornitza Stark reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 26741492, 31618474, 28887846, 25330800, 29615062, 30252186, 28496994, 23768514, 14975237; Phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Deafness, autosomal recessive 89, MIM# 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6527 APOO Zornitza Stark reviewed gene: APOO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, Lactic acidosis, Muscle weakness, Hypotonia, Repetitive infections, Cognitive impairment, Autistic behaviour; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.6526 APOO Arina Puzriakova gene: APOO was added
gene: APOO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOO was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: APOO were set to 32439808
Phenotypes for gene: APOO were set to Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour
Review for gene: APOO was set to RED
Added comment: - PMID: 32439808 (2021) - Three generation family with c.350T>C variant in APOO, encoding a component of the MICOS complex which plays a role in maintaining inner mitochondrial membrane architecture.
Phenotypes include fatigue and muscle weakness (6/8), learning difficulties and cognitive impairment (4/8), and increased blood lactate (2/8). Four individuals were asymptomatic carriers, including one male (authors indicate variability in female carriers was due to skewed X-inactivation, although skewing studies were inconclusive in some cases). Variability in clinical presentation suggests reduced penetrance or possible contribution of additional factors.
Functional studies showed altered MICOS assembly and abnormalities in mitochondria ultrastructure in patient-derived fibroblasts. Knockdown studies in Drosophila and yeast demonstrated mitochondrial structural and functional deficiencies.
Sources: Literature
Mendeliome v0.6525 ECE1 Zornitza Stark Publications for gene: ECE1 were set to
Mendeliome v0.6522 ECE1 Zornitza Stark reviewed gene: ECE1: Rating: RED; Mode of pathogenicity: None; Publications: 9915973, 9449665, 9449664; Phenotypes: Hirschsprung disease, cardiac defects, and autonomic dysfunction, OMIM # 613870; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6521 AMH Seb Lunke Publications for gene: AMH were set to
Mendeliome v0.6519 AMH Seb Lunke reviewed gene: AMH: Rating: GREEN; Mode of pathogenicity: None; Publications: 32172781; Phenotypes: Persistent Mullerian duct syndrome, type I (MIM#261550); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6518 PAX4 Zornitza Stark Publications for gene: PAX4 were set to
Mendeliome v0.6516 PAX4 Zornitza Stark reviewed gene: PAX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 17426099, 14561778, 25951767, 21263211; Phenotypes: Maturity-onset diabetes of the young, type IX MIM#612225, Diabetes mellitus, type 2, MIM# 125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6515 PCBD1 Zornitza Stark Publications for gene: PCBD1 were set to
Mendeliome v0.6513 PCBD1 Zornitza Stark reviewed gene: PCBD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24204001; Phenotypes: Hyperphenylalaninemia, BH4-deficient, D, MIM# 264070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6512 SPTAN1 Zornitza Stark Publications for gene: SPTAN1 were set to
Mendeliome v0.6510 SPTAN1 Zornitza Stark reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20493457, 22258530, 32811770; Phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6510 PSAP Zornitza Stark Publications for gene: PSAP were set to
Mendeliome v0.6508 PSAP Zornitza Stark reviewed gene: PSAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32201884; Phenotypes: Combined SAP deficiency 611721, Gaucher disease, atypical, MIM# 610539, Krabbe disease, atypical, MIM# 611722, Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6504 IRF4 Bryony Thompson Publications for gene: IRF4 were set to 29537367
Mendeliome v0.6502 IRF4 Bryony Thompson Added comment: Comment on list classification: Single case and mouse model for recessive combined immunodeficiency
Mendeliome v0.6501 IRF4 Bryony Thompson reviewed gene: IRF4: Rating: AMBER; Mode of pathogenicity: None; Publications: 29408330; Phenotypes: Combined immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6495 SPEN Chern Lim reviewed gene: SPEN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33596411; Phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6493 EPAS1 Seb Lunke Publications for gene: EPAS1 were set to
Mendeliome v0.6491 NLRP3 Alison Yeung Publications for gene: NLRP3 were set to
Mendeliome v0.6487 PCBD1 Michelle Torres reviewed gene: PCBD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24848070, 24204001; Phenotypes: MODY; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6487 SPTAN1 Melanie Marty reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33578420, 31332438; Phenotypes: hereditary motor neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6486 PSAP Ain Roesley reviewed gene: PSAP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32201884; Phenotypes: parkinson's disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6486 MED27 Alison Yeung gene: MED27 was added
gene: MED27 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia
Review for gene: MED27 was set to GREEN
gene: MED27 was marked as current diagnostic
Added comment: 16 patients from 11 families with balletic variants
Sources: Literature
Mendeliome v0.6485 ACTL9 Elena Savva gene: ACTL9 was added
gene: ACTL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL9 were set to PMID: 33626338
Phenotypes for gene: ACTL9 were set to Fertilization failure; male infertility
Review for gene: ACTL9 was set to GREEN
Added comment: Three families with homozygous pathogenic variants (two missense, one PTC). Single affected in each family. Functional analysis from patients shows all sperm had morphological defects, protein had reduced binding to ACTL7A
All variants very rare in gnomAD.
Sources: Literature
Mendeliome v0.6485 MAST2 Elena Savva gene: MAST2 was added
gene: MAST2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST2 were set to PMID: 33465109
Phenotypes for gene: MAST2 were set to Thrombophilia; venous thrombosis
Review for gene: MAST2 was set to RED
Added comment: Single missense identified in a family with venous thrombosis and thrombophilia. Missense variant reviewed by in silicos only. Shown to affect regulation of TFP1 and SERPINE1 gene expression.

RNAi of MAST2 followed by RNAseq showed expression changes in many downstream targets
Sources: Literature
Mendeliome v0.6485 ANGPTL6 Seb Lunke reviewed gene: ANGPTL6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33106390; Phenotypes: Cerebral aneurysm; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6485 EPAS1 Teresa Zhao reviewed gene: EPAS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27292716, 19208626; Phenotypes: Familial erythrocytosis (MIM#4611783), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6485 NLRP3 Elena Savva reviewed gene: NLRP3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 25038238; Phenotypes: Familial cold inflammatory syndrome 1, MIM#120100, Muckle-Wells syndrome, MIM#191900, CINCA syndrome, MIM#607115, Deafness, autosomal dominant 34, with or without inflammation, MIM#617772, Keratoendothelitis fugax hereditaria, MIM#148200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6484 AGPS Zornitza Stark Publications for gene: AGPS were set to
Mendeliome v0.6482 AGPS Zornitza Stark reviewed gene: AGPS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9553082, 8611652, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, MIM# 600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6481 BANF1 Zornitza Stark Publications for gene: BANF1 were set to
Mendeliome v0.6478 BANF1 Zornitza Stark reviewed gene: BANF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32783369, 21549337; Phenotypes: Nestor-Guillermo progeria syndrome, MIM# 614008; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6477 FOXP2 Zornitza Stark Publications for gene: FOXP2 were set to
Mendeliome v0.6475 FOXP2 Zornitza Stark reviewed gene: FOXP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15877281, 15983371, 27336128; Phenotypes: Speech-language disorder-1, MIM# 602081; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6474 GLI3 Zornitza Stark Publications for gene: GLI3 were set to
Mendeliome v0.6472 KIF22 Zornitza Stark Publications for gene: KIF22 were set to 22152677; 22152678
Mendeliome v0.6471 KIF22 Zornitza Stark reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: 25256152; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2, MIM# 603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6470 KIF22 Zornitza Stark Publications for gene: KIF22 were set to
Mendeliome v0.6467 ANKZF1 Bryony Thompson gene: ANKZF1 was added
gene: ANKZF1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ANKZF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANKZF1 were set to 28302725
Phenotypes for gene: ANKZF1 were set to Infantile-onset inflammatory bowel disease
Review for gene: ANKZF1 was set to AMBER
Added comment: Two unrelated cases (1 homozygous and 1 compound heterozygous), and supporting in vitro and yeast assays indicating that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity.
Sources: Other
Mendeliome v0.6465 ANGPT1 Bryony Thompson gene: ANGPT1 was added
gene: ANGPT1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ANGPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPT1 were set to 28601681; 24852101; 30689269; 10617467; 8980224
Phenotypes for gene: ANGPT1 were set to Hereditary angioedema
Review for gene: ANGPT1 was set to AMBER
Added comment: A missense variant (A119S) identified in 4 affected individuals in a single family. Supportive data in patient cells, functional assays of the variant, and animal models (both overexpression and null) for the gene.
Sources: Other
Mendeliome v0.6464 CLTCL1 Bryony Thompson Added comment: Comment on list classification: A single family, but also some compelling functional data for an association with insensitivity to pain.
Mendeliome v0.6463 CLTCL1 Bryony Thompson gene: CLTCL1 was added
gene: CLTCL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLTCL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLTCL1 were set to 26068709; 29402896; 22511880; 31354784
Phenotypes for gene: CLTCL1 were set to Congenital insensitivity to pain
Review for gene: CLTCL1 was set to AMBER
Added comment: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons.

PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system

Other reports of associations with limited evidence:
PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided.

PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively.
Sources: Literature
Mendeliome v0.6462 KIF22 Elena Savva reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22152677, 22152678; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6462 GLI3 Elena Savva reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32591344, 18000979, 24736735; Phenotypes: Polydactyly, postaxial, types A1 and B, MIM#174200, Greig cephalopolysyndactyly syndrome MIM#175700, Polydactyly, preaxial, type IV MIM#174700, Pallister-Hall syndrome MIM#146510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6461 C14orf39 Zornitza Stark reviewed gene: C14orf39: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 52, MIM# 619202, Premature ovarian failure 18 619203; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6459 G6PC Zornitza Stark Publications for gene: G6PC were set to
Mendeliome v0.6457 G6PC Zornitza Stark reviewed gene: G6PC: Rating: GREEN; Mode of pathogenicity: None; Publications: 8733042; Phenotypes: Glycogen storage disease Ia, MIM# 232200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6455 NMNAT2 Bryony Thompson gene: NMNAT2 was added
gene: NMNAT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NMNAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT2 were set to 31132363; 25271157; 20126265
Phenotypes for gene: NMNAT2 were set to polyneuropathy; erythromelalgia
Review for gene: NMNAT2 was set to AMBER
Added comment: A single family with siblings with a homozygous variant that confers a partial loss of function. Strong supporting functional evidence that the gene plays a key role in axonal survival.
Sources: Literature
Mendeliome v0.6453 CCT5 Bryony Thompson Publications for gene: CCT5 were set to
Mendeliome v0.6450 USF1 Bryony Thompson reviewed gene: USF1: Rating: RED; Mode of pathogenicity: None; Publications: 14991056, 16076849, 31725952; Phenotypes: Hyperlipidemia, familial combined, susceptibility to MIM#602491; Mode of inheritance: Unknown
Mendeliome v0.6450 PDXK Bryony Thompson Publications for gene: PDXK were set to 31187503
Mendeliome v0.6449 PDXK Bryony Thompson Added comment: Comment on list classification: Additional family published in 2020
Mendeliome v0.6446 LIPI Bryony Thompson reviewed gene: LIPI: Rating: RED; Mode of pathogenicity: None; Publications: 12719377; Phenotypes: Hypertriglycidaemia, familial; Mode of inheritance: Unknown
Mendeliome v0.6445 GALNT12 Bryony Thompson reviewed gene: GALNT12: Rating: RED; Mode of pathogenicity: None; Publications: 19617566, 30523343, 29749045; Phenotypes: Colorectal cancer, susceptibility to, 1 MIM#608812; Mode of inheritance: Unknown
Mendeliome v0.6444 ABCG2 Bryony Thompson reviewed gene: ABCG2: Rating: RED; Mode of pathogenicity: None; Publications: 22246505, 20368174, 26810134; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.6443 SAT1 Bryony Thompson reviewed gene: SAT1: Rating: RED; Mode of pathogenicity: None; Publications: 12215835, 20672378, 9228047; Phenotypes: Keratosis follicularis spinulosa decalvans; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6443 ALPI Zornitza Stark Publications for gene: ALPI were set to 29567797
Mendeliome v0.6441 ALPI Zornitza Stark edited their review of gene: ALPI: Added comment: Third family reported 2020, PMID 32084423.; Changed rating: GREEN; Changed publications: 29567797, 32084423
Mendeliome v0.6440 MIR5004 Bryony Thompson reviewed gene: MIR5004: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.6439 TOGARAM1 Zornitza Stark Publications for gene: TOGARAM1 were set to 32747439
Mendeliome v0.6437 TOGARAM1 Zornitza Stark reviewed gene: TOGARAM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32453716; Phenotypes: Joubert syndrome 37, MIM# 619185; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6436 ALDOA Zornitza Stark Publications for gene: ALDOA were set to
Mendeliome v0.6434 ALDOA Zornitza Stark reviewed gene: ALDOA: Rating: GREEN; Mode of pathogenicity: None; Publications: 7331996, 8598869, 25392908; Phenotypes: Glycogen storage disease XII , MIM#611881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6433 RDH5 Zornitza Stark Publications for gene: RDH5 were set to
Mendeliome v0.6430 RPGRIP1 Zornitza Stark Publications for gene: RPGRIP1 were set to
Mendeliome v0.6428 RPGRIP1 Ain Roesley reviewed gene: RPGRIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33308271, 31666973; Phenotypes: Cone-rod dystrophy 13 (MIM#608194) , Leber congenital amaurosis (MIM#61382); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6427 IRX4 Zornitza Stark Publications for gene: IRX4 were set to
Mendeliome v0.6424 IRX4 Zornitza Stark reviewed gene: IRX4: Rating: RED; Mode of pathogenicity: None; Publications: 21544582; Phenotypes: Ventricular septal defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6423 AKAP6 Zornitza Stark Publications for gene: AKAP6 were set to
Mendeliome v0.6419 ASCC3 Bryony Thompson gene: ASCC3 was added
gene: ASCC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASCC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASCC3 were set to 21937992; https://doi.org/10.1016/j.xhgg.2021.100024
Phenotypes for gene: ASCC3 were set to Neuromuscular syndrome; congenital myopathy
Review for gene: ASCC3 was set to GREEN
Added comment: 11 individuals from 7 unrelated families with homozygous (missense) or compound heterozygous variants (missense with a presumed LoF variant or 2 missense, no biallelic LoF) with a neurologic phenotype that ranges from severe developmental delay to muscle fatigue.
Sources: Literature
Mendeliome v0.6418 RDH5 Ain Roesley reviewed gene: RDH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32232344; Phenotypes: Fundus albipunctatus (MIM#136880); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6417 HS2ST1 Zornitza Stark reviewed gene: HS2ST1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6415 ARSG Bryony Thompson Publications for gene: ARSG were set to 29300381; 20679209; 25452429; 26975023; 32455177
Mendeliome v0.6414 ARSG Bryony Thompson Added comment: Comment on list classification: 2 additional families reported, upgraded to green
Mendeliome v0.6413 ARSG Bryony Thompson reviewed gene: ARSG: Rating: GREEN; Mode of pathogenicity: None; Publications: 33300174, 29300381, 32455177, 26975023; Phenotypes: Usher syndrome, type IV MIM#618144; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6412 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Mendeliome v0.6411 LMNB1 Zornitza Stark edited their review of gene: LMNB1: Changed phenotypes: Microcephaly 26, primary, autosomal dominant, MIM# 619179, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis, Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Mendeliome v0.6409 CRYM Zornitza Stark Publications for gene: CRYM were set to
Mendeliome v0.6407 CRYM Paul De Fazio reviewed gene: CRYM: Rating: GREEN; Mode of pathogenicity: None; Publications: 32742378, 12471561, 16740909, 18448257, 24676347, 26915689; Phenotypes: Deafness, autosomal dominant 40 MIM#616357; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.6406 HARS Zornitza Stark Publications for gene: HARS were set to 26072516
Mendeliome v0.6404 HARS Elena Savva reviewed gene: HARS: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32333447, 32940403, 26072516; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2W MIM#616625, Usher syndrome type 3B MIM#614504, Multisystemic ataxic syndrome; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6400 PMVK Zornitza Stark gene: PMVK was added
gene: PMVK was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PMVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMVK were set to 26202976
Phenotypes for gene: PMVK were set to Porokeratosis 1, multiple types, MIM# 175800
Review for gene: PMVK was set to GREEN
Added comment: At least 9 individuals reported.
Sources: Expert Review
Mendeliome v0.6398 MVD Zornitza Stark gene: MVD was added
gene: MVD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MVD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MVD were set to 30942823; 33491095
Phenotypes for gene: MVD were set to Porokeratosis 7, multiple types, MIM# 614714
Review for gene: MVD was set to GREEN
Added comment: Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. At least 5 individuals reported.
Sources: Expert list
Mendeliome v0.6395 UNC45B Zornitza Stark reviewed gene: UNC45B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myofibrillar myopathy 11, MIM# 619178; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6394 SHROOM3 Zornitza Stark gene: SHROOM3 was added
gene: SHROOM3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SHROOM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHROOM3 were set to 32621286
Phenotypes for gene: SHROOM3 were set to Anencephaly; cleft lip and palate
Review for gene: SHROOM3 was set to AMBER
Added comment: Animal model and other functional data link SHROOM3 to neural tube development. Single family reported with bi-allelic LoF in a fetus with anencephaly and CL/P.
Sources: Expert Review
Mendeliome v0.6392 FLT3 Zornitza Stark reviewed gene: FLT3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.6392 MSL3 Zornitza Stark Phenotypes for gene: MSL3 were changed from to Basilicata-Akhtar syndrome, OMIM # 301032
Mendeliome v0.6391 MSL3 Zornitza Stark Publications for gene: MSL3 were set to
Mendeliome v0.6389 MSL3 Zornitza Stark reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33173220; Phenotypes: Basilicata-Akhtar syndrome, OMIM # 301032; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6388 TOE1 Zornitza Stark Publications for gene: TOE1 were set to
Mendeliome v0.6386 TOE1 Zornitza Stark reviewed gene: TOE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28092684; Phenotypes: Pontocerebellar hypoplasia, type 7, MIM# 614969; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6385 VRK1 Zornitza Stark Publications for gene: VRK1 were set to
Mendeliome v0.6382 SPTBN2 Zornitza Stark Publications for gene: SPTBN2 were set to
Mendeliome v0.6379 SEPSECS Zornitza Stark Publications for gene: SEPSECS were set to
Mendeliome v0.6377 SEPSECS Zornitza Stark reviewed gene: SEPSECS: Rating: GREEN; Mode of pathogenicity: None; Publications: 20920667, 25044680, 31748115, 29464431; Phenotypes: Pontocerebellar hypoplasia type 2D, MIM# 613811; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6376 ITPR1 Zornitza Stark Publications for gene: ITPR1 were set to
Mendeliome v0.6374 ITPR1 Zornitza Stark reviewed gene: ITPR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27108797, 31340402, 30242502, 29169895; Phenotypes: Gillespie syndrome, MIM# 206700; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6373 EXOSC8 Zornitza Stark Publications for gene: EXOSC8 were set to
Mendeliome v0.6371 EXOSC8 Zornitza Stark reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia, type 1C, MIM# 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6370 EXOSC3 Zornitza Stark Publications for gene: EXOSC3 were set to
Mendeliome v0.6368 EXOSC3 Zornitza Stark reviewed gene: EXOSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22544365, 23284067, 24524299; Phenotypes: Pontocerebellar hypoplasia, type 1B, MIM# 614678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6367 CLP1 Zornitza Stark Publications for gene: CLP1 were set to
Mendeliome v0.6365 CLP1 Zornitza Stark reviewed gene: CLP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24766809, 29307788; Phenotypes: Pontocerebellar hypoplasia type 10, MIM# 615803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6364 CHMP1A Zornitza Stark Publications for gene: CHMP1A were set to
Mendeliome v0.6362 CHMP1A Zornitza Stark reviewed gene: CHMP1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23023333; Phenotypes: Pontocerebellar hypoplasia, type 8, MIM# 614961; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6361 BRF1 Zornitza Stark Publications for gene: BRF1 were set to
Mendeliome v0.6359 BRF1 Zornitza Stark reviewed gene: BRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25561519, 25561519, 27748960; Phenotypes: Cerebellofaciodental syndrome, MIM# 616202; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6358 DHODH Zornitza Stark Publications for gene: DHODH were set to
Mendeliome v0.6356 DHODH Zornitza Stark reviewed gene: DHODH: Rating: GREEN; Mode of pathogenicity: None; Publications: 19915526, 20220176, 33262786, 27370710; Phenotypes: Miller syndrome, MIM# 263750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6355 ITGB4 Zornitza Stark Publications for gene: ITGB4 were set to
Mendeliome v0.6353 ITGB4 Zornitza Stark reviewed gene: ITGB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11328943, 9670011, 33225458, 30079450, 29380424, 29198538, 28557647; Phenotypes: Epidermolysis bullosa of hands and feet, MIM# 131800, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650, Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6352 LAMA3 Zornitza Stark Publications for gene: LAMA3 were set to
Mendeliome v0.6350 LAMA3 Zornitza Stark reviewed gene: LAMA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 7633458, 8530087, 11810295, 10366601; Phenotypes: Epidermolysis bullosa, generalized atrophic benign, MIM# 226650, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6349 LAMB3 Zornitza Stark Publications for gene: LAMB3 were set to
Mendeliome v0.6347 LAMB3 Zornitza Stark reviewed gene: LAMB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11023379, 7706760; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6346 LAMC2 Zornitza Stark Publications for gene: LAMC2 were set to
Mendeliome v0.6344 LAMC2 Zornitza Stark reviewed gene: LAMC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11810295, 25888738, 24533970; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6342 KRT5 Zornitza Stark reviewed gene: KRT5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dowling-Degos disease 1, MIM# 179850, Epidermolysis bullosa simplex-MCR, MIM# 609352, Epidermolysis bullosa simplex-MP 131960, Epidermolysis bullosa simplex, Dowling-Meara type, MIM# 131760, Epidermolysis bullosa simplex, Koebner type, MIM# 131900, Epidermolysis bullosa simplex, recessive 1, MIM# 601001, Epidermolysis bullosa simplex, Weber-Cockayne type, MIM# 131800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6341 CLCN6 Zornitza Stark Publications for gene: CLCN6 were set to 25794116; 21107136
Mendeliome v0.6339 ITGA6 Zornitza Stark Publications for gene: ITGA6 were set to
Mendeliome v0.6337 ITGA6 Zornitza Stark reviewed gene: ITGA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31502654, 27607025, 9158140; Phenotypes: Epidermolysis bullosa, junctional, with pyloric stenosis, MIM# 226730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6336 ITGA3 Zornitza Stark Publications for gene: ITGA3 were set to
Mendeliome v0.6334 ITGA3 Zornitza Stark reviewed gene: ITGA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22512483, 25810266, 27717396, 32198874, 26854491; Phenotypes: Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital, MIM# 614748; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6333 FERMT1 Zornitza Stark Publications for gene: FERMT1 were set to
Mendeliome v0.6331 FERMT1 Zornitza Stark reviewed gene: FERMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12789646; Phenotypes: Kindler syndrome, MIM# 173650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6330 EXPH5 Zornitza Stark Publications for gene: EXPH5 were set to
Mendeliome v0.6328 EXPH5 Zornitza Stark reviewed gene: EXPH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176819, 32176379, 27730671, 27384765; Phenotypes: Epidermolysis bullosa, nonspecific, autosomal recessive, MIM# 615028; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6326 COL7A1 Zornitza Stark reviewed gene: COL7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: EBD inversa, MIM# 226600, EBD, Bart type MIM# 132000, EBD, localisata variant, Epidermolysis bullosa dystrophica, MIM# 131750, Epidermolysis bullosa dystrophica, 226600, Epidermolysis bullosa pruriginosa 604129, Epidermolysis bullosa, pretibial, MIM# 131850, Transient bullous of the newborn 131705; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6325 IGSF1 Zornitza Stark Publications for gene: IGSF1 were set to
Mendeliome v0.6323 IGSF1 Zornitza Stark reviewed gene: IGSF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27310681, 30086211, 24108313, 26840047, 27762734, 23143598; Phenotypes: Hypothyroidism, central, and testicular enlargement, MIM# 300888; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.6320 FSTL5 Eleanor Williams gene: FSTL5 was added
gene: FSTL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSTL5 was set to Unknown
Publications for gene: FSTL5 were set to 33105483
Phenotypes for gene: FSTL5 were set to isolated club-foot; iTEV; Talipes equinovarus
Review for gene: FSTL5 was set to RED
Added comment: PMID: 33105483 - Khanshour et al 20201 - GWAS study of isolated Talipes equinovarus (clubfoot, iTEV) identified an associated locus within FSTL5. They show that Fstl5 is expressed in the embryonic hindlimb in bats, chicks and mice. However, Fstl5 was expressed more highly in neural tissues in mice, and rats lacking Fstl5 showed no gross developmental malformations. Conditional overexpression of Fstl5 in osteochondroprogenitors resulted in sexually dimorphic differences in skeletal development in mice.
Sources: Literature
Mendeliome v0.6320 NCOA3 Eleanor Williams gene: NCOA3 was added
gene: NCOA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCOA3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCOA3 were set to 33326993
Phenotypes for gene: NCOA3 were set to non-syndromic hearing loss
Review for gene: NCOA3 was set to RED
Added comment: PMID: 33326993 - Salazar da Silva et al 2020 - report a 5 generation Brazilian family with 15 individuals with non-syndromic, bilateral and progressive hearing loss. Using linkage analysis and then exome sequencing they identified a heterozygous variant in NCOA3 (NM_181659, c.2810C > G; p.Ser937Cys) that was found in the 7 analysed affected individuals. It was also found in 4 unaffected individuals but they are within the range of onset of hearing loss observed in the family. Expression of nco3 was found in the inner ear of mice and zebrafish. ncoa3-/- zebrafish showed subtle alterations in cartilage, mineral density and abnormal adult swimming behaviour, which may suggest the mechanism of pathogenicity.
Sources: Literature
Mendeliome v0.6319 CFHR3 Zornitza Stark Publications for gene: CFHR3 were set to
Mendeliome v0.6317 CFHR3 Zornitza Stark reviewed gene: CFHR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to} MIM#235400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6316 CFHR1 Zornitza Stark Publications for gene: CFHR1 were set to
Mendeliome v0.6314 CFHR1 Zornitza Stark reviewed gene: CFHR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to} MIM#235400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6314 CFHR3 Elena Savva reviewed gene: CFHR3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:32424742; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to} MIM#235400, {Macular degeneration, age-related, reduced risk of} MIM#603075; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6314 CFHR1 Elena Savva reviewed gene: CFHR1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:32424742; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to} MIM#235400, {Macular degeneration, age-related, reduced risk of} MIM#603075; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6313 OTUD5 Zornitza Stark Publications for gene: OTUD5 were set to 33131077
Mendeliome v0.6311 OTUD5 Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931; Changed phenotypes: Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056
Mendeliome v0.6310 SCARB1 Bryony Thompson Publications for gene: SCARB1 were set to
Mendeliome v0.6308 SCARB1 Bryony Thompson Added comment: Comment on list classification: Benign clinical phenotype
Mendeliome v0.6307 SCARB1 Bryony Thompson reviewed gene: SCARB1: Rating: ; Mode of pathogenicity: None; Publications: 21226579, 30720493, 21480869, 26965621, 27604308; Phenotypes: High density lipoprotein cholesterol level QTL6 MIM#610762, Scavenger receptor class B type I deficiency, Inherited hypolipidaemias; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6306 CETP Bryony Thompson Publications for gene: CETP were set to
Mendeliome v0.6304 CETP Bryony Thompson Added comment: Comment on list classification: Benign metabolic condition
Mendeliome v0.6303 CETP Bryony Thompson reviewed gene: CETP: Rating: ; Mode of pathogenicity: None; Publications: 12070157, 2586614, 27604308, 2215607, 2390095; Phenotypes: Hyperalphalipoproteinemia MIM#143470, Disorders of high density lipoprotein metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6301 DMGDH Bryony Thompson reviewed gene: DMGDH: Rating: ; Mode of pathogenicity: None; Publications: 11231903, 18937046, 28881522, 27604308; Phenotypes: Dimethylglycine dehydrogenase deficiency MIM#605850, Disorders and variants of other enzymes that oxidise xenobiotics; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6300 CD320 Bryony Thompson Publications for gene: CD320 were set to
Mendeliome v0.6299 CD320 Bryony Thompson Added comment: Comment on list classification: Benign clinical condition
Mendeliome v0.6298 CD320 Bryony Thompson reviewed gene: CD320: Rating: ; Mode of pathogenicity: None; Publications: 29663633, 27604308, 30303736; Phenotypes: Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646, Disorders of cobalamin absorption, transport and metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6298 SHPK Bryony Thompson Added comment: Comment on list classification: Likely benign disorder
Mendeliome v0.6297 SHPK Bryony Thompson gene: SHPK was added
gene: SHPK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHPK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHPK were set to 25647543; 27604308
Phenotypes for gene: SHPK were set to Sedoheptulokinase deficiency MIM#617213
Review for gene: SHPK was set to AMBER
Added comment: 2 unrelated cases reported, with elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense variant. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Due to inconsistency in phenotypes, likely SHPK deficiency is a benign disorder.
Sources: Literature
Mendeliome v0.6296 PNLIP Bryony Thompson Added comment: Comment on list classification: Appears to be a clinically benign metabolic condition
Mendeliome v0.6295 PNLIP Bryony Thompson gene: PNLIP was added
gene: PNLIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PNLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308
Phenotypes for gene: PNLIP were set to Pancreatic lipase deficiency MIM#614338; disorders of lipid and lipoprotein metabolism
Review for gene: PNLIP was set to GREEN
Added comment: 4 cases from 2 unrelated families, with supporting biochemical assays in patient cells and cellular-based assays. The cases have decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health.
Sources: Literature
Mendeliome v0.6294 TDO2 Zornitza Stark gene: TDO2 was added
gene: TDO2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TDO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDO2 were set to 28285122; 27604308
Phenotypes for gene: TDO2 were set to Hypertryptophanemia MIM#600627; Disorders of histidine, tryptophan or lysine metabolism
Review for gene: TDO2 was set to RED
Added comment: Single case reported, biochemical phenotype of hypertryptophanemia and hyperserotoninemia does not appear to have significant clinical consequences
Sources: Expert list
Mendeliome v0.6292 SUGCT Zornitza Stark Publications for gene: SUGCT were set to
Mendeliome v0.6289 SUGCT Zornitza Stark reviewed gene: SUGCT: Rating: AMBER; Mode of pathogenicity: None; Publications: 28766179, 18926513, 33483254, 32779420, 27604308; Phenotypes: Glutaric aciduria III MIM#231690, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6288 SLC36A2 Zornitza Stark Publications for gene: SLC36A2 were set to
Mendeliome v0.6285 SLC36A2 Zornitza Stark reviewed gene: SLC36A2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19033659, 26141664, 27604308; Phenotypes: Hyperglycinuria MIM#138500, Iminoglycinuria, digenic MIM#242600, Disorders of amino acid transport; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6284 SARDH Zornitza Stark Publications for gene: SARDH were set to
Mendeliome v0.6281 SARDH Zornitza Stark reviewed gene: SARDH: Rating: AMBER; Mode of pathogenicity: None; Publications: 22825317, 27604308; Phenotypes: Sarcosinemia MIM#268900, Disorders of serine, glycine or glycerate metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6280 OPLAH Zornitza Stark Publications for gene: OPLAH were set to
Mendeliome v0.6277 OPLAH Zornitza Stark reviewed gene: OPLAH: Rating: AMBER; Mode of pathogenicity: None; Publications: 27604308, 27477828; Phenotypes: 5-oxoprolinase deficiency MIM#260005, Disorders of the gamma-glutamyl cycle; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6276 KHK Zornitza Stark Publications for gene: KHK were set to
Mendeliome v0.6273 KHK Zornitza Stark reviewed gene: KHK: Rating: AMBER; Mode of pathogenicity: None; Publications: 7833921, 27604308, 29870677; Phenotypes: Fructosuria MIM#229800, Disorders of fructose metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6272 HAL Zornitza Stark Publications for gene: HAL were set to
Mendeliome v0.6269 HAL Zornitza Stark reviewed gene: HAL: Rating: AMBER; Mode of pathogenicity: None; Publications: 27604308, 15806399, 20156889; Phenotypes: Histidinemia MIM#235800, Disorders of histidine, tryptophan or lysine metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6267 GGT1 Zornitza Stark reviewed gene: GGT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6266 DCXR Zornitza Stark gene: DCXR was added
gene: DCXR was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DCXR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCXR were set to 22042873
Phenotypes for gene: DCXR were set to Pentosuria MIM#260800; Disorders of pentose metabolism
Review for gene: DCXR was set to AMBER
Added comment: At least 9 Ashkenazi Jewish probands reported. The condition is clinically benign.
Sources: Expert list
Mendeliome v0.6264 CTH Zornitza Stark Publications for gene: CTH were set to
Mendeliome v0.6261 CTH Zornitza Stark reviewed gene: CTH: Rating: AMBER; Mode of pathogenicity: None; Publications: 12574942, 20584029, 24761004, 15151507; Phenotypes: Cystathioninuria MIM#219500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6260 ACSF3 Zornitza Stark Publications for gene: ACSF3 were set to
Mendeliome v0.6257 ACSF3 Zornitza Stark reviewed gene: ACSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: 21841779, 30740739; Phenotypes: Combined malonic and methylmalonic aciduria MIM#614265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6256 PHGDH Zornitza Stark Publications for gene: PHGDH were set to
Mendeliome v0.6254 PHGDH Zornitza Stark reviewed gene: PHGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24836451, 25152457, 11055895, 19235232; Phenotypes: Neu-Laxova syndrome 1 256520, Phosphoglycerate dehydrogenase deficiency 601815; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6253 REC114 Zornitza Stark reviewed gene: REC114: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte maturation defect 10, MIM# 619176; Mode of inheritance: None
Mendeliome v0.6252 PNP Zornitza Stark Publications for gene: PNP were set to
Mendeliome v0.6250 PNP Zornitza Stark reviewed gene: PNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 3029074, 1384322, 11453975, 32695102, 32514656; Phenotypes: Immunodeficiency due to purine nucleoside phosphorylase deficiency, MIM# 613179; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6249 PNPLA2 Zornitza Stark Publications for gene: PNPLA2 were set to
Mendeliome v0.6247 PNPLA2 Zornitza Stark reviewed gene: PNPLA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18952067, 25287355, 25956450, 21544567; Phenotypes: Neutral lipid storage disease with myopathy MIM#610717; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6247 RPIA Zornitza Stark reviewed gene: RPIA: Rating: GREEN; Mode of pathogenicity: None; Publications: 14988808, 31056085, 31247379; Phenotypes: Ribose 5-phosphate isomerase deficiency, MIM# 608611, Leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6246 ESRP2 Zornitza Stark Publications for gene: ESRP2 were set to
Mendeliome v0.6243 ESRP2 Zornitza Stark reviewed gene: ESRP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29805042; Phenotypes: Cleft lip; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6242 ACBD5 Zornitza Stark Publications for gene: ACBD5 were set to
Mendeliome v0.6240 ACBD5 Zornitza Stark reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 27799409, 23105016, 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, MIM# 618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6239 SAR1B Zornitza Stark Publications for gene: SAR1B were set to
Mendeliome v0.6237 SAR1B Zornitza Stark reviewed gene: SAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 12692552; Phenotypes: Chylomicron retention disease, MIM# 246700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6236 SC5D Zornitza Stark Publications for gene: SC5D were set to
Mendeliome v0.6234 SC5D Zornitza Stark reviewed gene: SC5D: Rating: GREEN; Mode of pathogenicity: None; Publications: 17853487, 12189593, 12812989, 24142275; Phenotypes: Lathosterolosis, MIM# 607330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6233 SLC39A14 Zornitza Stark Publications for gene: SLC39A14 were set to
Mendeliome v0.6231 SLC39A14 Zornitza Stark reviewed gene: SLC39A14: Rating: GREEN; Mode of pathogenicity: None; Publications: 27231142, 29685658; Phenotypes: Hypermanganesemia with dystonia 2, MIM# 617013; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6230 SLC46A1 Zornitza Stark Publications for gene: SLC46A1 were set to
Mendeliome v0.6228 SLC46A1 Zornitza Stark reviewed gene: SLC46A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17446347, 17129779, 21333572; Phenotypes: Folate malabsorption, hereditary, MIM# 229050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6227 ST3GAL3 Zornitza Stark Publications for gene: ST3GAL3 were set to
Mendeliome v0.6225 ST3GAL3 Zornitza Stark reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23252400, 21907012, 31584066; Phenotypes: Mental retardation, autosomal recessive 12 MIM# 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6225 DDX58 Zornitza Stark edited their review of gene: DDX58: Changed publications: 25620203, 30574673, 33495304
Mendeliome v0.6225 DDX58 Zornitza Stark Publications for gene: DDX58 were set to 25620203; 33495304
Mendeliome v0.6223 DDX58 Zornitza Stark Publications for gene: DDX58 were set to 25620203
Mendeliome v0.6221 DDX58 Zornitza Stark edited their review of gene: DDX58: Added comment: Prasov et al. 2021 (PMID: 33495304) - A heterozygous DDX58 variant (c.1529A>T) was identified in 5 individuals from 2 unrelated families from different ethnic backgrounds. Phenotypes varied with some being severely affected by systemic features and others solely with glaucoma.Functional analysis demonstrated the variant confers a dominant gain-of-function effect on interferon activity.; Changed mode of pathogenicity: Other; Changed publications: 25620203, 33495304
Mendeliome v0.6221 KL Bryony Thompson Publications for gene: KL were set to
Mendeliome v0.6218 KL Bryony Thompson reviewed gene: KL: Rating: AMBER; Mode of pathogenicity: None; Publications: 17710231, 31013726, 9363890; Phenotypes: Tumoral calcinosis, hyperphosphatemic, familial, 3 MIM#617994, Hyperphosphatemia; Mode of inheritance: None
Mendeliome v0.6217 GLRX2 Bryony Thompson reviewed gene: GLRX2: Rating: RED; Mode of pathogenicity: None; Publications: 25362663; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.6216 GLRX3 Bryony Thompson reviewed gene: GLRX3: Rating: RED; Mode of pathogenicity: None; Publications: 23615448; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.6215 GSTO2 Bryony Thompson reviewed gene: GSTO2: Rating: RED; Mode of pathogenicity: None; Publications: 12618591; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.6214 SIX1 Zornitza Stark Publications for gene: SIX1 were set to 15141091; 18330911; 21254961; 17637804; 29500469; 21700001; 24164807
Mendeliome v0.6212 BMP7 Zornitza Stark Publications for gene: BMP7 were set to 32266521; 24429398
Mendeliome v0.6211 BMP7 Zornitza Stark edited their review of gene: BMP7: Changed publications: 32266521, 24429398, 33434492
Mendeliome v0.6210 SIX1 Arina Puzriakova reviewed gene: SIX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33436522; Phenotypes: Sagittal synostosis, Multi-suture synostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6209 PRUNE1 Zornitza Stark Publications for gene: PRUNE1 were set to 26539891; 28334956
Mendeliome v0.6207 EGFR Eleanor Williams reviewed gene: EGFR: Rating: AMBER; Mode of pathogenicity: None; Publications: 33326033; Phenotypes: Adrenocortical carcinoma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6207 WBP11 Eleanor Williams gene: WBP11 was added
gene: WBP11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WBP11 were set to 33276377
Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems
Review for gene: WBP11 was set to GREEN
Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.
Sources: Literature
Mendeliome v0.6207 PRUNE1 Eleanor Williams reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33105479; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies , MIM#617481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6207 TTF2 Zornitza Stark gene: TTF2 was added
gene: TTF2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: TTF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TTF2 were set to 30022773
Phenotypes for gene: TTF2 were set to congenital hypothyroidism, thyroid dysgenesis, No OMIM #
Review for gene: TTF2 was set to RED
Added comment: 1 case only
Sources: Expert Review
Mendeliome v0.6205 DUOXA1 Zornitza Stark gene: DUOXA1 was added
gene: DUOXA1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DUOXA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DUOXA1 were set to 29650690
Phenotypes for gene: DUOXA1 were set to congenital hypothyroidism, No OMIM #
Review for gene: DUOXA1 was set to AMBER
Added comment: 12 cases, but digenic model with variants in other genes
Sources: Expert Review
Mendeliome v0.6203 DUOX1 Zornitza Stark gene: DUOX1 was added
gene: DUOX1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DUOX1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DUOX1 were set to 29650690
Phenotypes for gene: DUOX1 were set to congenital hypothyroidism, No OMIM #
Review for gene: DUOX1 was set to AMBER
Added comment: 11 cases, but digenic model, with variants in other genes.
Sources: Expert Review
Mendeliome v0.6201 TTF1 Zornitza Stark Publications for gene: TTF1 were set to
Mendeliome v0.6198 TTF1 Zornitza Stark reviewed gene: TTF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30022773; Phenotypes: congenital hypothyroidism, thyroid dysgenesis, No OMIM #; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6197 CDCA8 Zornitza Stark gene: CDCA8 was added
gene: CDCA8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CDCA8 were set to 28025328; 29546359
Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, thyroid dysgenesis, no OMIM #
Mode of pathogenicity for gene: CDCA8 was set to Other
Review for gene: CDCA8 was set to GREEN
Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants. GREEN for mono allelic, RED for biallelic.
Sources: Expert Review
Mendeliome v0.6195 DNAJC30 Zornitza Stark gene: DNAJC30 was added
gene: DNAJC30 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJC30 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC30 were set to 33465056
Phenotypes for gene: DNAJC30 were set to Leber Hereditary Optic Neuropathy
Review for gene: DNAJC30 was set to GREEN
Added comment: 33 individuals from 29 families had homozygous DNAJC30 missense variants. Three different variants identified (one responsible for most cases). All three variants absent from gnomAD. Incomplete penetrance and male predominance in affected individuals both typical of LHON due to mtDNA mutations. All 3 variants in the J domain of the protein. Functional evidence.
Sources: Literature
Mendeliome v0.6193 NFS1 Zornitza Stark edited their review of gene: NFS1: Added comment: Second paper reporting another family (consanguineous) with three affected children and supportive functional data. Homozygous for the same missense variant as reported in the 2014 paper - this family of Christian Arab descent; the family in the previous report of Mennonite background. Suggests this is a mutation hotspot.; Changed rating: GREEN; Changed publications: 24498631, 33457206
Mendeliome v0.6192 PCDH19 Zornitza Stark reviewed gene: PCDH19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Other
Mendeliome v0.6192 SLC7A6OS Zornitza Stark gene: SLC7A6OS was added
gene: SLC7A6OS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC7A6OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC7A6OS were set to 33085104
Phenotypes for gene: SLC7A6OS were set to Progressive myoclonus epilepsy
Review for gene: SLC7A6OS was set to RED
Added comment: Two unrelated families reported with same homozygous splice site variant, shared haplotype (founder effect). Limited functional data.
Sources: Literature
Mendeliome v0.6190 TLR8 Zornitza Stark gene: TLR8 was added
gene: TLR8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TLR8 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TLR8 were set to 33512449
Phenotypes for gene: TLR8 were set to Immunodeficiency; bone marrow failure
Mode of pathogenicity for gene: TLR8 was set to Other
Review for gene: TLR8 was set to GREEN
Added comment: Six unrelated males reported with a phenotype comprising neutropaenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure. Three different variants reported, the variant was somatic in 5/6 individuals. GoF mechanism demonstrated.
Sources: Literature
Mendeliome v0.6187 PIGF Paul De Fazio gene: PIGF was added
gene: PIGF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGF were set to 33386993
Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol\ deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Review for gene: PIGF was set to RED
gene: PIGF was marked as current diagnostic
Added comment: Identified in 2 individuals with a phenotype similar to DOORS (syndrome
Sources: Literature
Mendeliome v0.6187 BRWD1 Paul De Fazio gene: BRWD1 was added
gene: BRWD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BRWD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRWD1 were set to 33389130
Phenotypes for gene: BRWD1 were set to Asthenoteratozoospermia, likely primary ciliary dyskinesia
Review for gene: BRWD1 was set to GREEN
gene: BRWD1 was marked as current diagnostic
Added comment: Biallelic missense variants reported in 3 unrelated individuals. Apart from asthenoteratozoospermia, all 3 had PCD or "PCD-likely" symptoms of re-occurring airway infections, bronchiectasis, and rhinosinusitis. One individual had situs inversus. Studies on cells from one indivdidual showed abnormal respiratory cilia structure. BRWD1 staining was absent from respiratory cilia in this individual (present in controls).

