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Mendeliome v0.5190 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979 to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome, MIM#614979
Mendeliome v0.5189 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979
Mendeliome v0.5188 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndromeROSAH syndrome, MIM#614979
Mendeliome v0.5185 COG8 Zornitza Stark Gene: cog8 has been classified as Green List (High Evidence).
Mendeliome v0.5182 HBB Zornitza Stark Gene: hbb has been classified as Green List (High Evidence).
Mendeliome v0.5182 HBB Zornitza Stark Phenotypes for gene: HBB were changed from to Delta-beta thalassemia 141749; Erythrocytosis 6 617980; Heinz body anemia 140700; Hereditary persistence of fetal hemoglobin 141749; Methemoglobinemia, beta type 617971; Sickle cell anemia 603903; Thalassemia-beta, dominant inclusion-body 603902; Thalassemia, beta 613985
Mendeliome v0.5178 RAD51D Zornitza Stark Gene: rad51d has been classified as Red List (Low Evidence).
Mendeliome v0.5175 RAD51D Zornitza Stark Classified gene: RAD51D as Red List (low evidence)
Mendeliome v0.5175 RAD51D Zornitza Stark Gene: rad51d has been classified as Red List (Low Evidence).
Mendeliome v0.5174 HBB Elena Savva reviewed gene: HBB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31788855, 20301599, 29700171; Phenotypes: {Malaria, resistance to} 611162, Delta-beta thalassemia 141749, Erythrocytosis 6 617980, Heinz body anemia 140700, Hereditary persistence of fetal hemoglobin 141749, Methemoglobinemia, beta type 617971, Sickle cell anemia 603903, Thalassemia-beta, dominant inclusion-body 603902, Thalassemia, beta 613985; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5174 TPO Zornitza Stark Gene: tpo has been classified as Green List (High Evidence).
Mendeliome v0.5174 TPO Zornitza Stark Phenotypes for gene: TPO were changed from to Thyroid dyshormonogenesis 2A, MIM# 274500
Mendeliome v0.5171 TPO Zornitza Stark reviewed gene: TPO: Rating: GREEN; Mode of pathogenicity: None; Publications: 8027236, 10084596; Phenotypes: Thyroid dyshormonogenesis 2A, MIM# 274500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5171 SLC35A3 Zornitza Stark Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures; OMIM #615553 to Arthrogryposis, mental retardation, and seizures OMIM #615553; Skeletal dysplasia; Congenital disorder of glycosylation
Mendeliome v0.5169 SLC35A3 Zornitza Stark Classified gene: SLC35A3 as Green List (high evidence)
Mendeliome v0.5169 SLC35A3 Zornitza Stark Gene: slc35a3 has been classified as Green List (High Evidence).
Mendeliome v0.5168 SLC35A3 Zornitza Stark edited their review of gene: SLC35A3: Added comment: Third unrelated family reported in PMID 28777481 with prenatally diagnosed anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine, as well as cleft palate, micrognathia, patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs, camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism including proptosis, nevus flammeus, and a cupped left ear. Unclear if this is a distinct phenotype (note Holstein cows with variants in this gene have a skeletal phenotype) or part of a spectrum for a CDG. However, abnormal protein glycosylation, consistent with a defective Golgi UDP-GlcNAc transporter demonstrated, so overall, promoted to Green for CDG.; Changed rating: GREEN; Changed publications: 28777481, 28328131, 24031089; Changed phenotypes: Arthrogryposis, mental retardation, and seizures OMIM #615553, Skeletal dysplasia, Congenital disorder of glycosylation; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5168 VAC14 Zornitza Stark Gene: vac14 has been classified as Green List (High Evidence).
Mendeliome v0.5164 PHOX2A Zornitza Stark reviewed gene: PHOX2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16815872; Phenotypes: Fibrosis of extraocular muscles, congenital, 2 602078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5164 PHOX2A Zornitza Stark Classified gene: PHOX2A as Green List (high evidence)
Mendeliome v0.5164 PHOX2A Zornitza Stark Gene: phox2a has been classified as Green List (High Evidence).
Mendeliome v0.5163 COL25A1 Zornitza Stark Gene: col25a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5163 COL25A1 Zornitza Stark Phenotypes for gene: COL25A1 were changed from to Fibrosis of extraocular muscles, congenital, 5, MIM# 616219
Mendeliome v0.5160 COL25A1 Zornitza Stark Classified gene: COL25A1 as Amber List (moderate evidence)
Mendeliome v0.5160 COL25A1 Zornitza Stark Gene: col25a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5159 COL25A1 Zornitza Stark reviewed gene: COL25A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25500261, 26486031; Phenotypes: Fibrosis of extraocular muscles, congenital, 5, MIM# 616219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5159 KIF21A Zornitza Stark Gene: kif21a has been classified as Green List (High Evidence).
Mendeliome v0.5159 KIF21A Zornitza Stark Phenotypes for gene: KIF21A were changed from to Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700
Mendeliome v0.5156 KIF21A Zornitza Stark reviewed gene: KIF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 15621876, 15223798, 15621877, 18332320, 28930843, 27513105, 26190014, 24656932; Phenotypes: Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5156 NDUFAF6 Zornitza Stark Gene: ndufaf6 has been classified as Green List (High Evidence).
Mendeliome v0.5153 WNT5A Zornitza Stark Gene: wnt5a has been classified as Green List (High Evidence).
Mendeliome v0.5150 CYP3A4 Zornitza Stark Gene: cyp3a4 has been classified as Green List (High Evidence).
Mendeliome v0.5146 KCTD17 Zornitza Stark Gene: kctd17 has been classified as Green List (High Evidence).
Mendeliome v0.5143 TAF1 Zornitza Stark Gene: taf1 has been classified as Green List (High Evidence).
Mendeliome v0.5140 CTNNA3 Bryony Thompson Gene: ctnna3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5140 CTNNA3 Bryony Thompson Classified gene: CTNNA3 as Amber List (moderate evidence)
Mendeliome v0.5140 CTNNA3 Bryony Thompson Gene: ctnna3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5139 CTNNA3 Bryony Thompson gene: CTNNA3 was added
gene: CTNNA3 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: CTNNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTNNA3 were set to 23136403; 21254927; 22421363; 30415094; 31539150
Phenotypes for gene: CTNNA3 were set to Arrhythmogenic right ventricular cardiomyopathy; Arrhythmogenic right ventricular dysplasia, familial, 13 MIM#615616
Review for gene: CTNNA3 was set to AMBER
Added comment: Gene is classified as Limited by the ClinGen ARVC GCEP (Classification - 08/06/2019). PMID: 23136403 - an assumed de novo missense (V94D) was identified in an Italian proband with arrhythmogenic right ventricular dysplasia. An inframe deletion (Leu765del) was identified in a proband with arrhythmogenic right ventricular dysplasia, and was also present in the proband's asymptomatic father and paternal aunt, who had mild right ventricular dilation on echocardiography and increased trabeculations in the right ventricular apex on MRI, respectively, as well as in the aunt's asymptomatic son. There was supporting in vitro functional assay evidence for both variants. PMID: 21254927 - a missense variant was found in one of 55 Danish ARVD patients, but was found 37 times in 276,338 (1 homozygous) reference alleles in gnomAD making it less likely as a causal variant. PMID: 22421363 - null mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC. Additional publications identified - PMID: 30415094 - a VUS identified in a sudden unexpected death case with slight LV hypertrophy. PMID: 31539150 - 2 VUS and a nonsense variant identified in 3 probands with atrial fibrillation, with the nonsense variant segregating in an affected first-degree relative.
Sources: ClinGen
Mendeliome v0.5135 CHRNE Zornitza Stark Gene: chrne has been classified as Green List (High Evidence).
Mendeliome v0.5132 COLQ Zornitza Stark Gene: colq has been classified as Green List (High Evidence).
Mendeliome v0.5128 COX5A Zornitza Stark Phenotypes for gene: COX5A were changed from pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064; pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency
Mendeliome v0.5127 COX5A Zornitza Stark edited their review of gene: COX5A: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064, pulmonary arterial hypertension, lactic acidemia, failure to thrive, isolated complex IV deficiency
Mendeliome v0.5127 PET117 Zornitza Stark Phenotypes for gene: PET117 were changed from Developmental delay; Regression; Complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063; Developmental delay; Regression; Complex IV deficiency
Mendeliome v0.5126 PET117 Zornitza Stark edited their review of gene: PET117: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063, Developmental delay, Regression, Complex IV deficiency
Mendeliome v0.5125 APOPT1 Zornitza Stark Gene: apopt1 has been classified as Green List (High Evidence).
Mendeliome v0.5122 COX4I1 Zornitza Stark Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5122 COX4I1 Zornitza Stark Classified gene: COX4I1 as Amber List (moderate evidence)
Mendeliome v0.5122 COX4I1 Zornitza Stark Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5118 PET100 Zornitza Stark Gene: pet100 has been classified as Green List (High Evidence).
Mendeliome v0.5115 COX20 Zornitza Stark Gene: cox20 has been classified as Green List (High Evidence).
Mendeliome v0.5111 TACO1 Zornitza Stark Gene: taco1 has been classified as Green List (High Evidence).
Mendeliome v0.5108 PRKACA Zornitza Stark Gene: prkaca has been classified as Green List (High Evidence).
Mendeliome v0.5108 PRKACA Zornitza Stark Classified gene: PRKACA as Green List (high evidence)
Mendeliome v0.5108 PRKACA Zornitza Stark Gene: prkaca has been classified as Green List (High Evidence).
Mendeliome v0.5107 PRKACB Zornitza Stark Classified gene: PRKACB as Green List (high evidence)
Mendeliome v0.5107 PRKACB Zornitza Stark Gene: prkacb has been classified as Green List (High Evidence).
Mendeliome v0.5106 CNGA2 Zornitza Stark Gene: cnga2 has been classified as Red List (Low Evidence).
Mendeliome v0.5106 CNGA2 Zornitza Stark gene: CNGA2 was added
gene: CNGA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNGA2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CNGA2 were set to 28572688
Phenotypes for gene: CNGA2 were set to Congenital anosmia
Review for gene: CNGA2 was set to RED
Added comment: Single multiplex family with high-impact variant segregating with anosmia.
Sources: Literature
Mendeliome v0.5105 COX6B1 Zornitza Stark Gene: cox6b1 has been classified as Green List (High Evidence).
Mendeliome v0.5102 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to unknown
Mode of pathogenicity for gene: PRKACB 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: PRKACB was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Mendeliome v0.5102 PRKACA Konstantinos Varvagiannis gene: PRKACA was added
gene: PRKACA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACA were set to 33058759; 31130284
Phenotypes for gene: PRKACA were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACA were set to unknown
Mode of pathogenicity for gene: PRKACA 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: PRKACA was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Mendeliome v0.5102 SCO1 Zornitza Stark Gene: sco1 has been classified as Green List (High Evidence).
Mendeliome v0.5099 COX10 Zornitza Stark Gene: cox10 has been classified as Green List (High Evidence).
Mendeliome v0.5096 GFPT1 Zornitza Stark Gene: gfpt1 has been classified as Green List (High Evidence).
Mendeliome v0.5093 BMP7 Zornitza Stark Gene: bmp7 has been classified as Red List (Low Evidence).
Mendeliome v0.5093 BMP7 Zornitza Stark gene: BMP7 was added
gene: BMP7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP7 were set to 32266521; 24429398
Phenotypes for gene: BMP7 were set to Non-syndromic metopic craniosynostosis
Mode of pathogenicity for gene: BMP7 was set to Other
Review for gene: BMP7 was set to RED
Added comment: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5091 SMARCC1 Zornitza Stark Classified gene: SMARCC1 as Green List (high evidence)
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5089 SLC18A3 Zornitza Stark Gene: slc18a3 has been classified as Green List (High Evidence).
Mendeliome v0.5085 SYT2 Zornitza Stark changed review comment from: Mono-allelic disease, PMID 25192047: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in two families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.

Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.; to: Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.

Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.
Mendeliome v0.5085 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
Mendeliome v0.5082 CHAT Zornitza Stark Gene: chat has been classified as Green List (High Evidence).
Mendeliome v0.5079 ALG2 Zornitza Stark Gene: alg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5076 ALG2 Zornitza Stark Classified gene: ALG2 as Amber List (moderate evidence)
Mendeliome v0.5076 ALG2 Zornitza Stark Gene: alg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5075 AGRN Zornitza Stark Gene: agrn has been classified as Green List (High Evidence).
Mendeliome v0.5072 DPH1 Zornitza Stark Gene: dph1 has been classified as Green List (High Evidence).
Mendeliome v0.5068 LRP8 Bryony Thompson Gene: lrp8 has been classified as Red List (Low Evidence).
Mendeliome v0.5068 LRP8 Bryony Thompson Classified gene: LRP8 as Red List (low evidence)
Mendeliome v0.5068 LRP8 Bryony Thompson Gene: lrp8 has been classified as Red List (Low Evidence).
Mendeliome v0.5067 TCF21 Bryony Thompson Gene: tcf21 has been classified as Red List (Low Evidence).
Mendeliome v0.5067 TCF21 Bryony Thompson Classified gene: TCF21 as Red List (low evidence)
Mendeliome v0.5067 TCF21 Bryony Thompson Gene: tcf21 has been classified as Red List (Low Evidence).
Mendeliome v0.5066 SETD1A Zornitza Stark changed review comment from: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; to: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.
Mendeliome v0.5065 SETD1A Zornitza Stark edited their review of gene: SETD1A: Added comment: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM# 618832, Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Mendeliome v0.5064 JARID2 Zornitza Stark Classified gene: JARID2 as Green List (high evidence)
Mendeliome v0.5064 JARID2 Zornitza Stark Gene: jarid2 has been classified as Green List (High Evidence).
Mendeliome v0.5061 NUDT2 Zornitza Stark Classified gene: NUDT2 as Green List (high evidence)
Mendeliome v0.5061 NUDT2 Zornitza Stark Gene: nudt2 has been classified as Green List (High Evidence).
Mendeliome v0.5060 AFF2 Zornitza Stark changed review comment from: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.; to: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort.
Mendeliome v0.5060 AFF2 Zornitza Stark Gene: aff2 has been classified as Green List (High Evidence).
Mendeliome v0.5057 AFF2 Zornitza Stark commented on gene: AFF2: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.
Mendeliome v0.5057 AUTS2 Zornitza Stark Gene: auts2 has been classified as Green List (High Evidence).
Mendeliome v0.5051 ITSN2 Zornitza Stark Gene: itsn2 has been classified as Green List (High Evidence).
Mendeliome v0.5051 ITSN2 Zornitza Stark Classified gene: ITSN2 as Green List (high evidence)
Mendeliome v0.5051 ITSN2 Zornitza Stark Gene: itsn2 has been classified as Green List (High Evidence).
Mendeliome v0.5050 ITSN2 Elena Savva gene: ITSN2 was added
gene: ITSN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITSN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITSN2 were set to PMID: 29773874
Phenotypes for gene: ITSN2 were set to Nephrotic syndrome
Review for gene: ITSN2 was set to GREEN
Added comment: PMID: 29773874: 2 families (3 patients) with homozygous missense or chet missense/PTC + null mice recapitulating the human phenotype.
Functional analysis of all variants shows an inability for Cdc42 activation as shown by wildtype overexpression
Sources: Literature
Mendeliome v0.5050 PI4K2A Zornitza Stark Gene: pi4k2a has been classified as Red List (Low Evidence).
Mendeliome v0.5050 PI4K2A Zornitza Stark gene: PI4K2A was added
gene: PI4K2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 32418222
Phenotypes for gene: PI4K2A were set to Cutis laxa, intellectual disability, movement disorder
Review for gene: PI4K2A was set to RED
Added comment: Single individual reported with homozygous missense variant and functional data including mouse model.
Sources: Literature
Mendeliome v0.5049 NR5A1 Zornitza Stark Gene: nr5a1 has been classified as Green List (High Evidence).
Mendeliome v0.5046 HECW2 Zornitza Stark Gene: hecw2 has been classified as Green List (High Evidence).
Mendeliome v0.5045 HECW2 Zornitza Stark Phenotypes for gene: HECW2 were changed from to Neurodevelopmental disorder with hypotonia, seizures, and absent language, MIM# 617268; intellectual disability; epilepsy; regression; microcephaly
Mendeliome v0.5042 HECW2 Natasha Brown reviewed gene: HECW2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 29807643, 29395664, 27334371, 27389779; Phenotypes: intellectual disability, epilepsy, regression, microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5041 ZMYND10 Zornitza Stark Gene: zmynd10 has been classified as Green List (High Evidence).
Mendeliome v0.5041 ZMYND10 Zornitza Stark Phenotypes for gene: ZMYND10 were changed from to Ciliary dyskinesia, primary, 22, MIM#615444
Mendeliome v0.5038 ZMYND10 Zornitza Stark reviewed gene: ZMYND10: Rating: GREEN; Mode of pathogenicity: None; Publications: 23891471, 23891469; Phenotypes: Ciliary dyskinesia, primary, 22, MIM#615444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5038 SPAG1 Zornitza Stark Gene: spag1 has been classified as Green List (High Evidence).
Mendeliome v0.5038 SPAG1 Zornitza Stark Phenotypes for gene: SPAG1 were changed from to Ciliary dyskinesia, primary, 28 (MIM#615505)
Mendeliome v0.5035 SPAG1 Zornitza Stark reviewed gene: SPAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622824, 32502479, 24055112; Phenotypes: Ciliary dyskinesia, primary, 28 (MIM#615505); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5035 MMP21 Zornitza Stark Gene: mmp21 has been classified as Green List (High Evidence).
Mendeliome v0.5032 DNAAF1 Zornitza Stark Gene: dnaaf1 has been classified as Green List (High Evidence).
Mendeliome v0.5032 DNAAF1 Zornitza Stark Phenotypes for gene: DNAAF1 were changed from to Ciliary dyskinesia, primary, 13, MIM# 613193
Mendeliome v0.5029 DNAAF1 Zornitza Stark reviewed gene: DNAAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19944400, 19944405, 32502479, 29228333, 27261005; Phenotypes: Ciliary dyskinesia, primary, 13, MIM# 613193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5029 LRRC6 Zornitza Stark Gene: lrrc6 has been classified as Green List (High Evidence).
Mendeliome v0.5029 LRRC6 Zornitza Stark Phenotypes for gene: LRRC6 were changed from to Ciliary dyskinesia, primary, 19, MIM# 614935
Mendeliome v0.5026 LRRC6 Zornitza Stark reviewed gene: LRRC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23122589, 23891469, 32622824, 29511670; Phenotypes: Ciliary dyskinesia, primary, 19, MIM# 614935; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5026 GAS8 Zornitza Stark Gene: gas8 has been classified as Green List (High Evidence).
Mendeliome v0.5026 GAS8 Zornitza Stark Phenotypes for gene: GAS8 were changed from to Ciliary dyskinesia, primary, 33, MIM#616726
Mendeliome v0.5023 GAS8 Zornitza Stark reviewed gene: GAS8: Rating: GREEN; Mode of pathogenicity: None; Publications: 26387594, 27120127; Phenotypes: Ciliary dyskinesia, primary, 33, mIM# 616726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5023 DNAI2 Zornitza Stark Gene: dnai2 has been classified as Green List (High Evidence).
Mendeliome v0.5023 DNAI2 Zornitza Stark Phenotypes for gene: DNAI2 were changed from to Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444
Mendeliome v0.5020 DNAI2 Zornitza Stark reviewed gene: DNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18950741, 23261302; Phenotypes: Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5020 DNAI1 Zornitza Stark Gene: dnai1 has been classified as Green List (High Evidence).
Mendeliome v0.5020 DNAI1 Zornitza Stark Phenotypes for gene: DNAI1 were changed from to Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400
Mendeliome v0.5017 DNAI1 Zornitza Stark reviewed gene: DNAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10577904, 11231901, 32502479, 31765523, 30622330; Phenotypes: Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAH11 Zornitza Stark reviewed gene: DNAH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 12142464, 18022865, 22102620, 32633470, 31879361, 31765523, 31040315; Phenotypes: Ciliary dyskinesia, primary, 7, with or without situs inversus, MIM#611884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAAF5 Zornitza Stark Gene: dnaaf5 has been classified as Green List (High Evidence).
Mendeliome v0.5016 DNAAF5 Zornitza Stark Phenotypes for gene: DNAAF5 were changed from to Ciliary dyskinesia, primary, 18, MIM# 614874
Mendeliome v0.5013 DNAAF5 Zornitza Stark reviewed gene: DNAAF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23040496, 29363216, 25232951; Phenotypes: Ciliary dyskinesia, primary, 18, MIM# 614874; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5013 DNAAF3 Zornitza Stark Gene: dnaaf3 has been classified as Green List (High Evidence).
Mendeliome v0.5013 DNAAF3 Zornitza Stark Phenotypes for gene: DNAAF3 were changed from to Ciliary dyskinesia, primary, 2, MIM# 606763
Mendeliome v0.5010 DNAAF3 Zornitza Stark reviewed gene: DNAAF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22387996, 32622824, 31186518; Phenotypes: Ciliary dyskinesia, primary, 2, MIM# 606763; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5010 RAB27A Zornitza Stark Gene: rab27a has been classified as Green List (High Evidence).
Mendeliome v0.5007 DNAAF2 Zornitza Stark Gene: dnaaf2 has been classified as Green List (High Evidence).
Mendeliome v0.5007 DNAAF2 Zornitza Stark Phenotypes for gene: DNAAF2 were changed from to Ciliary dyskinesia, primary, 10, MIM# 612518
Mendeliome v0.5004 DNAAF2 Zornitza Stark reviewed gene: DNAAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19052621, 32638265, 31107948; Phenotypes: Ciliary dyskinesia, primary, 10, MIM# 612518; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5004 PPP1R13L Zornitza Stark Gene: ppp1r13l has been classified as Green List (High Evidence).
Mendeliome v0.5004 PPP1R13L Zornitza Stark Classified gene: PPP1R13L as Green List (high evidence)
Mendeliome v0.5004 PPP1R13L Zornitza Stark Gene: ppp1r13l has been classified as Green List (High Evidence).
Mendeliome v0.5003 PPP1R13L Zornitza Stark gene: PPP1R13L was added
gene: PPP1R13L was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PPP1R13L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R13L were set to 32666529; 28864777
Phenotypes for gene: PPP1R13L were set to Dilated cardiomyopathy, onset in infancy
Review for gene: PPP1R13L was set to GREEN
Added comment: Four families reported in PMID 28864777, but same homozygous variant, identity by descent. Five unrelated families reported in PMID 32666529. Severe progressive DCM with onset in infancy.
Sources: Expert list
Mendeliome v0.5002 CCNO Zornitza Stark Gene: ccno has been classified as Green List (High Evidence).
Mendeliome v0.5002 CCNO Zornitza Stark Phenotypes for gene: CCNO were changed from to Ciliary dyskinesia, primary, 29, MIM# 615872
Mendeliome v0.4999 CCNO Zornitza Stark reviewed gene: CCNO: Rating: GREEN; Mode of pathogenicity: None; Publications: 24747639, 31765523, 28801648; Phenotypes: Ciliary dyskinesia, primary, 29, MIM# 615872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Gene: csnk1g1 has been classified as Green List (High Evidence).
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Classified gene: CSNK1G1 as Green List (high evidence)
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Gene: csnk1g1 has been classified as Green List (High Evidence).
Mendeliome v0.4998 CSNK1G1 Zornitza Stark gene: CSNK1G1 was added
gene: CSNK1G1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSNK1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK1G1 were set to 33009664
Phenotypes for gene: CSNK1G1 were set to Global developmental delay; Intellectual disability; Autism; Seizures
Review for gene: CSNK1G1 was set to GREEN
Added comment: Borderline Green/Amber rating.

Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).
Sources: Literature
Mendeliome v0.4997 LMNB2 Zornitza Stark Gene: lmnb2 has been classified as Green List (High Evidence).
Mendeliome v0.4993 SREBF1 Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016 to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 SREBF1 Zornitza Stark edited their review of gene: SREBF1: Added comment: HMD phenotype: 5 unrelated families reported with heterozygous variants at same residue (p.Arg557Cys and p.Arg557His) and a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Individuals developed cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses.; Changed publications: 32497488, 31790666, 32902915; Changed phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016, Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 CCDC40 Zornitza Stark Gene: ccdc40 has been classified as Green List (High Evidence).
Mendeliome v0.4991 CCDC40 Zornitza Stark Phenotypes for gene: CCDC40 were changed from to Ciliary dyskinesia, primary, 15, MIM#613808
Mendeliome v0.4988 CCDC40 Zornitza Stark reviewed gene: CCDC40: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131974, 23255504, 31879361, 31765523, 31650533; Phenotypes: Ciliary dyskinesia, primary, 15, MIM#613808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4988 CCDC39 Zornitza Stark Gene: ccdc39 has been classified as Green List (High Evidence).
Mendeliome v0.4988 CCDC39 Zornitza Stark Phenotypes for gene: CCDC39 were changed from to Ciliary dyskinesia, primary, 14, MIM# 613807
Mendeliome v0.4985 CCDC39 Zornitza Stark reviewed gene: CCDC39: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131972, 23255504; Phenotypes: Ciliary dyskinesia, primary, 14, MIM# 613807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4985 CCDC151 Zornitza Stark Gene: ccdc151 has been classified as Green List (High Evidence).
Mendeliome v0.4985 CCDC151 Zornitza Stark Phenotypes for gene: CCDC151 were changed from to Ciliary dyskinesia, primary, 30, MIM# 616037
Mendeliome v0.4982 CCDC151 Zornitza Stark reviewed gene: CCDC151: Rating: GREEN; Mode of pathogenicity: None; Publications: 25192045, 25224326, 32490514, 32286033, 30504913; Phenotypes: Ciliary dyskinesia, primary, 30, MIM# 616037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4982 CCDC114 Zornitza Stark Gene: ccdc114 has been classified as Green List (High Evidence).
Mendeliome v0.4982 CCDC114 Zornitza Stark Phenotypes for gene: CCDC114 were changed from to Ciliary dyskinesia, primary, 20, MIM# 615067
Mendeliome v0.4979 CCDC114 Zornitza Stark reviewed gene: CCDC114: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261303, 23261302, 32855706, 23506398; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4979 CCDC103 Zornitza Stark Gene: ccdc103 has been classified as Green List (High Evidence).
Mendeliome v0.4979 CCDC103 Zornitza Stark Phenotypes for gene: CCDC103 were changed from to Ciliary dyskinesia, primary, 17, MIM# 614679
Mendeliome v0.4976 CCDC103 Zornitza Stark reviewed gene: CCDC103: Rating: GREEN; Mode of pathogenicity: None; Publications: 22581229, 32447765, 31858719, 28790179; Phenotypes: Ciliary dyskinesia, primary, 17, MIM# 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4976 GARS Zornitza Stark Gene: gars has been classified as Green List (High Evidence).
Mendeliome v0.4973 SELENON Zornitza Stark Gene: selenon has been classified as Green List (High Evidence).
Mendeliome v0.4970 TNNT1 Zornitza Stark Gene: tnnt1 has been classified as Green List (High Evidence).
Mendeliome v0.4968 TNNT3 Zornitza Stark Gene: tnnt3 has been classified as Green List (High Evidence).
Mendeliome v0.4968 TNNT3 Zornitza Stark Phenotypes for gene: TNNT3 were changed from to Arthrogryposis, distal, type 2B2, MIM# 618435
Mendeliome v0.4964 TNNT3 Zornitza Stark reviewed gene: TNNT3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 12865991, 19142688, 21402185, 25337069, 17194691; Phenotypes: Arthrogryposis, distal, type 2B2, MIM# 618435; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4964 STAC3 Zornitza Stark Gene: stac3 has been classified as Green List (High Evidence).
Mendeliome v0.4961 SPEG Zornitza Stark Gene: speg has been classified as Green List (High Evidence).
Mendeliome v0.4958 TPM3 Zornitza Stark Gene: tpm3 has been classified as Green List (High Evidence).
Mendeliome v0.4958 TPM3 Zornitza Stark Phenotypes for gene: TPM3 were changed from to CAP myopathy 1, MIM# 609284; Myopathy, congenital, with fiber-type disproportion, MIM# 255310; Nemaline myopathy 1, autosomal dominant or recessive, MIM# 609284; Congenital muscle stiffness
Mendeliome v0.4954 TPM3 Zornitza Stark reviewed gene: TPM3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 26418456, 7704029, 17376686, 18382475, 19487656; Phenotypes: CAP myopathy 1, MIM# 609284, Myopathy, congenital, with fiber-type disproportion, MIM# 255310, Nemaline myopathy 1, autosomal dominant or recessive, MIM# 609284, Congenital muscle stiffness; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4954 MICU1 Zornitza Stark Gene: micu1 has been classified as Green List (High Evidence).
Mendeliome v0.4954 MICU1 Zornitza Stark Phenotypes for gene: MICU1 were changed from to Myopathy with extrapyramidal signs, MIM# 615673
Mendeliome v0.4951 MICU1 Zornitza Stark reviewed gene: MICU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24336167, 29721912, 32395406; Phenotypes: Myopathy with extrapyramidal signs, MIM# 615673; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4951 LMOD3 Zornitza Stark Gene: lmod3 has been classified as Green List (High Evidence).
Mendeliome v0.4947 MYH2 Zornitza Stark Gene: myh2 has been classified as Green List (High Evidence).
Mendeliome v0.4944 KLHL41 Zornitza Stark Gene: klhl41 has been classified as Green List (High Evidence).
Mendeliome v0.4941 KLHL40 Zornitza Stark Gene: klhl40 has been classified as Green List (High Evidence).
Mendeliome v0.4941 KLHL40 Zornitza Stark Phenotypes for gene: KLHL40 were changed from to Nemaline myopathy 8, autosomal recessive, MIM# 615348
Mendeliome v0.4938 KLHL40 Zornitza Stark reviewed gene: KLHL40: Rating: GREEN; Mode of pathogenicity: None; Publications: 23746549, 24960163, 32352246, 31908664, 27528495; Phenotypes: Nemaline myopathy 8, autosomal recessive, MIM# 615348; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4938 MYO18B Zornitza Stark Gene: myo18b has been classified as Green List (High Evidence).
Mendeliome v0.4938 MYO18B Zornitza Stark Phenotypes for gene: MYO18B were changed from to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, MIM# 616549
Mendeliome v0.4935 MYO18B Zornitza Stark reviewed gene: MYO18B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25748484, 27858739, 32637634, 32184166, 27879346; Phenotypes: Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, MIM# 616549; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4935 MEGF10 Zornitza Stark Gene: megf10 has been classified as Green List (High Evidence).
Mendeliome v0.4931 WDPCP Zornitza Stark Classified gene: WDPCP as Green List (high evidence)
Mendeliome v0.4931 WDPCP Zornitza Stark Gene: wdpcp has been classified as Green List (High Evidence).