Rated Green as there are three unrelated individuals reported.
Sources: Literature
Mendeliome v0.6184 HIRA Paul De Fazio gene: HIRA was added
gene: HIRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIRA were set to 33417013; 28135719; 25363760
Phenotypes for gene: HIRA were set to Neurodevelopmental disorder
Review for gene: HIRA was set to GREEN
gene: HIRA was marked as current diagnostic
Added comment: Two unrelated patients with different de novo loss of function variants identified in PMID 33417013:

Individual 1: intragenic deletion, phenotype included psychomotor retardation, ID, growth retardation, microcephaly, and facial features reminiscent of 22q deletion syndrome.
Individual 2: canonical splice variant, phenotype mostly confined to ASD

Another two de novo variants were identified in the literature by the authors of that paper, one stop-gain (DDD study, PMID 28135719) and one missense (large autism cohort, PMID 25363760).

PMID 33417013 also showed that HIRA knockdown in mice results in neurodevelopmental abnormalities.

Rated Green due to 4 unrelated individuals (albeit 2 in large cohort studies) and a mouse model. NB: HIRA is within the common 22q deletion region.
Sources: Literature
Mendeliome v0.6183 POLR3B Zornitza Stark Publications for gene: POLR3B were set to
Mendeliome v0.6179 EYA3 Paul De Fazio gene: EYA3 was added
gene: EYA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EYA3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EYA3 were set to 33475861
Phenotypes for gene: EYA3 were set to Oculo-auriculo-vertebral spectrum (OAVS)
Review for gene: EYA3 was set to RED
gene: EYA3 was marked as current diagnostic
Added comment: 3 individuals with OAVS from two unrelated families with the same missense variant, p.(Asn358Ser). Variant has 20 heterozygotes in gnomAD. Unaffected carriers in both families were also identified - unknown if incomplete penetrance or nonsegregation.

Functional studies indicate the variant increases protein half life, and gene knockdown in zebrafish had an effect on craniofacial development.

Rated Red due to both families sharing the variant and uncertainty about incomplete penetrance versus nonsegregation.
Sources: Literature
Mendeliome v0.6178 HEY2 Zornitza Stark gene: HEY2 was added
gene: HEY2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEY2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: HEY2 were set to 32820247
Phenotypes for gene: HEY2 were set to congenital heart defects and thoracic aortic aneurysms
Review for gene: HEY2 was set to RED
Added comment: A very large family affected by CHD and familial thoracic aortic aneurysms. Trio genome sequencing was carried out in an index patient with critical CHD, and family members had either exome or Sanger sequencing. Identified homozygous loss-of-function variant (c.318_319delAG, p.G108*) in HEY2 in 3 individuals in family with critical CHD, whereas the 20 heterozygous carriers show a spectrum of CVDs (CHD and FTAA, but varying expressivity and incomplete penetrance). Other studies show that knockout of HEY2 in mice results in cardiovascular defects (CVDs), including septal defects, cardiomyopathy, a thin-walled aorta, and valve anomalies.
Sources: Literature
Mendeliome v0.6176 FGF9 Zornitza Stark Publications for gene: FGF9 were set to
Mendeliome v0.6174 FGF9 Zornitza Stark reviewed gene: FGF9: Rating: GREEN; Mode of pathogenicity: None; Publications: 33140402, 28730625, 19589401, 33174625, 19219044, 28730625; Phenotypes: Multiple synostoses syndrome 3, OMIM # 612961; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6174 OTUD5 Zornitza Stark gene: OTUD5 was added
gene: OTUD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to 33131077
Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality
Review for gene: OTUD5 was set to RED
Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. No functional studies.
Sources: Literature
Mendeliome v0.6173 BCAT2 Bryony Thompson Marked gene: BCAT2 as ready
Mendeliome v0.6173 BCAT2 Bryony Thompson Gene: bcat2 has been classified as Green List (High Evidence).
Mendeliome v0.6173 BCAT2 Bryony Thompson Classified gene: BCAT2 as Green List (high evidence)
Mendeliome v0.6173 BCAT2 Bryony Thompson Gene: bcat2 has been classified as Green List (High Evidence).
Mendeliome v0.6172 BCAT2 Bryony Thompson changed review comment from: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS; to: 6 cases from 5 unrelated families with homozygous or compound heterozygous variant, and supporting functional studies demonstrating decreased BCAT2 enzyme activity for some of the variants. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
Mendeliome v0.6172 BCAT2 Bryony Thompson edited their review of gene: BCAT2: Changed rating: GREEN; Changed publications: 14755340, 25653144, 31177572
Mendeliome v0.6172 BCAT2 Bryony Thompson gene: BCAT2 was added
gene: BCAT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: BCAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAT2 were set to 14755340; 25653144
Phenotypes for gene: BCAT2 were set to Hypervalinemia or hyperleucine-isoleucinemia MIM#618850; disorder of branched-chain amino acid metabolism
Review for gene: BCAT2 was set to AMBER
Added comment: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
Mendeliome v0.6171 CLRN2 Paul De Fazio gene: CLRN2 was added
gene: CLRN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLRN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLRN2 were set to 33496845
Phenotypes for gene: CLRN2 were set to Non-syndromic hearing loss
Review for gene: CLRN2 was set to AMBER
gene: CLRN2 was marked as current diagnostic
Added comment: Missense variant segregates with non-syndromic hearing loss in 3 members of a consanguineous family, two from one nuclear family and one from another. The variant was also shown to result in some transcripts being abnormally spliced, resulting in a premature stop codon.

Functional studies in zebrafish and mice show the gene plays an essential role in normal organization and maintenance of the auditory hair bundles, and for hearing function.

Rated Amber due to supporting functional studies in mice.
Sources: Literature
Mendeliome v0.6171 POLR3B Elena Savva reviewed gene: POLR3B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33417887, 22036171, 22036172; Phenotypes: Ataxia, spasticity, and demyelinating neuropathy, Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism MIM#614381; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6171 CFAP47 Hazel Phillimore gene: CFAP47 was added
gene: CFAP47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP47 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: CFAP47 were set to PMID: 33472045
Phenotypes for gene: CFAP47 were set to asthenoteratozoospermia; morphological abnormalities of the flagella (MMAF)
Review for gene: CFAP47 was set to AMBER
Added comment: CFAP47 also known as CXorf22. 3 different missense variants in 3 unrelated Chinese individuals with asthenoteratozoospermia associated with morphological abnormalities of the flagella (MMAF). Immunoblotting and immunofluorescence showed reduced levels of CFAP47 in spermatozoa in all 3 men. A separate asthenoteratozoospermia cohort showed 1 individual with CNV including whole gene deletion of CFAP47.
Mouse model (with frameshift variants generated (via CRISPR-Cas9 technology) were sterile and presented with reduced sperm motility and abnormal flagellar morphology.
Sources: Literature
Mendeliome v0.6171 C14orf39 Elena Savva gene: C14orf39 was added
gene: C14orf39 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C14orf39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf39 were set to PMID: 33508233; 27796301
Phenotypes for gene: C14orf39 were set to Azoospermia; Premature ovarian insufficiency
Review for gene: C14orf39 was set to GREEN
Added comment: PMID: 33508233
- 1 family with two males (azoospermia) and 1 female (premature ovarian insufficiency)
- 2 unrelated Chinese males with azoospermia
All patients had either homozygous PTCs or splice

PMID: 27796301
Mouse K/O had azoospermia and ovarian failure
Sources: Literature
Mendeliome v0.6167 ENO1 Kristin Rigbye gene: ENO1 was added
gene: ENO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ENO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ENO1 were set to 32488097
Phenotypes for gene: ENO1 were set to Polymicrogyria
Review for gene: ENO1 was set to RED
Added comment: ENO1 identified as a polymicrogyria candidate gene from the smallest case of 1p36 duplication reported to date, in a 35yo F (onset at 8mo) presenting intellectual disability, microcephaly, epilepsy and perisylvian polymicrogyria. The duplication only encompassed 2 genes, ENO1 and RERE, and gene expression analysis performed using the patient cells revealed reduced expression, mimicking haploinsufficiency. Eno1 inactivation in rats was shown to cause a brain development defect. According to OMIM, ENO1 is deleted in glioblastoma, which is tolerated by the expression of ENO2.
Sources: Literature
Mendeliome v0.6166 SATB1 Elena Savva reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33513338; Phenotypes: Neurodevelopmental disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6166 METAP1 Paul De Fazio gene: METAP1 was added
gene: METAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: METAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METAP1 were set to PMID: 32764695
Phenotypes for gene: METAP1 were set to Intellectual disability, aggression, neurodevelopmental delay
Review for gene: METAP1 was set to RED
gene: METAP1 was marked as current diagnostic
Added comment: Biallelic nonsense (NMD-predicted) variant identified in 4 sibs in a consanguineous family with dev delay. One sib had bilateral clinodactyly of her toes and her left 3rd finger, other sibs were not dysmorphic. Rated red due to single consanguineous family.
Sources: Literature
Mendeliome v0.6165 CCDC186 Zornitza Stark gene: CCDC186 was added
gene: CCDC186 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146
Phenotypes for gene: CCDC186 were set to Epileptic encephalopathy
Review for gene: CCDC186 was set to RED
Added comment: One individual reported with bi-allelic truncating variant and EE.
Sources: Literature
Mendeliome v0.6164 KCNN2 Ain Roesley gene: KCNN2 was added
gene: KCNN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNN2 were set to 33242881
Phenotypes for gene: KCNN2 were set to neurodevelopmental movement disorders
Penetrance for gene: KCNN2 were set to unknown
Review for gene: KCNN2 was set to GREEN
Added comment: - 11 probands all de novo except for 1 mother-daughter pair.
- a mix of null and missense variants
- 2/11 with microcephaly, 10/11 motor delay, 7/11 language delay (excluding 2 with regression), all with varying degrees of ID, 3/11 seizures, 7/11 movement disorder, 4/11 cerebellar ataxia, 6/11 MRI anomalies

additional variants were noted in 2 patients: 1x cHet for variants in MED12L and 1x de novo TNK2 variant

patch clamp functional studies were also done
Sources: Literature
Mendeliome v0.6164 MYADML2 Paul De Fazio gene: MYADML2 was added
gene: MYADML2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYADML2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYADML2 were set to 32778762
Phenotypes for gene: MYADML2 were set to Cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles
Review for gene: MYADML2 was set to RED
gene: MYADML2 was marked as current diagnostic
Added comment: 5 sibs from a consanguineous family identified to have biallelic deletion encompassing part of the PYCR1 gene and the coding region of the MYADML2 gene.

According to the authors: "All five affected sibs had the most common features of ARCL (autosomal recessive cutis laxa) but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found."