Mendeliome v0.4930 WDPCP Zornitza Stark Gene: wdpcp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4927 WDPCP Zornitza Stark Classified gene: WDPCP as Amber List (moderate evidence)
Mendeliome v0.4927 WDPCP Zornitza Stark Gene: wdpcp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4926 TUBGCP4 Zornitza Stark Gene: tubgcp4 has been classified as Green List (High Evidence).
Mendeliome v0.4926 TUBGCP4 Zornitza Stark Phenotypes for gene: TUBGCP4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 3, MIM# 616335
Mendeliome v0.4923 TUBGCP4 Zornitza Stark reviewed gene: TUBGCP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25817018, 32270730; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 3, MIM# 616335; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4923 DYNC2LI1 Zornitza Stark Gene: dync2li1 has been classified as Green List (High Evidence).
Mendeliome v0.4923 DYNC2LI1 Zornitza Stark Phenotypes for gene: DYNC2LI1 were changed from to Short-rib thoracic dysplasia 15 with polydactyly (MIM#617088)
Mendeliome v0.4917 DYNC2LI1 Ain Roesley reviewed gene: DYNC2LI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33030252; Phenotypes: Short-rib thoracic dysplasia 15 with polydactyly (MIM#617088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4916 GPC6 Elena Savva reviewed gene: GPC6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19481194, 32655339; Phenotypes: Omodysplasia 1 MIM#258315; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4916 FKBP14 Zornitza Stark Gene: fkbp14 has been classified as Green List (High Evidence).
Mendeliome v0.4913 EPG5 Zornitza Stark Gene: epg5 has been classified as Green List (High Evidence).
Mendeliome v0.4910 LMX1B Zornitza Stark Gene: lmx1b has been classified as Green List (High Evidence).
Mendeliome v0.4907 SEMA4A Zornitza Stark Gene: sema4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4904 SEMA4A Zornitza Stark Classified gene: SEMA4A as Amber List (moderate evidence)
Mendeliome v0.4904 SEMA4A Zornitza Stark Gene: sema4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4903 JPH2 Zornitza Stark Gene: jph2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4900 JPH2 Zornitza Stark Classified gene: JPH2 as Amber List (moderate evidence)
Mendeliome v0.4900 JPH2 Zornitza Stark Gene: jph2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4899 RGR Zornitza Stark Gene: rgr has been classified as Red List (Low Evidence).
Mendeliome v0.4896 RGR Zornitza Stark Classified gene: RGR as Red List (low evidence)
Mendeliome v0.4896 RGR Zornitza Stark Gene: rgr has been classified as Red List (Low Evidence).
Mendeliome v0.4895 RDH11 Zornitza Stark Gene: rdh11 has been classified as Red List (Low Evidence).
Mendeliome v0.4895 RDH11 Zornitza Stark gene: RDH11 was added
gene: RDH11 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 15634683; 30731079; 18326732
Phenotypes for gene: RDH11 were set to Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108
Review for gene: RDH11 was set to RED
Added comment: Single family reported with compound heterozygous LOF variants segregating with disease in three siblings. Some functional data, but note mouse KO did not have eye phenotype.
Sources: Expert list
Mendeliome v0.4894 CEP112 Zornitza Stark Gene: cep112 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4892 GPC6 Zornitza Stark Gene: gpc6 has been classified as Green List (High Evidence).
Mendeliome v0.4892 GPC6 Zornitza Stark Phenotypes for gene: GPC6 were changed from to Omodysplasia 1 (MIM#258315), AR
Mendeliome v0.4889 GPC6 Kristin Rigbye reviewed gene: GPC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 19481194; Phenotypes: Omodysplasia 1 (MIM#258315), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4889 SPATA7 Zornitza Stark Gene: spata7 has been classified as Green List (High Evidence).
Mendeliome v0.4889 SPATA7 Zornitza Stark Phenotypes for gene: SPATA7 were changed from to Leber congenital amaurosis 3, MIM#604232; Autosomal recessive juvenile retinitis pigmentosa, MIM#604232
Mendeliome v0.4886 SPATA7 Chern Lim reviewed gene: SPATA7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31908400, 32799588; Phenotypes: Leber congenital amaurosis 3, MIM#604232, Autosomal recessive juvenile retinitis pigmentosa, MIM#604232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.4886 KIRREL3 Zornitza Stark Gene: kirrel3 has been classified as Red List (Low Evidence).
Mendeliome v0.4886 KIRREL3 Zornitza Stark gene: KIRREL3 was added
gene: KIRREL3 was added to Mendeliome. Sources: Expert list
refuted tags were added to gene: KIRREL3.
Mode of inheritance for gene: KIRREL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIRREL3 were set to 19012874
Phenotypes for gene: KIRREL3 were set to Intellectual disability
Review for gene: KIRREL3 was set to RED
Added comment: Variants associated with ID have now been re-classified based on population frequency.
Sources: Expert list
Mendeliome v0.4885 NEUROD1 Zornitza Stark Gene: neurod1 has been classified as Green List (High Evidence).
Mendeliome v0.4882 DNAAF4 Zornitza Stark Gene: dnaaf4 has been classified as Green List (High Evidence).
Mendeliome v0.4882 DNAAF4 Zornitza Stark Phenotypes for gene: DNAAF4 were changed from to Ciliary dyskinesia, primary, 25, MIM# 615482
Mendeliome v0.4879 DNAAF4 Zornitza Stark reviewed gene: DNAAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23872636; Phenotypes: Ciliary dyskinesia, primary, 25, MIM# 615482; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4879 MAG Zornitza Stark Phenotypes for gene: MAG were changed from Spastic paraplegia 75, autosomal recessive, MIM# 616680 to Spastic paraplegia 75, autosomal recessive, MIM# 616680; Cerebellar ataxia
Mendeliome v0.4878 MAG Zornitza Stark changed review comment from: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported.; to: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms.
Mendeliome v0.4878 GZF1 Zornitza Stark Gene: gzf1 has been classified as Green List (High Evidence).
Mendeliome v0.4875 ITFG2 Zornitza Stark Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4875 ITFG2 Zornitza Stark Classified gene: ITFG2 as Amber List (moderate evidence)
Mendeliome v0.4875 ITFG2 Zornitza Stark Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4874 ITFG2 Zornitza Stark gene: ITFG2 was added
gene: ITFG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51). Cheema et al (2020 - https://doi.org/10.1038/s41525-020-00150-z) report briefly on a male, born to consanguineous parents presenting with NDD, seizures, regression and ataxia. There was a similarly affected female sibling. Evaluation of ROH revealed a homozygous ITFG2 nonsense variant [NM_018463.3:c.361C>T / p.(Gln121*)]. Families in this study were investigated by trio WES or WGS. Evaluation of data of the same lab revealed 3 additional unrelated subjects with overlapping phenotypes, notably NDD and ataxia. These individuals were - each - homozygous for pLoF variants [NM_018463.3:c.848-1G>A; NM_018463.3:c.704dupC, p.(Ala236fs), NM_018463.3:c.1000_1001delAT, p.(Ile334fs)]. As discussed in OMIM, ITFG2 encodes a subunit of the KICSTOR protein complex, having a role in regulating nutrient sensing by MTOR complex-1 (Wolfson et al 2017 - PMID : 28199306).

Rated Amber as Cheema et al report on diagnostic outcomes and multiple candidate genes as part of a heterogenous cohort and details are therefore limited.
Sources: Literature
Mendeliome v0.4873 SHMT2 Zornitza Stark Gene: shmt2 has been classified as Green List (High Evidence).
Mendeliome v0.4873 SHMT2 Zornitza Stark Classified gene: SHMT2 as Green List (high evidence)
Mendeliome v0.4873 SHMT2 Zornitza Stark Gene: shmt2 has been classified as Green List (High Evidence).
Mendeliome v0.4872 SHMT2 Zornitza Stark gene: SHMT2 was added
gene: SHMT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).
Sources: Literature
Mendeliome v0.4871 DHX38 Zornitza Stark Gene: dhx38 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4868 DHX38 Zornitza Stark Classified gene: DHX38 as Amber List (moderate evidence)
Mendeliome v0.4868 DHX38 Zornitza Stark Gene: dhx38 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4867 CCT2 Zornitza Stark Gene: cct2 has been classified as Red List (Low Evidence).
Mendeliome v0.4867 CCT2 Zornitza Stark gene: CCT2 was added
gene: CCT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: CCT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCT2 were set to 27645772; 29450543
Phenotypes for gene: CCT2 were set to Leber's congenital amaurosis
Review for gene: CCT2 was set to RED
Added comment: Single family reported with compound het missense variants, functional data, including animal model.
Sources: NHS GMS
Mendeliome v0.4866 CA4 Zornitza Stark Gene: ca4 has been classified as Red List (Low Evidence).
Mendeliome v0.4863 CA4 Zornitza Stark Classified gene: CA4 as Red List (low evidence)
Mendeliome v0.4863 CA4 Zornitza Stark Gene: ca4 has been classified as Red List (Low Evidence).
Mendeliome v0.4862 VPS41 Zornitza Stark Gene: vps41 has been classified as Red List (Low Evidence).
Mendeliome v0.4862 VPS41 Zornitza Stark gene: VPS41 was added
gene: VPS41 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683
Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability
Review for gene: VPS41 was set to RED
Added comment: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.
Sources: Literature
Mendeliome v0.4861 VPS16 Zornitza Stark Gene: vps16 has been classified as Green List (High Evidence).
Mendeliome v0.4861 VPS16 Zornitza Stark Classified gene: VPS16 as Green List (high evidence)
Mendeliome v0.4861 VPS16 Zornitza Stark Gene: vps16 has been classified as Green List (High Evidence).
Mendeliome v0.4860 VPS16 Zornitza Stark gene: VPS16 was added
gene: VPS16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS16 were set to 32808683
Phenotypes for gene: VPS16 were set to Dystonia
Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood. Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals.
Sources: Literature
Mendeliome v0.4859 KRIT1 Zornitza Stark Gene: krit1 has been classified as Green List (High Evidence).
Mendeliome v0.4856 SH3TC2 Zornitza Stark Gene: sh3tc2 has been classified as Green List (High Evidence).
Mendeliome v0.4853 ABCC6 Zornitza Stark Added comment: Comment when marking as ready: Evidence for mono-allelic variants causing disease is limited.
Mendeliome v0.4853 ABCC6 Zornitza Stark Gene: abcc6 has been classified as Green List (High Evidence).
Mendeliome v0.4853 CAPN3 Zornitza Stark Gene: capn3 has been classified as Green List (High Evidence).
Mendeliome v0.4853 CAPN3 Zornitza Stark Phenotypes for gene: CAPN3 were changed from to Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129; Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600
Mendeliome v0.4850 CAPN3 Zornitza Stark reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31937337, 28881388, 32342993, 32557990; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129, Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4850 SLC6A5 Zornitza Stark Gene: slc6a5 has been classified as Green List (High Evidence).
Mendeliome v0.4846 ARX Zornitza Stark Gene: arx has been classified as Green List (High Evidence).
Mendeliome v0.4843 ABCC6 Kristin Rigbye changed review comment from: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).; to: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PXE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).