Phenotype may still be explained by the PYCR1 deletion alone.
Sources: Literature
Mendeliome v0.6164 SQOR Zornitza Stark gene: SQOR was added
gene: SQOR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SQOR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQOR were set to 32160317
Phenotypes for gene: SQOR were set to Leigh-like disorder
Review for gene: SQOR was set to AMBER
Added comment: Two unrelated families and some functional data.
Sources: Literature
Mendeliome v0.6162 HYAL2 Zornitza Stark gene: HYAL2 was added
gene: HYAL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYAL2 were set to 28081210; 23172227; 26515055
Phenotypes for gene: HYAL2 were set to Cleft lip and palate; cor triatriatum; congenital cardiac malformations
Review for gene: HYAL2 was set to AMBER
Added comment: 2 unrelated consanguineous extended families (Amish and Arab) with an orofacial clefting phenotype with cardiac anomalies.
Sources: Literature
Mendeliome v0.6160 SLC6A20 Zornitza Stark Publications for gene: SLC6A20 were set to
Mendeliome v0.6158 SLC6A20 Zornitza Stark reviewed gene: SLC6A20: Rating: GREEN; Mode of pathogenicity: None; Publications: 24816252, 19033659; Phenotypes: Hyperglycinuria, MIM# 138500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6157 SUOX Zornitza Stark Publications for gene: SUOX were set to
Mendeliome v0.6155 SUOX Zornitza Stark reviewed gene: SUOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 9428520, 15952210, 31127934; Phenotypes: Sulfite oxidase deficiency, MIM# 272300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6147 DCT Zornitza Stark gene: DCT was added
gene: DCT was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DCT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCT were set to 33100333
Phenotypes for gene: DCT were set to Oculocutaneous albinism, type VIII, MIM# 619165
Review for gene: DCT was set to GREEN
Added comment: Two unrelated families reported. Functional data including mouse model.
Sources: Expert list
Mendeliome v0.6145 SDHAF1 Zornitza Stark Publications for gene: SDHAF1 were set to
Mendeliome v0.6143 SDHAF1 Zornitza Stark reviewed gene: SDHAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19465911, 26749241, 22995659; Phenotypes: Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6141 NDUFC2 Zornitza Stark gene: NDUFC2 was added
gene: NDUFC2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NDUFC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFC2 were set to 32969598
Phenotypes for gene: NDUFC2 were set to Mitochondrial complex I deficiency, nuclear type 36, MIM# 619170
Review for gene: NDUFC2 was set to AMBER
Added comment: Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome. Two unrelated families reported, some functional data.
Sources: Expert list
Mendeliome v0.6139 UPB1 Zornitza Stark Publications for gene: UPB1 were set to
Mendeliome v0.6137 UPB1 Zornitza Stark reviewed gene: UPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 24526388, 25638458, 22525402, 15385443, 17964839; Phenotypes: Beta-ureidopropionase deficiency, MIM# 613161; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6136 UROC1 Zornitza Stark Publications for gene: UROC1 were set to
Mendeliome v0.6133 UROC1 Zornitza Stark reviewed gene: UROC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19304569, 30619714; Phenotypes: Urocanase deficiency, MIM#276880; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6133 DLX4 Zornitza Stark gene: DLX4 was added
gene: DLX4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DLX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DLX4 were set to 25954033; 29738288
Phenotypes for gene: DLX4 were set to Orofacial cleft 15, MIM# 616788
Review for gene: DLX4 was set to RED
Added comment: Single family reported and a SNP association study.
Sources: Expert list
Mendeliome v0.6132 DLG1 Zornitza Stark gene: DLG1 was added
gene: DLG1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DLG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DLG1 were set to 28926086
Phenotypes for gene: DLG1 were set to Non-syndromic cleft lip and palate
Review for gene: DLG1 was set to RED
Added comment: GWAS study PMID: 28926086 found genome-wide significance for several SNPs within this gene, identifying it as a candidate gene for non-syndromic cleft lip with or without cleft palate.
Sources: Expert list
Mendeliome v0.6130 PLEKHA7 Zornitza Stark Publications for gene: PLEKHA7 were set to
Mendeliome v0.6127 PLEKHA7 Zornitza Stark reviewed gene: PLEKHA7: Rating: AMBER; Mode of pathogenicity: None; Publications: 29805042; Phenotypes: Cleft lip and palate; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6127 ALMS1 Elena Savva reviewed gene: ALMS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 17594715; Phenotypes: Alstrom syndrome MIM#203800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6126 GYS2 Zornitza Stark Publications for gene: GYS2 were set to
Mendeliome v0.6124 GYS2 Zornitza Stark reviewed gene: GYS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32395408, 28245189; Phenotypes: Glycogen storage disease 0, liver (MIM#240600); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6123 HNRNPU Elena Savva reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28944577, 28393272; Phenotypes: Developmental and epileptic encephalopathy 54 MIM# 617391; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6123 OPA3 Zornitza Stark Phenotypes for gene: OPA3 were changed from to 3-methylglutaconic aciduria, type III (MGA3) (MIM#258501), AR; Optic atrophy 3 with cataract (MIM#165300), AD
Mendeliome v0.6122 OPA3 Zornitza Stark Publications for gene: OPA3 were set to
Mendeliome v0.6119 OPA3 Zornitza Stark reviewed gene: OPA3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 25159689, 31119193, 31928268; Phenotypes: 3-methylglutaconic aciduria, type III (MGA3) (MIM#258501), AR, Optic atrophy 3 with cataract (MIM#165300), AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6118 FOXF1 Zornitza Stark Publications for gene: FOXF1 were set to
Mendeliome v0.6116 FOXF1 Zornitza Stark reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19500772, 23505205; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6116 FOXF1 Kristin Rigbye reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23505205, 27071622, 27855150; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins (MIM#265380), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6115 STEAP3 Zornitza Stark Publications for gene: STEAP3 were set to
Mendeliome v0.6112 STEAP3 Zornitza Stark reviewed gene: STEAP3: Rating: AMBER; Mode of pathogenicity: None; Publications: 22031863, 25515317; Phenotypes: Anemia, hypochromic microcytic, with iron overload 2, MIM# 615234; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6112 FTH1 Zornitza Stark gene: FTH1 was added
gene: FTH1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FTH1 were set to 11389486
Phenotypes for gene: FTH1 were set to Hemochromatosis, type 5, MIM# 615517
Review for gene: FTH1 was set to RED
Added comment: One multi-generational family with 5' UTR variant.
Sources: Expert list
Mendeliome v0.6111 CYBRD1 Zornitza Stark gene: CYBRD1 was added
gene: CYBRD1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CYBRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CYBRD1 were set to 15338274
Phenotypes for gene: CYBRD1 were set to Iron overload
Review for gene: CYBRD1 was set to RED
Added comment: Paucity of publications. One of the variants reported in PMID 15338274, p.Arg226His is present in over 1,000 hets in gnomad.
Sources: Expert list
Mendeliome v0.6109 BMP6 Zornitza Stark gene: BMP6 was added
gene: BMP6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: BMP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP6 were set to 26582087; 32464486
Phenotypes for gene: BMP6 were set to Iron overload, mild to moderate
Review for gene: BMP6 was set to GREEN
Added comment: More than 9 individuals reported with iron overload and variants in this gene.
Sources: Expert list
Mendeliome v0.6107 CREB3L3 Bryony Thompson gene: CREB3L3 was added
gene: CREB3L3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CREB3L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CREB3L3 were set to 32580631; 29954705; 27982131; 27291420; 26427795; 21666694
Phenotypes for gene: CREB3L3 were set to Hyperlipidaemia; hypertriglyceridemia
Review for gene: CREB3L3 was set to AMBER
Added comment: PMID: 26427795 - a loss of function variant (c.359delG p.K120fsX20) was identified in 2 affected adult siblings and a 13 yo normotriglyceridemic daughter of one of the siblings.
PMID: 21666694 - Lipoprotein profiles of the families of 4 individuals with CREB3L3 nonsense mutations showed a significantly elevated mean plasma TG level in 11 mutation carriers compared with 5 non-carrier first-degree relatives (9.67 ± 4.70 vs. 1.66 ± 0.55 mM, P = 0.021, Wilcoxon test). 3 of those families have the same variant - Lys245GlufsTer130, which has 126 (281,946 alleles) hets in gnomAD v2.1.
PMID: 32580631 - case-control analysis of nonmonogenic severe hypertriglyceridemia cases (N=265) vs normolipidemic controls (N=477), identified 5 cases with LoF variants (3 of whom had the Lys245GlufsTer130 frameshift) and none in controls. OR 20.2 (95% CI 1.11–366.1) p = 0.002, adjusted p = 0.03.
The frequency of Lys245GlufsTer130 is higher than expected for a dominant disorder, but other loss of function variants have been identified. The gene may be associated with variable penetrance. There are multiple supporting null mouse models with hyperlipidaemia.
Sources: Expert list
Mendeliome v0.6105 GPIHBP1 Bryony Thompson gene: GPIHBP1 was added
gene: GPIHBP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPIHBP1 were set to 17883852; 19304573; 20026666; 17403372
Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome
Review for gene: GPIHBP1 was set to GREEN
gene: GPIHBP1 was marked as current diagnostic
Added comment: Well-established cause of familial chylomicronemia (see OMIM). Greater than 3 families reported and a supporting mouse model.
Sources: Expert list
Mendeliome v0.6102 CBY1 Bryony Thompson gene: CBY1 was added
gene: CBY1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBY1 were set to 33131181; 25103236; 25220153
Phenotypes for gene: CBY1 were set to intellectual disability; cerebellar ataxia; molar tooth sign; polydactyly; Joubert syndrome
Review for gene: CBY1 was set to GREEN
Added comment: Three cases in two unrelated consanguineous families with homozygous loss of function variants. Multiple null model organisms recapitulate the human phenotype: Null mouse model had cystic kidneys, a phenotype common to ciliopathies. Reducing Cby levels in Xenopus laevis model reduced the density of multiciliated cells, the number of basal bodies per multiciliated cell, and the numbers of neural tube primary cilia; it also led to abnormal development of the neural crest, central nervous system, and pronephros. Depletion of cby1 in zebrafish results in ciliopathy‐related phenotypes.
Sources: Literature
Mendeliome v0.6100 ZMYND15 Bryony Thompson gene: ZMYND15 was added
gene: ZMYND15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYND15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZMYND15 were set to 24431330; 33169450; 20675388
Phenotypes for gene: ZMYND15 were set to Severe oligozoospermia
Review for gene: ZMYND15 was set to GREEN
Added comment: 4 unrelated consanguineous cases with homozygous loss of function variants. Zmynd15-null male mice display reduced testis weight and azoospermia
Sources: Literature
Mendeliome v0.6098 PNPLA1 Zornitza Stark Publications for gene: PNPLA1 were set to
Mendeliome v0.6096 PNPLA1 Zornitza Stark reviewed gene: PNPLA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22246504, 24344921, 26691440; Phenotypes: Ichthyosis, congenital, autosomal recessive 10, MIM# 615024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6095 TMEM251 Bryony Thompson gene: TMEM251 was added
gene: TMEM251 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM251 were set to 33252156
Phenotypes for gene: TMEM251 were set to Dysostosis multiplex‐like skeletal dysplasia; severe short stature
Review for gene: TMEM251 was set to AMBER
Added comment: Two unrelated consanguineous families with homozygous variants (c.133C>T; p.Arg45Trp and c.215dupA; p.Tyr72Ter), with co-segregation data in one family. Preliminary in vitro functional assays conducted - Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes.
Sources: Literature
Mendeliome v0.6093 LOR Zornitza Stark Publications for gene: LOR were set to
Mendeliome v0.6091 LOR Zornitza Stark reviewed gene: LOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8673107, 9326398, 9326323, 25234742, 25142840; Phenotypes: Vohwinkel syndrome with ichthyosis, MIM# 604117; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6090 CYP4F22 Zornitza Stark Publications for gene: CYP4F22 were set to
Mendeliome v0.6088 CYP4F22 Zornitza Stark reviewed gene: CYP4F22: Rating: GREEN; Mode of pathogenicity: None; Publications: 16436457; Phenotypes: Ichthyosis, congenital, autosomal recessive 5, MIM# 604777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6087 CERS3 Zornitza Stark Publications for gene: CERS3 were set to
Mendeliome v0.6085 CERS3 Zornitza Stark reviewed gene: CERS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23754960, 23549421, 31168818, 30578701; Phenotypes: Ichthyosis, congenital, autosomal recessive 9, MIM# 615023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6084 ALOX12B Zornitza Stark Publications for gene: ALOX12B were set to
Mendeliome v0.6082 ALOX12B Zornitza Stark reviewed gene: ALOX12B: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116617, 11773004; Phenotypes: Ichthyosis, congenital, autosomal recessive 2, MIM# 242100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6081 ALX3 Zornitza Stark Publications for gene: ALX3 were set to
Mendeliome v0.6078 ALX1 Zornitza Stark Publications for gene: ALX1 were set to
Mendeliome v0.6076 ALX1 Zornitza Stark reviewed gene: ALX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27324866, 20451171, 23059813; Phenotypes: Frontonasal dysplasia 3, MIM#613456; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6075 HIST1H1E Zornitza Stark Publications for gene: HIST1H1E were set to
Mendeliome v0.6073 HIST1H1E Zornitza Stark reviewed gene: HIST1H1E: Rating: GREEN; Mode of pathogenicity: None; Publications: 28475857, 33270410, 31910894, 31400068; Phenotypes: Rahman syndrome, MIM# 617537; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6072 EED Zornitza Stark Publications for gene: EED were set to
Mendeliome v0.6070 EED Zornitza Stark reviewed gene: EED: Rating: GREEN; Mode of pathogenicity: None; Publications: 25787343, 27193220, 27868325, 28229514; Phenotypes: Cohen-Gibson syndrome, MIM# 617561; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6069 CLCN1 Zornitza Stark Publications for gene: CLCN1 were set to
Mendeliome v0.6067 CLCN1 Zornitza Stark reviewed gene: CLCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1379744, 7981750, 8533761; Phenotypes: Myotonia congenita, dominant 160800, Myotonia congenita, recessive 255700; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6066 TUBG1 Zornitza Stark Publications for gene: TUBG1 were set to
Mendeliome v0.6064 TUBG1 Zornitza Stark reviewed gene: TUBG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 31086189; Phenotypes: Cortical dysplasia, complex, with other brain malformations 4, MIM# 615412; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6063 TUBB3 Zornitza Stark Publications for gene: TUBB3 were set to
Mendeliome v0.6061 TUBB3 Zornitza Stark reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20829227, 25059107, 33318778, 20074521; Phenotypes: Cortical dysplasia, complex, with other brain malformations 1, MIM# 614039, Fibrosis of extraocular muscles, congenital, 3A, MIM# 600638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6060 TUBB2B Zornitza Stark Publications for gene: TUBB2B were set to
Mendeliome v0.6058 TUBB2B Zornitza Stark reviewed gene: TUBB2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 19465910, 22333901, 26732629, 33082561; Phenotypes: Cortical dysplasia, complex, with other brain malformations 7, MIM# 610031; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6057 TUBB Zornitza Stark Publications for gene: TUBB were set to
Mendeliome v0.6055 TUBB Zornitza Stark reviewed gene: TUBB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23246003, 32085672; Phenotypes: Cortical dysplasia, complex, with other brain malformations 6, MIM# 615771; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6054 FZD4 Zornitza Stark Publications for gene: FZD4 were set to
Mendeliome v0.6052 FZD4 Zornitza Stark reviewed gene: FZD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21097938, 33302760, 31999491; Phenotypes: Exudative vitreoretinopathy 1, MIM# 133780; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6051 TSPAN12 Zornitza Stark Publications for gene: TSPAN12 were set to
Mendeliome v0.6049 TSPAN12 Zornitza Stark reviewed gene: TSPAN12: Rating: GREEN; Mode of pathogenicity: None; Publications: 20159111, 20159112, 21334594; Phenotypes: Exudative vitreoretinopathy 5, MIM# 613310; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6048 PPP2R5D Zornitza Stark Publications for gene: PPP2R5D were set to
Mendeliome v0.6044 KAT6B Zornitza Stark Publications for gene: KAT6B were set to
Mendeliome v0.6040 DVL1 Zornitza Stark Publications for gene: DVL1 were set to
Mendeliome v0.6036 SCAMP5 Zornitza Stark Publications for gene: SCAMP5 were set to 31439720
Mendeliome v0.6035 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Added comment: PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed publications: 31439720, 33390987
Mendeliome v0.6034 TSPYL1 Zornitza Stark Publications for gene: TSPYL1 were set to 15273283; 19463995; 22137496; 25449952; 16418600
Mendeliome v0.6032 ZNF526 Zornitza Stark Phenotypes for gene: ZNF526 were changed from to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Mendeliome v0.6031 ZNF526 Zornitza Stark Publications for gene: ZNF526 were set to
Mendeliome v0.6027 CYLD Zornitza Stark reviewed gene: CYLD: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6026 PPP2R5D Elena Savva reviewed gene: PPP2R5D: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32074998, 26168268; Phenotypes: Mental retardation, autosomal dominant 35, MIM#616355; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6026 KAT6B Elena Savva reviewed gene: KAT6B: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 22715153, 32424177; Phenotypes: SBBYSS syndrome MIM#603736, Genitopatellar syndrome MIM#606170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.6026 DVL1 Kristin Rigbye reviewed gene: DVL1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 25817014, 25817016; Phenotypes: Robinow syndrome, autosomal dominant 2 (MIM#616331); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Mendeliome v0.6026 ZFP36L1 Sebastian Lunke reviewed gene: ZFP36L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.6026 TSPYL1 Eleanor Williams reviewed gene: TSPYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32885560, 33075815; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome OMIM:608800, sudden infant death-dysgenesis of the testes syndrome MONDO:0012124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6026 ZNF526 Arina Puzriakova reviewed gene: ZNF526: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 25558065, 33397746; Phenotypes: Intellectual disability, Microcephaly, Cataracts, Epilepsy, Hypertonia, Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6024 BCS1L Zornitza Stark Publications for gene: BCS1L were set to
Mendeliome v0.6022 BCS1L Zornitza Stark edited their review of gene: BCS1L: Changed publications: 26563427, 24172246, 17314340
Mendeliome v0.6022 BCS1L Zornitza Stark reviewed gene: BCS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6021 MRPS22 Zornitza Stark Publications for gene: MRPS22 were set to
Mendeliome v0.6019 KRT10 Elena Savva reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 26176760, 20798280, 31638346, 18219278, 16505000; Phenotypes: Epidermolytic hyperkeratosis, MIM#113800, Ichthyosis with confetti, MIM#609165, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, MIM#607602; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6019 BRPF1 Elena Savva reviewed gene: BRPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32652122, 27939640; Phenotypes: Intellectual developmental disorder with dysmorphic facies and ptosis MIM#617333; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6019 INTS6 Elena Savva reviewed gene: INTS6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.6019 BCS1L Elena Savva reviewed gene: BCS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 17314340; Phenotypes: Bjornstad syndrome MIM#262000, GRACILE syndrome, MIM#603358, Mitochondrial complex III deficiency, nuclear type MIM#1124000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6019 MRPS22 Elena Savva reviewed gene: MRPS22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29566152; Phenotypes: Combined oxidative phosphorylation deficiency 5 MIM#611719, Ovarian dysgenesis 7 MIM#618117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6018 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Mendeliome v0.6016 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay.