In addition to missense, PTCs and splice variants, deletions and duplications in this gene comprise a significant proportion of variants and are a recognised mechanism / cause of PXE.
Mendeliome v0.4842 MCM2 Zornitza Stark Gene: mcm2 has been classified as Red List (Low Evidence).
Mendeliome v0.4842 MCM2 Zornitza Stark gene: MCM2 was added
gene: MCM2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MCM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MCM2 were set to 26196677
Phenotypes for gene: MCM2 were set to Deafness, autosomal dominant 70, MIM# 616968
Review for gene: MCM2 was set to RED
Added comment: One family, expression studies.
Sources: Expert Review
Mendeliome v0.4841 ATP1A4 Zornitza Stark Gene: atp1a4 has been classified as Red List (Low Evidence).
Mendeliome v0.4841 ATP1A4 Zornitza Stark gene: ATP1A4 was added
gene: ATP1A4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP1A4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A4 were set to 32549268
Phenotypes for gene: ATP1A4 were set to Hemiplegic migraine
Review for gene: ATP1A4 was set to RED
Added comment: Single family reported where missense variant segregated with hemiplegic migraine in four affected individuals.
Sources: Literature
Mendeliome v0.4840 BSND Zornitza Stark Gene: bsnd has been classified as Green List (High Evidence).
Mendeliome v0.4837 LTBP2 Zornitza Stark Gene: ltbp2 has been classified as Green List (High Evidence).
Mendeliome v0.4832 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10, MIM# 617022; Skeletal dysplasia to Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia
Mendeliome v0.4830 NEK9 Zornitza Stark Classified gene: NEK9 as Amber List (moderate evidence)
Mendeliome v0.4830 NEK9 Zornitza Stark Gene: nek9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4829 NEK9 Zornitza Stark edited their review of gene: NEK9: Added comment: Another Saudi family described with which 2 sisters and a female cousin who had a similar disorder characterised by arthrogryposis apparent since early childhood, avascular necrosis of the hip (Perthes disease), and upward gaze palsy. Homozygous missense variant segregated with the phenotype. Given the small number of reports, it is unclear whether this represents a distinct association is part of a spectrum with includes the more severe phenotype described in the Irish traveller families.; Changed publications: 26908619, 21271645; Changed phenotypes: Lethal congenital contracture syndrome 10, MIM# 617022, Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262, Skeletal dysplasia
Mendeliome v0.4829 IL11RA Zornitza Stark Gene: il11ra has been classified as Green List (High Evidence).
Mendeliome v0.4829 IL11RA Zornitza Stark Phenotypes for gene: IL11RA were changed from to Craniosynostosis and dental anomalies, MIM# 614188
Mendeliome v0.4826 IL11RA Zornitza Stark reviewed gene: IL11RA: Rating: GREEN; Mode of pathogenicity: None; Publications: 21741611, 32277509, 30811827, 29926465, 24498618; Phenotypes: Craniosynostosis and dental anomalies, MIM# 614188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4825 EFNB1 Zornitza Stark Gene: efnb1 has been classified as Green List (High Evidence).
Mendeliome v0.4825 EFNB1 Zornitza Stark Phenotypes for gene: EFNB1 were changed from to Craniofrontonasal dysplasia, MIM# 304110
Mendeliome v0.4822 EFNB1 Zornitza Stark reviewed gene: EFNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15166289, 18627045, 23335590; Phenotypes: Craniofrontonasal dysplasia, MIM# 304110; Mode of inheritance: Other
Mendeliome v0.4822 AGAP1 Zornitza Stark Gene: agap1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4822 AGAP1 Zornitza Stark Classified gene: AGAP1 as Amber List (moderate evidence)
Mendeliome v0.4822 AGAP1 Zornitza Stark Gene: agap1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4820 SMN1 Zornitza Stark Gene: smn1 has been classified as Green List (High Evidence).
Mendeliome v0.4817 BUB1B Zornitza Stark Gene: bub1b has been classified as Green List (High Evidence).
Mendeliome v0.4814 ROM1 Zornitza Stark Gene: rom1 has been classified as Green List (High Evidence).
Mendeliome v0.4811 FOXC1 Zornitza Stark Gene: foxc1 has been classified as Green List (High Evidence).
Mendeliome v0.4808 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Disorder of N-glycosylation to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation
Mendeliome v0.4807 ALG14 Zornitza Stark edited their review of gene: ALG14: Changed phenotypes: Myasthenic syndrome, congenital, 15, without tubular aggregates 616227, Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031, Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036, Disorder of N-glycosylation
Mendeliome v0.4807 ACER3 Zornitza Stark Gene: acer3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4804 ACER3 Zornitza Stark Classified gene: ACER3 as Amber List (moderate evidence)
Mendeliome v0.4804 ACER3 Zornitza Stark Gene: acer3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4802 TRPV1 Bryony Thompson Classified gene: TRPV1 as Amber List (moderate evidence)
Mendeliome v0.4802 TRPV1 Bryony Thompson Gene: trpv1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4796 AP1S1 Zornitza Stark Gene: ap1s1 has been classified as Green List (High Evidence).
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AKNA Seb Lunke Gene: akna has been classified as Red List (Low Evidence).
Mendeliome v0.4791 GOLGA3 Zornitza Stark Gene: golga3 has been classified as Red List (Low Evidence).
Mendeliome v0.4791 GOLGA3 Zornitza Stark Classified gene: GOLGA3 as Red List (low evidence)
Mendeliome v0.4791 GOLGA3 Zornitza Stark Gene: golga3 has been classified as Red List (Low Evidence).
Mendeliome v0.4790 AKNA Seb Lunke Classified gene: AKNA as Red List (low evidence)
Mendeliome v0.4790 AKNA Seb Lunke Gene: akna has been classified as Red List (Low Evidence).
Mendeliome v0.4789 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the hypomorphic thoc1 in mouse induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4789 GOLGA3 Elena Savva gene: GOLGA3 was added
gene: GOLGA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GOLGA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA3 were set to PMID: 23495255
Phenotypes for gene: GOLGA3 were set to Primary ciliary dyskinesia
Review for gene: GOLGA3 was set to RED
Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2
Two siblings with a homozygous missense and PCD