The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Mendeliome v0.6014 SCUBE3 Zornitza Stark gene: SCUBE3 was added
gene: SCUBE3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature; skeletal abnormalities; craniofacial abnormalities; dental anomalies
Review for gene: SCUBE3 was set to GREEN
Added comment: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies.
Sources: Literature
Mendeliome v0.6012 UBR7 Zornitza Stark gene: UBR7 was added
gene: UBR7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: Seven individuals from 6 unrelated families. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile). Physical examination revealed various dysmorphic features, including prominent forehead (3/7), hypertelorism (4/7), telecanthus (1/7), epicanthus(1/7), downslanting palpebral fissures (3/7), thick eyebrow (1/7), low-set ears (3/7), long philtrum (2/7), unilateral single transverse palmar crease (1/7), and hypertrichosis (1/7).
Sources: Literature
Mendeliome v0.6009 RABL2A Zornitza Stark Publications for gene: RABL2A were set to 33075816
Mendeliome v0.6006 RABL2A Zornitza Stark reviewed gene: RABL2A: Rating: RED; Mode of pathogenicity: None; Publications: 24825419; Phenotypes: Male infertility; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6005 AKT1 Zornitza Stark reviewed gene: AKT1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 21793738; Phenotypes: Proteus syndrome, somatic 176920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6004 CEP250 Zornitza Stark Publications for gene: CEP250 were set to
Mendeliome v0.6002 CEP250 Zornitza Stark reviewed gene: CEP250: Rating: GREEN; Mode of pathogenicity: None; Publications: 24780881, 29718797, 30459346; Phenotypes: Cone-rod dystrophy and hearing loss 2, MIM# 618358; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6002 RABL2A Eleanor Williams gene: RABL2A was added
gene: RABL2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RABL2A was set to Unknown
Publications for gene: RABL2A were set to 33075816
Phenotypes for gene: RABL2A were set to male infertility; ciliopathy
Review for gene: RABL2A was set to RED
Added comment: PMID: 33075816 - Ding et al 2020 - with the aim of identifying variants that affect male fertility, the authors report on mice expressing two RABL2A SNPs found to be rare (MAF between 2% and 0.02% in gnomAD, with a deleterious prediction from SIFT and PolyPhen-2, and to affect protein stability. Mice homozygous for these variants (p.L119F and p.V158F) were found to be show ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus.
Sources: Literature
Mendeliome v0.6002 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.6001 VCAN Zornitza Stark Publications for gene: VCAN were set to
Mendeliome v0.5999 VCAN Zornitza Stark reviewed gene: VCAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 16877430, 22739342, 16636652, 16043844, 32854301, 30657523, 30055036, 29071374, 27667122; Phenotypes: Wagner syndrome 1, MIM# 143200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5998 CAPN5 Zornitza Stark Publications for gene: CAPN5 were set to
Mendeliome v0.5996 CAPN5 Zornitza Stark reviewed gene: CAPN5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23055945, 32274441, 31110225, 30986125; Phenotypes: Vitreoretinopathy, neovascular inflammatory, MIM# 193235; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5995 UBIAD1 Zornitza Stark Publications for gene: UBIAD1 were set to
Mendeliome v0.5993 UBIAD1 Zornitza Stark reviewed gene: UBIAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18176953, 23169578, 31323021, 30785396, 30223810; Phenotypes: Corneal dystrophy, Schnyder type, MIM# 121800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5992 TGFBI Zornitza Stark Publications for gene: TGFBI were set to
Mendeliome v0.5990 TGFBI Zornitza Stark reviewed gene: TGFBI: Rating: GREEN; Mode of pathogenicity: None; Publications: 9054935; Phenotypes: Corneal dystrophy, multiple types, MONDO:0000764; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5989 TACSTD2 Zornitza Stark Publications for gene: TACSTD2 were set to
Mendeliome v0.5987 TACSTD2 Zornitza Stark reviewed gene: TACSTD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10192395, 12107443, 12614764, 31666974, 31534795; Phenotypes: Corneal dystrophy, gelatinous drop-like, MIM# 204870; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5986 KIF27 Anna Le Fevre reviewed gene: KIF27: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mendeliome v0.5985 ZEB1 Zornitza Stark Publications for gene: ZEB1 were set to
Mendeliome v0.5983 ZEB1 Zornitza Stark reviewed gene: ZEB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16252232, 20036349, 26622166; Phenotypes: Corneal dystrophy, Fuchs endothelial, 6, MIM# 613270, Corneal dystrophy, posterior polymorphous, 3, MIM# 609141; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5982 ZNF469 Zornitza Stark Publications for gene: ZNF469 were set to
Mendeliome v0.5980 ZNF469 Zornitza Stark reviewed gene: ZNF469: Rating: GREEN; Mode of pathogenicity: None; Publications: 18452888, 19661234, 20938016, 21664999, 32671420; Phenotypes: Brittle cornea syndrome 1, MIM# 229200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5979 PIKFYVE Zornitza Stark Publications for gene: PIKFYVE were set to
Mendeliome v0.5977 PIKFYVE Zornitza Stark reviewed gene: PIKFYVE: Rating: GREEN; Mode of pathogenicity: None; Publications: 15902656, 23288988, 26396486; Phenotypes: Corneal fleck dystrophy, MIM# 121850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5976 OVOL2 Zornitza Stark Publications for gene: OVOL2 were set to
Mendeliome v0.5974 OVOL2 Zornitza Stark reviewed gene: OVOL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26749309; Phenotypes: Corneal dystrophy, posterior polymorphous, 1, MIM# 122000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5973 KRT3 Zornitza Stark Publications for gene: KRT3 were set to
Mendeliome v0.5971 KRT3 Zornitza Stark reviewed gene: KRT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9171831, 16227835, 18806880, 26788030; Phenotypes: Meesmann corneal dystrophy 2, MIM# 618767; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5970 DCN Zornitza Stark Publications for gene: DCN were set to
Mendeliome v0.5968 DCN Zornitza Stark reviewed gene: DCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 15671264, 16935612, 21993463, 24413633, 26828927; Phenotypes: Corneal dystrophy, congenital stromal, MIM# 610048; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5967 COL8A2 Zornitza Stark Publications for gene: COL8A2 were set to
Mendeliome v0.5965 COL8A2 Zornitza Stark reviewed gene: COL8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11689488, 15914606, 18024822, 18464802; Phenotypes: Corneal dystrophy, Fuchs endothelial, 1, MIM# 136800, Corneal dystrophy, posterior polymorphous 2, MIM# 609140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5964 STX3 Zornitza Stark Publications for gene: STX3 were set to
Mendeliome v0.5962 STX3 Zornitza Stark reviewed gene: STX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24726755, 29266534, 25358429, 29282386, 30909251, 29282386; Phenotypes: Microvillus inclusion disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5961 SPINT2 Zornitza Stark Publications for gene: SPINT2 were set to
Mendeliome v0.5959 SPINT2 Zornitza Stark reviewed gene: SPINT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24142340, 30445423; Phenotypes: Diarrhoea 3, secretory sodium, congenital, syndromic 270420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5958 SLC9A3 Zornitza Stark Publications for gene: SLC9A3 were set to
Mendeliome v0.5956 SLC9A3 Zornitza Stark reviewed gene: SLC9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30633106, 31276831, 26358773; Phenotypes: Diarrhoea 8, secretory sodium, congenital 616868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5955 SLC5A1 Zornitza Stark Publications for gene: SLC5A1 were set to
Mendeliome v0.5953 SLC5A1 Zornitza Stark reviewed gene: SLC5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20486940, 32946683; Phenotypes: Glucose/galactose malabsorption, MIM# 606824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5952 SLC39A4 Zornitza Stark Publications for gene: SLC39A4 were set to
Mendeliome v0.5950 SLC39A4 Zornitza Stark reviewed gene: SLC39A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19370757; Phenotypes: Acrodermatitis enteropathica, MIM# 201100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5949 SLC26A3 Zornitza Stark Publications for gene: SLC26A3 were set to
Mendeliome v0.5947 SLC26A3 Zornitza Stark reviewed gene: SLC26A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31325522, 19861545, 11524734; Phenotypes: Diarrhoea 1, secretory chloride, congenital, MIM# 214700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5947 SLC51B Zornitza Stark gene: SLC51B was added
gene: SLC51B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SLC51B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51B were set to 28898457
Phenotypes for gene: SLC51B were set to Congenital diarrhoea; Cholestasis
Review for gene: SLC51B was set to RED
Added comment: Two siblings reported with homozygous LOF variant in this gene and congenital diarrhoea/cholestasis.
Sources: Expert Review
Mendeliome v0.5945 SLC10A2 Zornitza Stark Publications for gene: SLC10A2 were set to
Mendeliome v0.5942 SLC10A2 Zornitza Stark reviewed gene: SLC10A2: Rating: RED; Mode of pathogenicity: None; Publications: 9109432; Phenotypes: Bile acid malabsorption, primary, MIM# 613291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5941 PLVAP Zornitza Stark Publications for gene: PLVAP were set to
Mendeliome v0.5939 PLVAP Zornitza Stark reviewed gene: PLVAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29875123, 29661969, 26207260, 31215290; Phenotypes: Diarrhoea 10, protein-losing enteropathy type, MIM# 618183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5938 NEUROG3 Zornitza Stark Publications for gene: NEUROG3 were set to
Mendeliome v0.5936 NEUROG3 Zornitza Stark reviewed gene: NEUROG3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16855267, 32574610, 28724572, 21490072; Phenotypes: Diarrhoea 4, malabsorptive, congenital, MIM# 610370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5935 TMPRSS15 Zornitza Stark Publications for gene: TMPRSS15 were set to
Mendeliome v0.5933 TMPRSS15 Zornitza Stark reviewed gene: TMPRSS15: Rating: GREEN; Mode of pathogenicity: None; Publications: 11719902, 33061943; Phenotypes: Enterokinase deficiency, MIM# 226200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5932 TTC37 Zornitza Stark Publications for gene: TTC37 were set to
Mendeliome v0.5930 TTC37 Zornitza Stark reviewed gene: TTC37: Rating: GREEN; Mode of pathogenicity: None; Publications: 20176027, 17318842; Phenotypes: Trichohepatoenteric syndrome 1, MIM# 222470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5929 WNT2B Zornitza Stark Publications for gene: WNT2B were set to
Mendeliome v0.5927 WNT2B Zornitza Stark reviewed gene: WNT2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29909964; Phenotypes: Diarrhoea 9, MIM# 618168; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5926 MYO5B Zornitza Stark Publications for gene: MYO5B were set to
Mendeliome v0.5924 MYO5B Zornitza Stark reviewed gene: MYO5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30564347, 29266534, 28027573, 27532546; Phenotypes: Microvillus inclusion disease, MIM# 251850, Cholestasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5922 LCT Zornitza Stark reviewed gene: LCT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lactase deficiency, congenital, MIM# 223000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5921 CAMK2B Zornitza Stark Publications for gene: CAMK2B were set to
Mendeliome v0.5919 CAMK2B Zornitza Stark reviewed gene: CAMK2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100089, 29560374, 32875707; Phenotypes: Mental retardation, autosomal dominant 54, MIM# 617799; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5917 RALGAPB Elena Savva gene: RALGAPB was added
gene: RALGAPB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RALGAPB were set to PMID: 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to GREEN
Added comment: PMID: 32853829 - 2 patients with de novo missense variants, 1 patient with a de novo PTC with autism spectrum disorder from a large cohort.
Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense) in patients with ASD (7/10), epilepsy (2/10) and developmental delay (1/10).
Functional studies of patient cells show reduced mRNA expression (PTC).
Sources: Literature
Mendeliome v0.5916 LSM11 Seb Lunke changed review comment from: Comment on list classification: Very little evidence at this stage, just one consanguineous family with a some functional data.; to: Comment on list classification: Very little evidence at this stage, just one consanguineous family with some functional data.
Mendeliome v0.5916 LSM11 Seb Lunke Added comment: Comment on list classification: Very little evidence at this stage, just one consanguineous family with a some functional data.
Mendeliome v0.5914 RNU7-1 Ee Ming Wong changed review comment from: - 16 affected individuals from 11 families
- - Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature; to: - 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Mendeliome v0.5914 RNU7-1 Ee Ming Wong gene: RNU7-1 was added
gene: RNU7-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to PMID: 33230297
Phenotypes for gene: RNU7-1 were set to PMID: 33230297
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: - 16 affected individuals from 11 families
- - Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Mendeliome v0.5914 RPL3L Elena Savva gene: RPL3L was added
gene: RPL3L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to PMID: 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy
Review for gene: RPL3L was set to GREEN
Added comment: PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype.

PMID: 32870709 - 1 hom patient w/ neonatal DCM
Sources: Literature
Mendeliome v0.5914 LSM11 Ee Ming Wong gene: LSM11 was added
gene: LSM11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LSM11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM11 were set to PMID: 33230297
Phenotypes for gene: LSM11 were set to type I interferonopathy Aicardi–Goutières syndrome
Review for gene: LSM11 was set to AMBER
gene: LSM11 was marked as current diagnostic
Added comment: - Two affected siblings from a consanguineous family carrying a homozygous variant in LSM11
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
- Knockdown of LSM11 in THP-1 cells results in an increase in misprocessed RDH mRNA and
interferon signaling
Sources: Literature
Mendeliome v0.5914 DPH2 Paul De Fazio gene: DPH2 was added
gene: DPH2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH2 were set to 32576952; 27421267
Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome
Review for gene: DPH2 was set to AMBER
gene: DPH2 was marked as current diagnostic
Added comment: One family reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency.

Another family was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative.