PMID: 23495255; null mice have failed spermatogenesis
Sources: Literature
Mendeliome v0.4789 PRICKLE3 Seb Lunke Gene: prickle3 has been classified as Red List (Low Evidence).
Mendeliome v0.4789 PRICKLE3 Seb Lunke Classified gene: PRICKLE3 as Red List (low evidence)
Mendeliome v0.4789 PRICKLE3 Seb Lunke Added comment: Comment on list classification: Single variant only and questionable association due to uncertainty of role around ND4.
Mendeliome v0.4789 PRICKLE3 Seb Lunke Gene: prickle3 has been classified as Red List (Low Evidence).
Mendeliome v0.4788 AKNA Elena Savva gene: AKNA was added
gene: AKNA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AKNA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AKNA were set to PMID: 21606955
Phenotypes for gene: AKNA were set to Primary ciliary dyskinesia
Review for gene: AKNA was set to RED
Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2
Two siblings with homozygous PTCs with PCD. Carrier parents and mutation negative siblings (5) was normal.

PMID: 21606955: Null mice have neonatal death with systemic inflammation and alveolar loss
Sources: Literature
Mendeliome v0.4788 THOC1 Zornitza Stark Gene: thoc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4788 THOC1 Zornitza Stark Classified gene: THOC1 as Amber List (moderate evidence)
Mendeliome v0.4788 THOC1 Zornitza Stark Gene: thoc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4787 GBF1 Seb Lunke Gene: gbf1 has been classified as Green List (High Evidence).
Mendeliome v0.4787 GBF1 Seb Lunke Classified gene: GBF1 as Green List (high evidence)
Mendeliome v0.4787 GBF1 Seb Lunke Gene: gbf1 has been classified as Green List (High Evidence).
Mendeliome v0.4786 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4786 NUAK2 Seb Lunke Classified gene: NUAK2 as Amber List (moderate evidence)
Mendeliome v0.4786 NUAK2 Seb Lunke Gene: nuak2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4785 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4785 RNPC3 Zornitza Stark Classified gene: RNPC3 as Amber List (moderate evidence)
Mendeliome v0.4785 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4784 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814
Phenotypes for gene: RNPC3 were set to Growth hormone deficiency
Review for gene: RNPC3 was set to AMBER
Added comment: Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Sources: Literature
Mendeliome v0.4783 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4783 PRICKLE3 Teresa Zhao gene: PRICKLE3 was added
gene: PRICKLE3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRICKLE3 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: PRICKLE3 were set to 32516135
Phenotypes for gene: PRICKLE3 were set to Leber’s hereditary optic neuropathy MIM#535000
Review for gene: PRICKLE3 was set to AMBER
Added comment: Reported as X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision.

Defective assembly, stability, and function of ATP synthase observed using Lymphoblastoid cell lines from one of the families.

This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON.

Prickle3-deficient mice exhibited pronounced ATPase deficiencies.
Sources: Literature
Mendeliome v0.4783 NUAK2 Seb Lunke Gene: nuak2 has been classified as Red List (Low Evidence).
Mendeliome v0.4783 NUAK2 Seb Lunke gene: NUAK2 was added
gene: NUAK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NUAK2 were set to 32845958
Phenotypes for gene: NUAK2 were set to ANENCEPHALY (OMIM#206500)
Review for gene: NUAK2 was set to AMBER
Added comment: Novel gene described in single consanguineous family with three FDIU and extensive anencephaly. Hom inframe del affecting functional kinase domain, parents confirmed carriers. Good functional data showing loss of enzyme function and mouse model with 40% anencephaly after knock-out.
Sources: Literature
Mendeliome v0.4782 THOC1 Melanie Marty gene: THOC1 was added
gene: THOC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THOC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THOC1 were set to 32776944
Phenotypes for gene: THOC1 were set to Nonsyndromic hearing loss
Review for gene: THOC1 was set to AMBER
Added comment: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4782 MBTPS1 Zornitza Stark Gene: mbtps1 has been classified as Green List (High Evidence).
Mendeliome v0.4782 MBTPS1 Zornitza Stark Classified gene: MBTPS1 as Green List (high evidence)
Mendeliome v0.4782 MBTPS1 Zornitza Stark Gene: mbtps1 has been classified as Green List (High Evidence).
Mendeliome v0.4781 MBTPS1 Zornitza Stark gene: MBTPS1 was added
gene: MBTPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013
Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia
Review for gene: MBTPS1 was set to GREEN
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature.
Sources: Literature
Mendeliome v0.4780 ALS2 Ain Roesley 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 32214227
Phenotypes for gene: ALS2 were set to Tetraparesis with affection of upper and lower motor neuron
Penetrance for gene: ALS2 were set to unknown
Review for gene: ALS2 was set to RED
Added comment: In a cohort of Palestinian and Israeli Arabs with neurological disorders, a family with 2 affecteds were homozygous for a nonsense variant. Authors classified as likely path by ACMG guidelines
Sources: Literature
Mendeliome v0.4780 QRICH1 Zornitza Stark Gene: qrich1 has been classified as Green List (High Evidence).
Mendeliome v0.4777 GREB1L Zornitza Stark Gene: greb1l has been classified as Green List (High Evidence).
Mendeliome v0.4777 GREB1L Zornitza Stark Phenotypes for gene: GREB1L were changed from to Renal hypodysplasia/aplasia 3, OMIM# 617805
Mendeliome v0.4774 GREB1L Zornitza Stark reviewed gene: GREB1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100091; Phenotypes: Renal hypodysplasia/aplasia 3, OMIM# 617805; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4774 IL1RAP Zornitza Stark Gene: il1rap has been classified as Red List (Low Evidence).
Mendeliome v0.4774 IL1RAP Zornitza Stark gene: IL1RAP was added
gene: IL1RAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL1RAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL1RAP were set to 31954058
Phenotypes for gene: IL1RAP were set to Steroid-sensitive nephrotic syndrome
Review for gene: IL1RAP was set to RED
Added comment: A pair of siblings with compound heterozygous variants in this gene and steroid-sensitive nephrotic syndrome. Functional effect of variants demonstrated but mouse model does not have proteinuria.
Sources: Literature
Mendeliome v0.4770 NEMF Zornitza Stark changed review comment from: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature; to: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.