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Mendeliome v0.5914 FBRSL1 Elena Savva gene: FBRSL1 was added
gene: FBRSL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBRSL1 were set to PMID: 32424618
Phenotypes for gene: FBRSL1 were set to Malformation and intellectual disability syndrome
Review for gene: FBRSL1 was set to GREEN
Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement.
Supported by Xenopus oocyte functional studies
Sources: Literature
Mendeliome v0.5913 EPCAM Zornitza Stark Publications for gene: EPCAM were set to
Mendeliome v0.5911 EPCAM Zornitza Stark reviewed gene: EPCAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 24142340; Phenotypes: Diarrhea 5, with tufting enteropathy, congenital, MIM# 613217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5910 DGAT1 Zornitza Stark Publications for gene: DGAT1 were set to
Mendeliome v0.5908 DGAT1 Zornitza Stark reviewed gene: DGAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33261563, 32786057, 31778854, 28373485, 29604290; Phenotypes: Diarrhoea 7, protein-losing enteropathy type, MIM# 615863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5907 CPA6 Zornitza Stark Publications for gene: CPA6 were set to
Mendeliome v0.5902 HSD17B10 Zornitza Stark reviewed gene: HSD17B10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: HSD10 mitochondrial disease, MIM# 300438; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5901 HMGCS2 Zornitza Stark Publications for gene: HMGCS2 were set to
Mendeliome v0.5899 HMGCS2 Zornitza Stark reviewed gene: HMGCS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33045405; Phenotypes: HMG-CoA synthase-2 deficiency, MIM# 605911; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5898 HMGCL Zornitza Stark Publications for gene: HMGCL were set to
Mendeliome v0.5896 HMGCL Zornitza Stark reviewed gene: HMGCL: Rating: GREEN; Mode of pathogenicity: None; Publications: 8617516; Phenotypes: HMG-CoA lyase deficiency, MIM# 246450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5895 GLUD1 Zornitza Stark Publications for gene: GLUD1 were set to
Mendeliome v0.5893 GLUD1 Zornitza Stark reviewed gene: GLUD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11214910, 11297618; Phenotypes: Hyperinsulinism-hyperammonemia syndrome, MIM# 606762; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5892 CFAP58 Zornitza Stark reviewed gene: CFAP58: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 49, MIM#619144; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5892 AGPAT2 Zornitza Stark Publications for gene: AGPAT2 were set to 32876150
Mendeliome v0.5891 AGPAT2 Zornitza Stark reviewed gene: AGPAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11967537; Phenotypes: Lipodystrophy, congenital generalized, type 1, MIM# 608594; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5890 AGPAT2 Zornitza Stark Publications for gene: AGPAT2 were set to
Mendeliome v0.5888 AGPAT2 Elena Savva reviewed gene: AGPAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32876150; Phenotypes: Lipodystrophy, congenital generalized, type 1 MIM#608594; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5887 LPIN1 Zornitza Stark Publications for gene: LPIN1 were set to
Mendeliome v0.5885 LPIN1 Zornitza Stark reviewed gene: LPIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18817903, 32549891, 32522502, 32410653; Phenotypes: Myoglobinuria, acute recurrent, autosomal recessive, MIM# 268200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5884 MLYCD Zornitza Stark Publications for gene: MLYCD were set to
Mendeliome v0.5882 MLYCD Zornitza Stark reviewed gene: MLYCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 12955715; Phenotypes: Malonyl-CoA decarboxylase deficiency, MIM# 248360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5881 SLC25A20 Zornitza Stark Publications for gene: SLC25A20 were set to
Mendeliome v0.5879 SLC25A20 Zornitza Stark reviewed gene: SLC25A20: Rating: GREEN; Mode of pathogenicity: None; Publications: 15363639, 15365988, 24088670; Phenotypes: Carnitine-acylcarnitine translocase deficiency, MIM# 212138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5878 GABRD Zornitza Stark Publications for gene: GABRD were set to
Mendeliome v0.5875 GABRD Zornitza Stark reviewed gene: GABRD: Rating: RED; Mode of pathogenicity: None; Publications: 15115768; Phenotypes: Susceptibility to epilepsy, MIM#613060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5874 SPR Zornitza Stark Publications for gene: SPR were set to
Mendeliome v0.5873 SPR Zornitza Stark edited their review of gene: SPR: Changed publications: 22522443, 16650784, 21431957, 28189489
Mendeliome v0.5871 PRRT2 Zornitza Stark Publications for gene: PRRT2 were set to
Mendeliome v0.5869 PRRT2 Zornitza Stark reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33126500; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis 602066, Episodic kinesigenic dyskinesia 1 128200, Seizures, benign familial infantile, 2 605751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5868 KCNQ3 Zornitza Stark Publications for gene: KCNQ3 were set to
Mendeliome v0.5866 KCNQ3 Zornitza Stark reviewed gene: KCNQ3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33337327; Phenotypes: Seizures, benign neonatal, 2, MIM# 121201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5865 PRKACB Zornitza Stark reviewed gene: PRKACB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 2, MIM# 619143; Mode of inheritance: None
Mendeliome v0.5864 PRKACA Zornitza Stark reviewed gene: PRKACA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 1, MIM# 619142; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5863 SCARF2 Zornitza Stark Publications for gene: SCARF2 were set to
Mendeliome v0.5861 SCARF2 Zornitza Stark reviewed gene: SCARF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20887961, 23808541, 24478002, 27375131, 24478002; Phenotypes: Van den Ende-Gupta syndrome, MIM# 600920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5859 GSTO1 Zornitza Stark Publications for gene: GSTO1 were set to
Mendeliome v0.5857 GSTO1 Elena Savva reviewed gene: GSTO1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 21106529; Phenotypes: Deficiency of Human Glutathione Transferase Omega 1; Mode of inheritance: None
Mendeliome v0.5856 PRR12 Zornitza Stark Publications for gene: PRR12 were set to
Mendeliome v0.5854 PRR12 Zornitza Stark reviewed gene: PRR12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33314030, 29556724; Phenotypes: Intellectual disability, Iris abnormalities, Complex microphthalmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5853 PRSS56 Zornitza Stark Publications for gene: PRSS56 were set to
Mendeliome v0.5851 PRSS56 Zornitza Stark reviewed gene: PRSS56: Rating: GREEN; Mode of pathogenicity: None; Publications: 21532570, 23127749, 31992737; Phenotypes: Microphthalmia, isolated 6, MIM# 613517; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5851 GJA8 Zornitza Stark Phenotypes for gene: GJA8 were changed from to Cataract 1, multiple types, MIM# 116200; Microphthalmia
Mendeliome v0.5850 GJA8 Zornitza Stark Publications for gene: GJA8 were set to
Mendeliome v0.5848 GJA8 Zornitza Stark reviewed gene: GJA8: Rating: GREEN; Mode of pathogenicity: None; Publications: 30498267, 29464339, 10480374, 18006672; Phenotypes: Cataract 1, multiple types, MIM# 116200, Microphthalmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5847 ATIC Zornitza Stark Publications for gene: ATIC were set to
Mendeliome v0.5845 ATIC Zornitza Stark reviewed gene: ATIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 15114530, 32557644; Phenotypes: AICA-ribosiduria due to ATIC deficiency, MIM# 608688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5844 FZD5 Zornitza Stark gene: FZD5 was added
gene: FZD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FZD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FZD5 were set to 32737437; 26908622
Phenotypes for gene: FZD5 were set to Coloboma
Review for gene: FZD5 was set to GREEN
Added comment: Four unrelated families reported.
Sources: Literature
Mendeliome v0.5842 STRA6 Zornitza Stark Publications for gene: STRA6 were set to
Mendeliome v0.5840 STRA6 Zornitza Stark reviewed gene: STRA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273977, 17503335, 19213032, 26373900, 30880327, 26373900, 25457163; Phenotypes: Microphthalmia, isolated, with coloboma 8, MIM# 601186, Microphthalmia, syndromic 9, MIM# 601186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5839 SOX2 Zornitza Stark Publications for gene: SOX2 were set to
Mendeliome v0.5837 SOX2 Zornitza Stark reviewed gene: SOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30450772, 28121235, 25542770, 24498598, 24211324, 24033328, 21326281; Phenotypes: Microphthalmia, syndromic 3, MIM# 206900, Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5836 SIX6 Zornitza Stark Publications for gene: SIX6 were set to
Mendeliome v0.5834 SIX6 Zornitza Stark reviewed gene: SIX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23167593, 24702266, 33108933, 31207931, 24702266; Phenotypes: Optic disc anomalies with retinal and/or macular dystrophy, MIM# 212550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5833 RERE Zornitza Stark Publications for gene: RERE were set to
Mendeliome v0.5831 RERE Zornitza Stark reviewed gene: RERE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27087320, 23451234, 30896913, 30061196; Phenotypes: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, MIM# 616975; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5828 RAX Zornitza Stark Publications for gene: RAX were set to
Mendeliome v0.5826 RAX Zornitza Stark reviewed gene: RAX: Rating: GREEN; Mode of pathogenicity: None; Publications: 14662654, 18783408, 30811539, 24033328, 22524605; Phenotypes: Microphthalmia, isolated 3, MIM# 611038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5825 RARB Zornitza Stark Publications for gene: RARB were set to
Mendeliome v0.5822 RARB Zornitza Stark reviewed gene: RARB: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30880327, 30281527, 24075189, 27120018, 25457163, 17506106; Phenotypes: Microphthalmia, syndromic 12, MIM# 615524; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5821 RARA Zornitza Stark Publications for gene: RARA were set to
Mendeliome v0.5819 RARA Zornitza Stark edited their review of gene: RARA: Added comment: Single case report of de novo missense variant in association with syndromic coloboma.; Changed publications: 31343737; Changed phenotypes: Syndromic chorioretinal coloboma
Mendeliome v0.5818 PXDN Zornitza Stark Publications for gene: PXDN were set to
Mendeliome v0.5816 PXDN Zornitza Stark reviewed gene: PXDN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907015, 24939590, 32499604, 32224865, 32015378, 31817535; Phenotypes: Anterior segment dysgenesis 7, with sclerocornea, MIM# 269400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5815 SMOC1 Zornitza Stark Publications for gene: SMOC1 were set to
Mendeliome v0.5813 SMOC1 Zornitza Stark reviewed gene: SMOC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21194678, 21194680, 30445150; Phenotypes: Microphthalmia with limb anomalies, MIM# 206920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5812 MFRP Zornitza Stark Publications for gene: MFRP were set to
Mendeliome v0.5810 MFRP Zornitza Stark reviewed gene: MFRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 17167404, 18554571, 20361016; Phenotypes: Microphthalmia, isolated 5, MIM# 611040; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5809 MAB21L2 Zornitza Stark Publications for gene: MAB21L2 were set to
Mendeliome v0.5807 MAB21L2 Zornitza Stark reviewed gene: MAB21L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24906020, 25719200, 31037784, 30375740, 30073347, 26116559; Phenotypes: Microphthalmia/coloboma and skeletal dysplasia syndrome, MIM# 615877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5806 PDSS1 Zornitza Stark Publications for gene: PDSS1 were set to
Mendeliome v0.5804 PDSS1 Paul De Fazio reviewed gene: PDSS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17332895, 22494076, 33285023; Phenotypes: Coenzyme Q10 deficiency, primary, 2 MIM#614651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5802 POLR1A Zornitza Stark Publications for gene: POLR1A were set to
Mendeliome v0.5800 POLR1A Ain Roesley reviewed gene: POLR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25913037, 28051070; Phenotypes: Acrofacial dysostosis, Cincinnati type, (MIM#616462); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5799 LOXL3 Zornitza Stark gene: LOXL3 was added
gene: LOXL3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 30362103; 25663169
Phenotypes for gene: LOXL3 were set to Stickler syndrome
Review for gene: LOXL3 was set to AMBER
Added comment: Two unrelated families reported with homozygous missense variants, mouse model supports gene-disease association.
Sources: Expert Review
Mendeliome v0.5797 RBP4 Zornitza Stark Publications for gene: RBP4 were set to
Mendeliome v0.5795 RBP4 Zornitza Stark reviewed gene: RBP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25910211, 29178648, 23189188, 9888420, 32323592; Phenotypes: Microphthalmia, isolated, with coloboma 10 MIM#616428, Retinal dystrophy, iris coloboma, and comedogenic acne syndrome MIM#615147; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5794 VAX1 Zornitza Stark Publications for gene: VAX1 were set to
Mendeliome v0.5791 VAX1 Zornitza Stark reviewed gene: VAX1: Rating: RED; Mode of pathogenicity: None; Publications: 22095910; Phenotypes: Microphthalmia, syndromic 11, MIM# 614402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5790 VSX2 Zornitza Stark Publications for gene: VSX2 were set to
Mendeliome v0.5788 VSX2 Zornitza Stark reviewed gene: VSX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15257456, 17661825, 31884615, 28121235, 27301076, 24033328; Phenotypes: Microphthalmia with coloboma 3, MIM# 610092, Microphthalmia, isolated 2, MIM# 610093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5787 WDR37 Zornitza Stark Publications for gene: WDR37 were set to
Mendeliome v0.5785 WDR37 Zornitza Stark reviewed gene: WDR37: Rating: GREEN; Mode of pathogenicity: None; Publications: 31327508, 31327508; Phenotypes: Neurooculocardiogenitourinary syndrome, MIM# 618652; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5784 ALDH1A3 Zornitza Stark Publications for gene: ALDH1A3 were set to
Mendeliome v0.5782 ALDH1A3 Zornitza Stark reviewed gene: ALDH1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23312594, 23591992, 30200890, 28890889, 26873617, 24777706; Phenotypes: Microphthalmia, isolated 8, MIM# 615113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5780 VEGFC Zornitza Stark Publications for gene: VEGFC were set to
Mendeliome v0.5778 VEGFC Elena Savva reviewed gene: VEGFC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23410910, 24744435, 30071673; Phenotypes: Lymphatic malformation 4, MIM#615907; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5775 NSD1 Chern Lim reviewed gene: NSD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16010675, 15942875; Phenotypes: Sotos syndrome 1 (MIM#117550), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.5774 RNASEH2B Zornitza Stark Publications for gene: RNASEH2B were set to
Mendeliome v0.5772 RNASEH2B Zornitza Stark reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 16845400, 33307271, 29239743; Phenotypes: Aicardi-Goutieres syndrome 2, MIM# 610181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5772 PDGFB Zornitza Stark Phenotypes for gene: PDGFB were changed from to Basal ganglia calcification, idiopathic, 5 , MIM#615483
Mendeliome v0.5771 PDGFB Zornitza Stark Publications for gene: PDGFB were set to
Mendeliome v0.5769 PDGFB Zornitza Stark reviewed gene: PDGFB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23913003, 30952898, 30609140; Phenotypes: Basal ganglia calcification, idiopathic, 5 , MIM#615483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5769 XYLT1 Zornitza Stark reviewed gene: XYLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30554721, 24581741, 23982343; Phenotypes: Desbuquois dysplasia 2, MIM# 615777, Baratela-Scott syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5768 TUSC3 Zornitza Stark Publications for gene: TUSC3 were set to
Mendeliome v0.5766 TUSC3 Zornitza Stark reviewed gene: TUSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18452889, 18455129, 21739581, 27148795, 31606977; Phenotypes: Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615, TUSC3-CDG (Disorders of protein N-glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5765 TMEM165 Zornitza Stark Publications for gene: TMEM165 were set to
Mendeliome v0.5763 TMEM165 Zornitza Stark reviewed gene: TMEM165: Rating: GREEN; Mode of pathogenicity: None; Publications: 22683087, 28323990, 27401145, 27008884, 26238249, 25609749; Phenotypes: Congenital disorder of glycosylation, type IIk, MIM# 614727, TMEM165-CDG, MONDO:0013870; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5762 SLC35D1 Zornitza Stark Publications for gene: SLC35D1 were set to 31423530; 19508970
Mendeliome v0.5761 SLC35D1 Zornitza Stark reviewed gene: SLC35D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17952091, 19508970, 31423530; Phenotypes: Schneckenbecken dysplasia 269250, O-xylosyl/N-acetylgalactosaminylglycan synthesis deficiencies (Disorders of protein O-glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5760 SLC35C1 Zornitza Stark Publications for gene: SLC35C1 were set to
Mendeliome v0.5758 SLC35C1 Zornitza Stark reviewed gene: SLC35C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11326279, 12116250, 33098347, 32313197, 24403049; Phenotypes: Congenital disorder of glycosylation, type IIc, MIM# 266265, MONDO:0009953; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5757 SEC23B Zornitza Stark Publications for gene: SEC23B were set to 19561605; 19621418
Mendeliome v0.5756 SEC23B Zornitza Stark edited their review of gene: SEC23B: Changed publications: 19561605, 19621418, 26522472
Mendeliome v0.5755 GNE Zornitza Stark Publications for gene: GNE were set to
Mendeliome v0.5753 GNE Zornitza Stark reviewed gene: GNE: Rating: GREEN; Mode of pathogenicity: None; Publications: 12177386, 12473753, 32053088, 29923088, 10356312, 11326336, 11486897, 27142465; Phenotypes: Nonaka myopathy 605820, Sialuria MIM#269921, ADUDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5750 CHSY1 Zornitza Stark Publications for gene: CHSY1 were set to
Mendeliome v0.5748 CHSY1 Zornitza Stark reviewed gene: CHSY1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21129728, 21129727, 24269551; Phenotypes: VTemtamy preaxial brachydactyly syndrome, MIM# 605282, MONDO:0011533, CHSY1-CDG (Disorders of protein O-glycosylation, O-mannosylglycan synthesis deficiencies); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5747 DHDDS Zornitza Stark Publications for gene: DHDDS were set to
Mendeliome v0.5745 DHDDS Zornitza Stark reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27343064, 29100083, 21295283; Phenotypes: Developmental delay and seizures with or without movement abnormalities, MIM#617836, Congenital disorder of glycosylation, type 1bb, MIM# 613861; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5745 FBLN1 Zornitza Stark Publications for gene: FBLN1 were set to 11836357
Mendeliome v0.5743 FBLN1 Zornitza Stark reviewed gene: FBLN1: Rating: RED; Mode of pathogenicity: None; Publications: 24084572; Phenotypes: Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5742 FBLN1 Zornitza Stark Publications for gene: FBLN1 were set to
Mendeliome v0.5739 TBL1X Elena Savva gene: TBL1X was added
gene: TBL1X was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBL1X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TBL1X were set to PMID: 27603907
Phenotypes for gene: TBL1X were set to Hypothyroidism, congenital, nongoitrous, 8 MIM#301033
Review for gene: TBL1X was set to GREEN
Added comment: PMID: 27603907 - mostly males but also a female diagnosed with central hypothyroidism. 6 families reported (5/6 missense, 1/6 splice). Supported by functional studies ->LOF

All mutations were located in the highly conserved WD40-repeat domains.
Sources: Literature
Mendeliome v0.5738 ST3GAL5 Zornitza Stark Publications for gene: ST3GAL5 were set to
Mendeliome v0.5736 ST3GAL5 Zornitza Stark reviewed gene: ST3GAL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23436467, 22990144, 15502825, 27232954, 30691927, 30688114, 30576498; Phenotypes: Salt and pepper developmental regression syndrome 609056, GM3 synthase deficiency, MONDO:0018274, Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5736 FBLN1 Elena Savva reviewed gene: FBLN1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 11836357; Phenotypes: Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5735 SUCLA2 Zornitza Stark Publications for gene: SUCLA2 were set to
Mendeliome v0.5733 SUCLA2 Zornitza Stark reviewed gene: SUCLA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15877282, 17287286, 17301081, 23759946, 33231368, 33230181, 28243576, 27913098, 27651038; Phenotypes: Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), MIM# 612073; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5732 RFT1 Zornitza Stark Publications for gene: RFT1 were set to
Mendeliome v0.5730 RFT1 Zornitza Stark reviewed gene: RFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18313027, 19701946, 19856127, 23111317, 30071302, 29923091, 27927990, 26892341; Phenotypes: Congenital disorder of glycosylation, type In, MIM# 612015, RFT1-CDG, MONDO:0012783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5729 CHST6 Zornitza Stark Publications for gene: CHST6 were set to
Mendeliome v0.5727 CHST6 Zornitza Stark reviewed gene: CHST6: Rating: GREEN; Mode of pathogenicity: None; Publications: 11818380, 16207214, 26604660; Phenotypes: Macular corneal dystrophy, MIM# 217800, MONDO:0009020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5726 MGAT2 Zornitza Stark Publications for gene: MGAT2 were set to
Mendeliome v0.5724 MGAT2 Zornitza Stark reviewed gene: MGAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8808595, 11228641, 22105986, 33044030, 31420886; Phenotypes: Congenital disorder of glycosylation, type IIa, MIM# 212066, MGAT2-CDG, MONDO:0008908; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5723 MPI Zornitza Stark Publications for gene: MPI were set to
Mendeliome v0.5721 MPI Zornitza Stark reviewed gene: MPI: Rating: GREEN; Mode of pathogenicity: None; Publications: 12414827, 9585601, 10980531, 33098580, 33204592, 32905087, 32266963, 30242110; Phenotypes: Congenital disorder of glycosylation, type Ib, MIM# 602579, MPI-CDG MONDO:0011257; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5720 PGM3 Zornitza Stark Publications for gene: PGM3 were set to
Mendeliome v0.5718 PGM3 Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation.

Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity.

More than 10 unrelated families reported.
Mendeliome v0.5718 PGM3 Zornitza Stark reviewed gene: PGM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30578875, 31231132, 33098103, 30157810, 28704707; Phenotypes: Immunodeficiency 23, MIM# 615816, PGM3-CDG, MONDO:0014353; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5717 PGAP3 Zornitza Stark Publications for gene: PGAP3 were set to
Mendeliome v0.5715 PGAP3 Zornitza Stark reviewed gene: PGAP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24439110, 29620724, 30345601, 30217754; Phenotypes: Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5714 PGAP2 Zornitza Stark Publications for gene: PGAP2 were set to
Mendeliome v0.5712 PGAP2 Zornitza Stark reviewed gene: PGAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561846, 23561847, 31805394, 29119105, 27871432; Phenotypes: Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5711 PIGV Zornitza Stark Publications for gene: PIGV were set to
Mendeliome v0.5709 PIGV Zornitza Stark reviewed gene: PIGV: Rating: GREEN; Mode of pathogenicity: None; Publications: 20802478, 22315194, 28817240, 24129430; Phenotypes: Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5707 PIGO Zornitza Stark Publications for gene: PIGO were set to
Mendeliome v0.5705 PIGO Zornitza Stark reviewed gene: PIGO: Rating: GREEN; Mode of pathogenicity: None; Publications: 22683086, 31698102, 28900819, 28545593, 28337824; Phenotypes: Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5704 PIGN Zornitza Stark Publications for gene: PIGN were set to
Mendeliome v0.5702 PIGN Zornitza Stark reviewed gene: PIGN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21493957, 24253414, 26364997, 26394714, 33193741, 32585529, 29330547; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5701 PIGA Zornitza Stark Publications for gene: PIGA were set to
Mendeliome v0.5699 PIGA Zornitza Stark reviewed gene: PIGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305531, 24357517, 24706016, 26545172, 33333793, 32694024; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5698 PIGL Zornitza Stark Publications for gene: PIGL were set to
Mendeliome v0.5696 PIGL Zornitza Stark reviewed gene: PIGL: Rating: GREEN; Mode of pathogenicity: None; Publications: 22444671, 31535386, 30023290, 29473937, 28371479, 25706356; Phenotypes: CHIME syndrome, MIM# 280000, MONDO:0010221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5695 B3GALT6 Zornitza Stark Publications for gene: B3GALT6 were set to
Mendeliome v0.5693 B3GALT6 Zornitza Stark reviewed gene: B3GALT6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25149931, 29443383, 23664117, 29931299, 23664117, 23664118, 31614862; Phenotypes: Al-Gazali syndrome, MIM# 609465, Ehlers-Danlos syndrome, spondylodysplastic type, 2, MIM# 615349, MONDO:0014139, Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, MIM# 271640, MONDO:0010075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5692 B3GALNT2 Zornitza Stark Publications for gene: B3GALNT2 were set to
Mendeliome v0.5690 B3GALNT2 Zornitza Stark reviewed gene: B3GALNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23453667, 33290285, 29791932, 29273094, 28688748, 28303321; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181, MONDO:0014071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5689 MPDU1 Zornitza Stark Publications for gene: MPDU1 were set to
Mendeliome v0.5687 MPDU1 Zornitza Stark reviewed gene: MPDU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11733564, 11733556, 31741824, 29721919; Phenotypes: Congenital disorder of glycosylation, type If, MIM# 609180, MPDU1-CDG, MONDO:0012211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5686 DPAGT1 Zornitza Stark Publications for gene: DPAGT1 were set to
Mendeliome v0.5684 DPAGT1 Zornitza Stark changed review comment from: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties.

Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder.; to: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties.

Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder. More than 5 unrelated families reported with this presentation.
Mendeliome v0.5684 DPAGT1 Zornitza Stark edited their review of gene: DPAGT1: Changed publications: 12872255, 22492991, 22304930, 31153949, 30653653, 30117111, 22742743, 29356258, 28712839, 28662078
Mendeliome v0.5684 DPAGT1 Zornitza Stark reviewed gene: DPAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872255, 22492991, 22304930, 31153949, 30653653, 30117111; Phenotypes: Congenital disorder of glycosylation, type Ij, MIM# 608093, DPAGT1-CDG MONDO:0011964, Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM# 614750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5683 DOLK Zornitza Stark Publications for gene: DOLK were set to
Mendeliome v0.5681 DOLK Zornitza Stark reviewed gene: DOLK: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273964, 22242004, 23890587, 30653653, 28816422, 24144945; Phenotypes: DK1-CDG, MONDO:0012556, Congenital disorder of glycosylation, type Im, MIM# 610768; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5680 SLC2A1 Zornitza Stark Publications for gene: SLC2A1 were set to
Mendeliome v0.5678 MTX2 Zornitza Stark Phenotypes for gene: MTX2 were changed from Mandibuloacral dysplasia; lipodystrophy; arterial calcification to Mandibuloacral dysplasia progeroid syndrome, MIM# 619127; Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Mendeliome v0.5677 MTX2 Zornitza Stark edited their review of gene: MTX2: Changed phenotypes: Mandibuloacral dysplasia progeroid syndrome, MIM# 619127, Mandibuloacral dysplasia, lipodystrophy, arterial calcification
Mendeliome v0.5677 SLC2A1 Elena Savva reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:18451999, 20129935, 10980529, 20221955, 31196579; Phenotypes: GLUT1 deficiency syndrome 1, infantile onset, severe, MIM#606777, Dystonia 9, MIM#601042, Stomatin-deficient cryohydrocytosis with neurologic defects, MIM#608885, GLUT1 deficiency syndrome 2, childhood onset, MIM#612126, {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM#614847; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5676 ERCC1 Zornitza Stark Publications for gene: ERCC1 were set to
Mendeliome v0.5674 ERCC1 Zornitza Stark reviewed gene: ERCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273966, 23623389, 33315086; Phenotypes: Cerebrooculofacioskeletal syndrome 4, MIM# 610758; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5673 POR Zornitza Stark Publications for gene: POR were set to
Mendeliome v0.5670 MYH6 Zornitza Stark Publications for gene: MYH6 were set to
Mendeliome v0.5668 MYH6 Zornitza Stark reviewed gene: MYH6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32656206, 31638415, 29969989, 29536580, 29332214, 30681346; Phenotypes: Atrial septal defect 3 MIM#614089, Congenital heart disease, Cardiomyopathy, dilated, 1EE MIM#613252, Cardiomyopathy, hypertrophic, 14 MIM#613251, {Sick sinus syndrome 3} MIM#614090; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5667 EZH2 Zornitza Stark Publications for gene: EZH2 were set to
Mendeliome v0.5665 EZH2 Zornitza Stark reviewed gene: EZH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23865096; Phenotypes: Weaver syndrome MIM#277590; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5665 POR Elena Savva reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27068427; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750, Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5665 MYH6 Elena Savva reviewed gene: MYH6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 3 MIM#614089, Cardiomyopathy, dilated, 1EE MIM#613252, Cardiomyopathy, hypertrophic, 14 MIM#613251, {Sick sinus syndrome 3} MIM#614090; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5665 EZH2 Elena Savva reviewed gene: EZH2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29244146; Phenotypes: Weaver syndrome MIM#277590; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5664 COG6 Zornitza Stark Publications for gene: COG6 were set to
Mendeliome v0.5662 COG6 Zornitza Stark reviewed gene: COG6: Rating: GREEN; Mode of pathogenicity: None; Publications: 20605848, 23430903, 26260076, 32905044, 32683677, 31420886; Phenotypes: Congenital disorder of glycosylation, type IIl, MIM# 614576; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5661 COG5 Zornitza Stark Publications for gene: COG5 were set to
Mendeliome v0.5659 COG5 Zornitza Stark reviewed gene: COG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23228021, 31572517, 32174980; Phenotypes: Congenital disorder of glycosylation, type IIi, MIM# 613612; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5658 FIGLA Zornitza Stark Publications for gene: FIGLA were set to
Mendeliome v0.5656 FIGLA Zornitza Stark reviewed gene: FIGLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 18499083, 25314148, 29914564; Phenotypes: Premature ovarian failure 6, MIM# 612310; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5655 ESR1 Zornitza Stark Publications for gene: ESR1 were set to
Mendeliome v0.5653 ESR1 Zornitza Stark reviewed gene: ESR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27754803, 23841731, 24152274; Phenotypes: Estrogen resistance, MIM# 615363; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5651 BMP15 Zornitza Stark Publications for gene: BMP15 were set to
Mendeliome v0.5649 BMP15 Zornitza Stark reviewed gene: BMP15: Rating: GREEN; Mode of pathogenicity: None; Publications: 15136966, 16508750, 16464940; Phenotypes: Ovarian dysgenesis 2, MIM# 300510, Premature ovarian failure 4, MIM# 300510; Mode of inheritance: Other
Mendeliome v0.5648 PANX1 Zornitza Stark gene: PANX1 was added
gene: PANX1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PANX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PANX1 were set to 30918116; 32838805
Phenotypes for gene: PANX1 were set to Oocyte maturation defect 7, MIM# 618550
Review for gene: PANX1 was set to AMBER
Added comment: Two unrelated families, some functional data. Clinical presentation is with infertility.
Sources: Expert list
Mendeliome v0.5646 NANOS3 Bryony Thompson gene: NANOS3 was added
gene: NANOS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NANOS3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NANOS3 were set to 25054146; 24091668
Phenotypes for gene: NANOS3 were set to Primary ovarian insufficiency
Review for gene: NANOS3 was set to AMBER
Added comment: A homozygous missense (p.Glu120Lys) was identified in two Brazillian sisters with primary amenorrhea, and supporting in vitro functional assays. A heterozygous missense (p.Arg153Trp) was identified in a Chinese woman with POI, with supporting in vitro functional assays. Also, supporting null mouse model.
Sources: Literature
Mendeliome v0.5644 MSH5 Bryony Thompson gene: MSH5 was added
gene: MSH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MSH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSH5 were set to 28175301; 9916805; 24970489
Phenotypes for gene: MSH5 were set to Premature ovarian failure 13 MIM#617442
Review for gene: MSH5 was set to AMBER
Added comment: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5.
Sources: Literature
Mendeliome v0.5642 PATL2 Zornitza Stark gene: PATL2 was added
gene: PATL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PATL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PATL2 were set to 28965844; 28965849; 32048119; 30765866
Phenotypes for gene: PATL2 were set to Oocyte maturation defect 4, MIM# 617743
Review for gene: PATL2 was set to GREEN
Added comment: More than 5 unrelated families reported, presentation is with infertility.
Sources: Expert list
Mendeliome v0.5640 FANCM Bryony Thompson Publications for gene: FANCM were set to 30075111; 29895858; 28837162
Mendeliome v0.5639 FANCM Bryony Thompson Added comment: Comment on list classification: Green for POI
Mendeliome v0.5638 FANCM Bryony Thompson reviewed gene: FANCM: Rating: GREEN; Mode of pathogenicity: None; Publications: 29231814, 28837162, 33036707, 25010009; Phenotypes: Premature ovarian failure 15 MIM#618096; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5638 PGRMC1 Zornitza Stark gene: PGRMC1 was added
gene: PGRMC1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PGRMC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PGRMC1 were set to 25246111; 18782852
Phenotypes for gene: PGRMC1 were set to Premature ovarian failure
Review for gene: PGRMC1 was set to RED
Added comment: One family with translocation reported and two affected individuals. Another individual identified as part of a cohort with a missense variant (H165R), but the variant is present in >200 hets in gnomad. Subsequent cohort study did not find an association.
Sources: Expert list
Mendeliome v0.5636 EIF4ENIF1 Bryony Thompson gene: EIF4ENIF1 was added
gene: EIF4ENIF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF4ENIF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF4ENIF1 were set to 31810472; 23902945; 33095795
Phenotypes for gene: EIF4ENIF1 were set to Primary ovarian insufficiency
Review for gene: EIF4ENIF1 was set to AMBER
Added comment: 3 families: A missense (p.Q842P) segregated between a mother and daughter with diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI). A nonsense variant (p.Ser429Ter) segregated in 7 affected women over 3 consecutive generations with early menopause at approximately age 30 years. A missense (p.Lys669Arg) was identified in a Brazilian case with POI.
Sources: Literature
Mendeliome v0.5634 POF1B Zornitza Stark Publications for gene: POF1B were set to
Mendeliome v0.5631 POF1B Zornitza Stark reviewed gene: POF1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 16773570, 25676666; Phenotypes: Premature ovarian failure 2B, MIM# 300604; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.5630 DIAPH2 Bryony Thompson reviewed gene: DIAPH2: Rating: RED; Mode of pathogenicity: None; Publications: 9497258, 30689869, 26175800, 11129329; Phenotypes: ?Premature ovarian failure 2A MIM#300511; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5630 POU5F1 Zornitza Stark gene: POU5F1 was added
gene: POU5F1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: POU5F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU5F1 were set to 21273125
Phenotypes for gene: POU5F1 were set to Premature ovarian failure
Review for gene: POU5F1 was set to RED
Added comment: Single individual reported in 2011 and a missense variant.
Sources: Expert list
Mendeliome v0.5628 CCDC141 Bryony Thompson gene: CCDC141 was added
gene: CCDC141 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC141 was set to Unknown
Publications for gene: CCDC141 were set to 27014940; 28324054; 25192046
Phenotypes for gene: CCDC141 were set to Anosmic hypogonadotropic hypogonadism
Review for gene: CCDC141 was set to AMBER
Added comment: A consanguineous family had a homozygous nonsense variant, but also had a homozygous missense in FEZF1. 3 other families reported with heterozygous variants, but other variants in other genes present. In an olfactory mouse model, Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration.
Sources: Literature
Mendeliome v0.5627 SGO2 Zornitza Stark gene: SGO2 was added
gene: SGO2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGO2 were set to 27629923
Phenotypes for gene: SGO2 were set to Perrault syndrome
Review for gene: SGO2 was set to RED
Added comment: Single affected individual reported, though deafness was thought to be explained by a CLDN14 variant. Protein is known to be involved in meiosis.
Sources: Expert list
Mendeliome v0.5626 SOHLH2 Zornitza Stark gene: SOHLH2 was added
gene: SOHLH2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SOHLH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOHLH2 were set to 24524832; 19014927
Phenotypes for gene: SOHLH2 were set to Premature ovarian failure
Review for gene: SOHLH2 was set to RED
Added comment: Heterozygous variants in this gene found to be enriched in a cohort of women with POF, substantial data including mouse models implicating this gene in infertility but paucity of well characterised cases.
Sources: Expert list
Mendeliome v0.5624 SYCE1 Zornitza Stark gene: SYCE1 was added
gene: SYCE1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SYCE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCE1 were set to 25062452; 32917591; 32741963; 32402064; 31925770; 31916078
Phenotypes for gene: SYCE1 were set to Premature ovarian failure 12, MIM# 616947; Spermatogenic failure 15 ,MIM#616950
Review for gene: SYCE1 was set to GREEN
Added comment: More than 5 families reported with POF/SF and bi-allelic variants in this gene. Mechanism is thought to be disruption of meiosis, mouse model data also supports gene-disease association.
Sources: Expert list
Mendeliome v0.5623 DACH2 Zornitza Stark gene: DACH2 was added
gene: DACH2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DACH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DACH2 were set to 15459172
Phenotypes for gene: DACH2 were set to Primary ovarian insufficiency
Review for gene: DACH2 was set to RED
Added comment: In a small candidate gene study, missense were more common in POI cases than controls (p= 0.0125). 5 missense reported in 7 POI cases, although 2 of the missense are too common in gnomAD for a dominant disorder. No other reports with evidence for an association with POI.
Sources: Expert list
Mendeliome v0.5621 TUBB8 Zornitza Stark Publications for gene: TUBB8 were set to
Mendeliome v0.5619 TUBB8 Zornitza Stark reviewed gene: TUBB8: Rating: GREEN; Mode of pathogenicity: None; Publications: 26789871, 27273344; Phenotypes: Oocyte maturation defect 2, MIM# 616780; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5618 WEE2 Zornitza Stark Publications for gene: WEE2 were set to
Mendeliome v0.5616 WEE2 Zornitza Stark reviewed gene: WEE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29606300, 30628060; Phenotypes: Oocyte maturation defect 5, MIM# 617996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5615 ZP1 Zornitza Stark gene: ZP1 was added
gene: ZP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZP1 were set to 24670168; 30810869; 32573113; 33272616
Phenotypes for gene: ZP1 were set to Oocyte maturation defect 1, MIM# 615774
Review for gene: ZP1 was set to GREEN
Added comment: Multiple unrelated individuals reported, presents as primary infertility.
Sources: Expert list
Mendeliome v0.5612 ZP3 Zornitza Stark gene: ZP3 was added
gene: ZP3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZP3 were set to 28886344; 30810869; 33272616; 32573113
Phenotypes for gene: ZP3 were set to Oocyte maturation defect 3, MIM# 617712
Review for gene: ZP3 was set to GREEN
Added comment: Oocyte maturation defect with normal ovarian reserves and menstrual cycles, presents as infertility.
Sources: Expert list
Mendeliome v0.5610 ECEL1P2 Zornitza Stark reviewed gene: ECEL1P2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.5609 CDC40 Zornitza Stark gene: CDC40 was added
gene: CDC40 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC40 were set to 33220177
Phenotypes for gene: CDC40 were set to Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: CDC40 was set to RED
Added comment: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association. Gene referred to as PRP17 in paper.
Sources: Literature
Mendeliome v0.5607 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Mendeliome v0.5605 FRA12A Bryony Thompson STR: FRA12A was added
STR: FRA12A was added to Mendeliome. Sources: Other
5'UTR tags were added to STR: FRA12A.
Mode of inheritance for STR: FRA12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FRA12A were set to 17236128
Phenotypes for STR: FRA12A were set to Mental retardation, FRA12A type MIM#136630
Review for STR: FRA12A was set to AMBER
Added comment: NM_173602.2:c.-137CGG[X]
All individuals expressing FRA12A had CGG-repeat expansion. The length of the expanded allele in 3 unaffected FRA12A carriers was 650–850 bp. In the two affected patients from 2 families with FRA12A, the length of the expanded allele was ∼1,050-1,150 bp.
70 controls used to determine the "normal" repeat range.
Sources: Other
Mendeliome v0.5604 DIP2B Bryony Thompson Added comment: Comment on list classification: Only repeat expansion reported. Added as an STR
Mendeliome v0.5603 DIP2B Bryony Thompson Added comment: Comment on list classification: Only repeat expansion reported. Added as an STR
Mendeliome v0.5602 PTPRQ Zornitza Stark Publications for gene: PTPRQ were set to 20346435; 20472657; 25919374; 14534255; 22357859; 29849575; 29309402; 31655630
Mendeliome v0.5601 PTPRQ Zornitza Stark edited their review of gene: PTPRQ: Added comment: Additional heterozygous variants reported in PMID: 33229591; Changed publications: 20346435, 20472657, 25919374, 14534255, 22357859, 29849575, 29309402, 31655630, 33229591
Mendeliome v0.5601 CANVAS_ACAGG Bryony Thompson Added comment: Comment on list classification: Used the pathogenic cut-off of 400 repeats from original CANVAS repeat
Mendeliome v0.5600 CANVAS_ACAGG Bryony Thompson STR: CANVAS_ACAGG was added
STR: CANVAS_ACAGG was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: CANVAS_ACAGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: CANVAS_ACAGG were set to 33103729
Phenotypes for STR: CANVAS_ACAGG were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome; fasciculations; elevated serum creatine kinase levels; denervation
Review for STR: CANVAS_ACAGG was set to AMBER
Added comment: A novel RFC1 repeat expansion motif, (ACAGG)exp, identified in three affected individuals from 2 families in an Asian-Pacific cohort for CANVAS. Southern blot was used to identify the repeat was ~1000kb in one of the cases, equivalent to ~1000 repeats.
Sources: Literature
Mendeliome v0.5598 CANVAS Bryony Thompson STR: CANVAS was added
STR: CANVAS was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: CANVAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: CANVAS were set to 30926972; 32851396
Phenotypes for STR: CANVAS were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575
Review for STR: CANVAS was set to GREEN
STR: CANVAS was marked as clinically relevant
Added comment: Simple tandem repeat (AAAAG)11 replaced with (AAGGG)n in intron 2 of RFC1. Loss of function is not the mechanism of disease. Maori population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp. (AAAGG)n repeat alone is not pathogenic.
Sources: Expert list
Mendeliome v0.5594 RNASEH2C Zornitza Stark Publications for gene: RNASEH2C were set to
Mendeliome v0.5590 RNASEH2C Chern Lim reviewed gene: RNASEH2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 24183309, 23322642; Phenotypes: Aicardi-Goutieres syndrome 3 (MIM# 610329), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5588 RAP1A Zornitza Stark Publications for gene: RAP1A were set to
Mendeliome v0.5585 RAP1A Zornitza Stark reviewed gene: RAP1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 26280580; Phenotypes: Kabuki syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5585 RAP1B Zornitza Stark Publications for gene: RAP1B were set to 32627184
Mendeliome v0.5583 RAP1B Zornitza Stark edited their review of gene: RAP1B: Added comment: Another individual with de novo missense reported from a cohort of Kabuki-like patients but note facial gestalt was not typical.; Changed rating: GREEN; Changed publications: 32627184, 26280580
Mendeliome v0.5582 RAP1B Zornitza Stark Publications for gene: RAP1B were set to
Mendeliome v0.5579 RAP1B Zornitza Stark reviewed gene: RAP1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 32627184; Phenotypes: RAP1B‐associated syndrome, intellectual disability, microcephaly, thrombocytopaenia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5579 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858
Phenotypes for gene: EMC10 were set to Intellectual disability
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Mendeliome v0.5577 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO28 were set to 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy
Review for gene: FBXO28 was set to GREEN
Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Mendeliome v0.5576 CFAP52 Zornitza Stark gene: CFAP52 was added
gene: CFAP52 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP52 were set to 25469542; 33139725
Phenotypes for gene: CFAP52 were set to Heterotaxy
Review for gene: CFAP52 was set to GREEN
Added comment: Five unrelated families and functional data.
Sources: Literature
Mendeliome v0.5575 CFAP45 Zornitza Stark gene: CFAP45 was added
gene: CFAP45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP45 were set to 33139725
Phenotypes for gene: CFAP45 were set to Situs inversus; asthenospermia
Review for gene: CFAP45 was set to GREEN
Added comment: Three unrelated individuals reported with bi-alleic LOF variants, mouse model recapitulated phenotype.
Sources: Literature
Mendeliome v0.5572 CLCN6 Zornitza Stark edited their review of gene: CLCN6: Added comment: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans.; Changed rating: GREEN; Changed publications: 25794116, 21107136, 33217309; Changed phenotypes: Neurodegeneration, Benign partial epilepsy, febrile seizures, NCL; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5570 GDF6 Zornitza Stark Publications for gene: GDF6 were set to 18425797; 19129173; 32737436
Mendeliome v0.5569 GDF6 Zornitza Stark Publications for gene: GDF6 were set to
Mendeliome v0.5567 GDF6 Zornitza Stark reviewed gene: GDF6: Rating: RED; Mode of pathogenicity: None; Publications: 18425797, 19129173; Phenotypes: Klippel-Feil syndrome 1, autosomal dominant 118100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5567 GDF6 Belinda Chong reviewed gene: GDF6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32737436; Phenotypes: Klippel-Feil syndrome 1, autosomal dominant 118100, Leber congenital amaurosis 17 615360, Microphthalmia with coloboma 6, digenic 613703, Microphthalmia, isolated 4 613094, Multiple synostoses syndrome 4 617898; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5567 PEX6 Dean Phelan reviewed gene: PEX6: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 32399598; Phenotypes: Perrault syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5567 VPS4A Kristin Rigbye changed review comment from: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.
"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Sources: Literature; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.

"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Mendeliome v0.5567 VPS4A Elena Savva changed review comment from: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents).
Demonstrated defective CD71 trafficking in all 3 patients.

Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Mendeliome v0.5567 VPS4A Elena Savva Added comment: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Mendeliome v0.5565 DAAM2 Zornitza Stark reviewed gene: DAAM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33232676; Phenotypes: Steroid-resistant nephrotic syndrome (SRNS); Mode of inheritance: None
Mendeliome v0.5565 DAAM2 Zornitza Stark Publications for gene: DAAM2 were set to
Mendeliome v0.5558 VPS4A Kristin Rigbye gene: VPS4A was added
gene: VPS4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to PMID: 33186543; 33186545
Phenotypes for gene: VPS4A were set to Neurodevelopmental disorder
Review for gene: VPS4A was set to GREEN
Added comment: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.
"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Sources: Literature
Mendeliome v0.5557 AGO2 Zornitza Stark gene: AGO2 was added
gene: AGO2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO2 were set to 33199684
Phenotypes for gene: AGO2 were set to Intellectual disability
Review for gene: AGO2 was set to GREEN
Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID.
Sources: Literature
Mendeliome v0.5555 RRP7A Zornitza Stark gene: RRP7A was added
gene: RRP7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRP7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRP7A were set to 33199730
Phenotypes for gene: RRP7A were set to Microcephaly
Review for gene: RRP7A was set to AMBER
Added comment: 10 affected individuals from a single large consanguineous family where bi-allelic variant segregated with severe microcephaly (-6-8SD), variable ID. Supportive functional data from mouse and zebrafish.
Sources: Literature
Mendeliome v0.5554 BICRA Paul De Fazio gene: BICRA was added
gene: BICRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BICRA were set to 33232675
Phenotypes for gene: BICRA were set to Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Review for gene: BICRA was set to GREEN
gene: BICRA was marked as current diagnostic
Added comment: 12 individuals reported, 11 de novo (1 not resolved), "with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features". Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association.
Sources: Literature
Mendeliome v0.5554 HS2ST1 Ain Roesley gene: HS2ST1 was added
gene: HS2ST1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Penetrance for gene: HS2ST1 were set to unknown
Review for gene: HS2ST1 was set to GREEN
Added comment: - 4 affected from 3 unrelated families
- 3 unique missense and 2 PTCs
- Developmental Delay, Corpus Callosum Hypoplasia or Aplasia, and Skeletal and Renal Abnormalities
Sources: Literature
Mendeliome v0.5553 KDM4B Kristin Rigbye gene: KDM4B was added
gene: KDM4B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to PMID: 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Mendeliome v0.5553 MINPP1 Zornitza Stark gene: MINPP1 was added
gene: MINPP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Review for gene: MINPP1 was set to GREEN
Added comment: 8 individuals from 6 unrelated families reported with bi-allelic LOF variants. All presented with almost complete absence of motor and cognitive development, progressive or congenital microcephaly, spastic tetraplegia or dystonia, and vision impairments. For most, the first symptoms included neonatal severe axial hypotonia and epilepsy that started during the first months or years of life. Prenatal symptoms of microcephaly associated with increased thalami echogenicity were detected in one, while the seven other individuals presented with progressive microcephaly. Some exhibited rapidly progressive phenotype and the affected children died in their infancy or middle-childhood. Strikingly, all the affected children had a unique brain MRI showing a mild to severe PCH, fluid-filled posterior fossa, with dilated lateral ventricles. In addition, severe atrophy at the level of the basal ganglia or thalami often associated with typical T2 hypersignal were identified in all the patients MRI.

Supportive functional data showing accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions.
Sources: Literature
Mendeliome v0.5552 UNC45B Paul De Fazio gene: UNC45B was added
gene: UNC45B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UNC45B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45B were set to 33217308
Phenotypes for gene: UNC45B were set to Progressive Myopathy with Eccentric Cores
Review for gene: UNC45B was set to GREEN
gene: UNC45B was marked as current diagnostic
Added comment: 10 individuals from 8 families reported with biallelic variants clinically manifesting with childhood-onset, progressive proximal and axial muscle weakness and various degrees of respiratory insufficiency. 4 missense variants and a +5 splice variant reported, p.Arg754Gln is recurrent. Functional studies support pathogenicity.
Sources: Literature
Mendeliome v0.5552 SMG8 Kristin Rigbye reviewed gene: SMG8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33242396; Phenotypes: Neuorodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5552 RFC1 Teresa Zhao reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33103729; Phenotypes: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5551 DNAJB11 Zornitza Stark Publications for gene: DNAJB11 were set to 29706351; 29777155
Mendeliome v0.5549 DNAJB11 Zornitza Stark edited their review of gene: DNAJB11: Added comment: Single family reported with bi-allelic variant and severe, fetal onset renal cystic disease, dilation and proliferation of pancreatic duct cells, and liver ductal plate malformation, an association known as Ivemark II syndrome.; Changed publications: 29706351, 29777155, 33129895; Changed phenotypes: Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061, Ivermark II syndrome.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.5547 HHAT Zornitza Stark gene: HHAT was added
gene: HHAT was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome 600092
Review for gene: HHAT was set to AMBER
Added comment: Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia.
Sources: Expert list
Mendeliome v0.5544 H3F3B Zornitza Stark Publications for gene: H3F3B were set to
Mendeliome v0.5541 H3F3B Zornitza Stark edited their review of gene: H3F3B: Added comment: 13 unrelated individuals reported with missense variants in H3F3B. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression, seizures; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5540 H3F3A Zornitza Stark Publications for gene: H3F3A were set to
Mendeliome v0.5537 H3F3A Zornitza Stark edited their review of gene: H3F3A: Added comment: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5536 ALDH7A1 Zornitza Stark Publications for gene: ALDH7A1 were set to
Mendeliome v0.5534 ALDH7A1 Zornitza Stark reviewed gene: ALDH7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, pyridoxine-dependent, MIM# 266100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5533 PRPS1 Zornitza Stark Publications for gene: PRPS1 were set to
Mendeliome v0.5529 HIVEP2 Zornitza Stark Publications for gene: HIVEP2 were set to
Mendeliome v0.5527 HIVEP2 Zornitza Stark reviewed gene: HIVEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26153216, 27003583, 16836985, 31602191; Phenotypes: Mental retardation, autosomal dominant 43, MIM# 616977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5527 HIVEP2 Elena Savva reviewed gene: HIVEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31207095; Phenotypes: Mental retardation, autosomal dominant 43 MIM#616977; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5527 PRPS1 Elena Savva reviewed gene: PRPS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32781272, 17701896, 7593598; Phenotypes: Arts syndrome MIM#301835, Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070, Deafness, X-linked 1 MIM#304500, Gout, PRPS-related MIM#300661, Phosphoribosylpyrophosphate synthetase superactivity MIM#300661; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5526 YIPF5 Zornitza Stark gene: YIPF5 was added
gene: YIPF5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Neonatal diabetes; microcephaly; seizures
Review for gene: YIPF5 was set to GREEN
Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association.
Sources: Literature
Mendeliome v0.5525 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.5525 TFE3 Zornitza Stark Publications for gene: TFE3 were set to 30595499; 31833172; 33057194
Mendeliome v0.5523 TFE3 Zornitza Stark edited their review of gene: TFE3: Added comment: PMID: 32409512 (2020) - 14 variants reported as de novo events in 17 unrelated cases (including 5 previously published) of severe intellectual disability with pigmentary mosaicism and storage disorder-like features; Changed publications: 30595499, 31833172, 32409512; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.5522 SLC38A8 Zornitza Stark Publications for gene: SLC38A8 were set to
Mendeliome v0.5518 TONSL Zornitza Stark Publications for gene: TONSL were set to
Mendeliome v0.5513 NPPA Zornitza Stark Publications for gene: NPPA were set to
Mendeliome v0.5511 NPPA Zornitza Stark reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 18614783, 20064500, 31034774, 31077706; Phenotypes: Atrial fibrillation, familial, 6, (MIM#612201); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5510 FOXA2 Zornitza Stark gene: FOXA2 was added
gene: FOXA2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FOXA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXA2 were set to 29329447; 28973288; 11445544
Phenotypes for gene: FOXA2 were set to Hyperinsulinaemia
Review for gene: FOXA2 was set to GREEN
Added comment: At least two families reported and functional data.
Sources: Expert Review
Mendeliome v0.5508 USP7 Zornitza Stark Publications for gene: USP7 were set to 30679821
Mendeliome v0.5507 USP7 Zornitza Stark edited their review of gene: USP7: Added comment: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay, behavioral abnormalities, such as autism, and mild dysmorphic facies. Additional features are variable, but may include hypotonia, feeding problems, delayed walking with unsteady gait, hypogonadism in males, and ocular anomalies, such as strabismus. Some patients develop seizures and some have mild white matter abnormalities on brain imaging.; Changed publications: 26365382, 30679821; Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, Intellectual disability, Autism
Mendeliome v0.5507 FKBP8 Eleanor Williams gene: FKBP8 was added
gene: FKBP8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FKBP8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FKBP8 were set to 32969478
Phenotypes for gene: FKBP8 were set to spina bifida HP:0002414
Review for gene: FKBP8 was set to AMBER
Added comment: Not associated with a phenotype in OMIM.

PMID: 32969478 - Tian et al 2020 - performed Sanger sequencing of FKBP8 on DNA samples from 472 spina bifida (SB) affected fetuses and 565 unaffected controls. 5 different rare heterozygous variants (MAF ≤ 0.001) were identified among the SB patients, while no deleterious rare variants were identified in the controls. 4 of the variants are missense, the other is a stop-gain. 2 cases were in white-Hispanic patients while the other 3 were non-white Hispanic. Functional studies showed that p.Glu140* affected FKBP8 localization to the mitochondria and impaired its interaction with BCL2 ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. Gene expression was studied in mouse Fkbp8-/- embryos and found to be abnormal. Previous mouse models have shown neural tube defects.

Sufficient cases to rate green, but only the FKBP8 gene looked at so perhaps some caution required while further evidence is gathered.
Sources: Literature
Mendeliome v0.5507 TONSL Eleanor Williams reviewed gene: TONSL: Rating: GREEN; Mode of pathogenicity: None; Publications: 30773277, 30773278, 32959051; Phenotypes: Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510, spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5507 CAPN15 Eleanor Williams changed review comment from: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families).
Sources: Literature; to: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth.

Sources: Literature
Mendeliome v0.5507 CAPN15 Eleanor Williams gene: CAPN15 was added
gene: CAPN15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 32885237
Phenotypes for gene: CAPN15 were set to microphthalmia HP:0000568; coloboma HP:0000589
Review for gene: CAPN15 was set to GREEN
Added comment: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families).
Sources: Literature
Mendeliome v0.5507 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5506 MYF5 Zornitza Stark Publications for gene: MYF5 were set to
Mendeliome v0.5504 MYF5 Zornitza Stark reviewed gene: MYF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29887215, 15386014, 1423602, 9268580, 8918877; Phenotypes: Ophthalmoplegia, external, with rib and vertebral anomalies, OMIM 61855; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5504 TARS2 Zornitza Stark Publications for gene: TARS2 were set to 24827421; 26811336
Mendeliome v0.5503 TARS2 Zornitza Stark edited their review of gene: TARS2: Added comment: Second family reported, single affected individual, compound heterozygous missense variants, computational data only in support of pathogenicity.; Changed publications: 24827421, 26811336, 33153448
Mendeliome v0.5502 COX16 Bryony Thompson gene: COX16 was added
gene: COX16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX16 were set to 33169484
Phenotypes for gene: COX16 were set to Hypertrophic cardiomyopathy; encephalopathy; severe fatal lactic acidosis
Review for gene: COX16 was set to AMBER
Added comment: 2 unrelated patients with the same homozygous (non-consanguineous) nonsense variant c.244C>T (p.Arg82*), and isolated complex IV deficiency present in both patient fibroblasts/skeletal muscle biopsy. COX16 is involved in the biogenesis of complex IV, the terminal complex of the mitochondrial respiratory chain (RC)
Sources: Literature
Mendeliome v0.5500 THBD Bryony Thompson reviewed gene: THBD: Rating: GREEN; Mode of pathogenicity: None; Publications: 32634856, 25564403, 32935436, 25049278, 27436851, 28267383, 10627464; Phenotypes: Thrombomodulin‐associated coagulopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5500 KCNJ18 Zornitza Stark gene: KCNJ18 was added
gene: KCNJ18 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KCNJ18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ18 were set to 20074522; 27008341
Phenotypes for gene: KCNJ18 were set to {Thyrotoxic periodic paralysis, susceptibility to, 2}, MIM# 613239
Review for gene: KCNJ18 was set to RED
Added comment: Six variants reported in original publication, however note lack of segregation data and limited functional data. Subsequently, concerns raised about high nucleotide sequence homology between multiple potassium channel genes, with variant misattribution.
Sources: Expert Review
Mendeliome v0.5498 DPM3 Zornitza Stark Publications for gene: DPM3 were set to
Mendeliome v0.5496 DPM3 Zornitza Stark reviewed gene: DPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31266720, 28803818, 19576565, 31266720, 31469168; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 , MIM#612937, Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15 618992; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5496 B3GAT3 Zornitza Stark Phenotypes for gene: B3GAT3 were changed from to Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects, MIM# 245600
Mendeliome v0.5495 B3GAT3 Zornitza Stark Publications for gene: B3GAT3 were set to
Mendeliome v0.5493 B3GAT3 Zornitza Stark reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26754439, 31988067, 26086840, 25893793, 21763480, 24668659; Phenotypes: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects, MIM# 245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5492 SLC10A7 Zornitza Stark Publications for gene: SLC10A7 were set to
Mendeliome v0.5490 SLC10A7 Zornitza Stark reviewed gene: SLC10A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30082715, 29878199, 31191616; Phenotypes: Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, MIM# 618363; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5488 PIGH Zornitza Stark Publications for gene: PIGH were set to 29573052; 29603516
Mendeliome v0.5487 PIGH Zornitza Stark edited their review of gene: PIGH: Added comment: Further three families reported.

Common clinical features include developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies.; Changed publications: 29573052, 29603516, 33156547