Single individual with de novo variant reported, postulated dominant negative effect. Evidence for mono allelic variants causing disease is limited.
Sources: Literature
Mendeliome v0.4769 HOMER2 Zornitza Stark Gene: homer2 has been classified as Green List (High Evidence).
Mendeliome v0.4766 TPRN Zornitza Stark Gene: tprn has been classified as Green List (High Evidence).
Mendeliome v0.4766 TPRN Zornitza Stark Phenotypes for gene: TPRN were changed from to Deafness, autosomal recessive 79, MIM# 613307
Mendeliome v0.4763 TPRN Zornitza Stark reviewed gene: TPRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 19603065, 20170898, 20170899, 23340767, 25129962, 20170899, 20170899, 27693694, 24285636; Phenotypes: Deafness, autosomal recessive 79, MIM# 613307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4763 TMC1 Zornitza Stark Gene: tmc1 has been classified as Green List (High Evidence).
Mendeliome v0.4763 TMC1 Zornitza Stark Phenotypes for gene: TMC1 were changed from to Deafness, autosomal dominant 36, MIM# 606705; Deafness, autosomal recessive 7, MIM# 600974
Mendeliome v0.4760 TMC1 Zornitza Stark reviewed gene: TMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11850618, 17250663, 18616530, 24827932, 11850623, 22105175; Phenotypes: Deafness, autosomal dominant 36, MIM# 606705, Deafness, autosomal recessive 7, MIM# 600974; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4760 TMIE Zornitza Stark Gene: tmie has been classified as Green List (High Evidence).
Mendeliome v0.4760 TMIE Zornitza Stark Phenotypes for gene: TMIE were changed from to Deafness, autosomal recessive 6, MIM# 600971
Mendeliome v0.4757 TMIE Zornitza Stark reviewed gene: TMIE: Rating: GREEN; Mode of pathogenicity: None; Publications: 12145746, 19438934, 24416283, 25467981, 25475183, 19934034, 12140191; Phenotypes: Deafness, autosomal recessive 6, MIM# 600971; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4757 TRIOBP Zornitza Stark Gene: triobp has been classified as Green List (High Evidence).
Mendeliome v0.4757 TRIOBP Zornitza Stark Phenotypes for gene: TRIOBP were changed from to Deafness, autosomal recessive 28, MIM# 609823
Mendeliome v0.4754 TRIOBP Zornitza Stark reviewed gene: TRIOBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16385458, 16385457, 23226338, 27014650, 24853665, 27344577, 20510926; Phenotypes: Deafness, autosomal recessive 28, MIM# 609823; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4754 STRC Zornitza Stark Gene: strc has been classified as Green List (High Evidence).
Mendeliome v0.4754 STRC Zornitza Stark Phenotypes for gene: STRC were changed from to Deafness, autosomal recessive 16, MIM# 603720
Mendeliome v0.4751 STRC Zornitza Stark reviewed gene: STRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11687802, 26011646, 26746617, 20301780; Phenotypes: Deafness, autosomal recessive 16, MIM# 603720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4750 SETD1A Zornitza Stark Gene: setd1a has been classified as Green List (High Evidence).
Mendeliome v0.4750 SETD1A Zornitza Stark Classified gene: SETD1A as Green List (high evidence)
Mendeliome v0.4750 SETD1A Zornitza Stark Gene: setd1a has been classified as Green List (High Evidence).
Mendeliome v0.4748 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome to Spastic paraplegia-83 (SPG83), MIM#619027; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.4747 HPDL Zornitza Stark edited their review of gene: HPDL: Added comment: Although two distinct distinct disease associations have been assigned by OMIM, these clinical presentations likely represent a continuum of severity for an underlying mitochondrial disorder.; Changed phenotypes: Spastic paraplegia-83 (SPG83), MIM#619027, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026
Mendeliome v0.4747 HPDL Zornitza Stark commented on gene: HPDL: 17 individuals from 13 families, with a spectrum of neurologic impairment ranging from a severe congenital form without any neurological development (n = 2/17, 12%) to infantile-onset presentations (n = 10/17, 59%) with moderate to severe neurodevelopmental issues, partly with a pathology reminiscent of mitochondrial disease (Leigh-like syndrome), to juvenile-onset spastic paraplegia (n = 5/17, 29%).

Frequently observed clinical findings included chronic progression of neurological signs (n = 16/17, 94%), motor developmental delay (n = 12/17, 71%), intellectual impairment (n = 11/17, 65%), microcephaly (n = 9/16, 56%), and seizures/epilepsy (n = 9/17, 53%). Other relevant clinical findings were visual disturbances/strabismus (n = 9/17, 53%) and loss of developmental milestones (n = 6/17, 35%).

Acute central respiratory failure leading to life-threatening events requiring partly mechanically assisted ventilation occurred in half of individuals with infantile presentation (n = 5/10, 50%), respectively one third of all individuals (n = 5/17, 29%).

Demyelinating neuropathy was present in three individuals (n = 3/11, 27%), with reduced sensory nerve conduction velocity (NCV) in all and severely reduced motor NCV in one.
Mendeliome v0.4747 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Progressive neurological disorder; Leigh-like syndrome to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.4746 HPDL Zornitza Stark reviewed gene: HPDL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Mode of inheritance: None
Mendeliome v0.4745 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208 to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita
Mendeliome v0.4743 SCN1A Zornitza Stark edited their review of gene: SCN1A: Added comment: Note we have reported the association with AMC previously in PMID 29543227 (Supplementary info) in an infant presenting with AMC and severe EE, and de novo p.(Ile1347Asn) variant which at the time was thought to only partially explain the phenotype, but in light of this new report, likely fully explains the phenotype. Given the presence of severe seizure disorder in the two infants who were phenotyped in the newborn period, this likely represents the severe end of the spectrum of SCN1A-related disorders rather than a distinct association.; Changed phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures, Arthrogryposis multiplex congenita
Mendeliome v0.4743 PRKD1 Zornitza Stark changed review comment from: PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; to: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.'

PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.
Mendeliome v0.4742 PRKD1 Zornitza Stark reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4742 SCN1A Arina Puzriakova reviewed gene: SCN1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 32928894; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4742 SIX1 Zornitza Stark Marked gene: SIX1 as ready
Mendeliome v0.4742 SIX1 Zornitza Stark Gene: six1 has been classified as Green List (High Evidence).
Mendeliome v0.4742 SIX1 Zornitza Stark Phenotypes for gene: SIX1 were changed from to Deafness, autosomal dominant 23, MIM# 605192; Branchiootic syndrome 3, MIM# 608389
Mendeliome v0.4741 SIX1 Zornitza Stark Publications for gene: SIX1 were set to
Mendeliome v0.4740 SIX1 Zornitza Stark Mode of inheritance for gene: SIX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4739 SIX1 Zornitza Stark reviewed gene: SIX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15141091, 18330911, 21254961, 17637804, 29500469, 21700001, 24164807; Phenotypes: Deafness, autosomal dominant 23, MIM# 605192, Branchiootic syndrome 3, MIM# 608389; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4739 PTPRQ Zornitza Stark Gene: ptprq has been classified as Green List (High Evidence).
Mendeliome v0.4739 PTPRQ Zornitza Stark Phenotypes for gene: PTPRQ were changed from to Deafness, autosomal recessive 84A, MIM# 613391; Deafness, autosomal dominant 73, MIM# 617663
Mendeliome v0.4736 PTPRQ Zornitza Stark reviewed gene: PTPRQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 20346435, 20472657, 25919374, 14534255, 22357859, 29849575, 29309402, 31655630; Phenotypes: Deafness, autosomal recessive 84A, MIM# 613391, Deafness, autosomal dominant 73, MIM# 617663; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4736 POU4F3 Zornitza Stark Gene: pou4f3 has been classified as Green List (High Evidence).
Mendeliome v0.4733 KPTN Zornitza Stark Gene: kptn has been classified as Green List (High Evidence).
Mendeliome v0.4733 KPTN Zornitza Stark Phenotypes for gene: KPTN were changed from to Mental retardation, autosomal recessive 41 (MIM#615637)
Mendeliome v0.4730 NPHS1 Zornitza Stark Gene: nphs1 has been classified as Green List (High Evidence).
Mendeliome v0.4728 TTI2 Zornitza Stark Gene: tti2 has been classified as Green List (High Evidence).
Mendeliome v0.4728 TTI2 Zornitza Stark Phenotypes for gene: TTI2 were changed from to Mental retardation, autosomal recessive 39, MIM#615541
Mendeliome v0.4725 TTI2 Zornitza Stark reviewed gene: TTI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32061250, 23956177, 31737043; Phenotypes: Mental retardation, autosomal recessive 39, MIM#615541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4725 IGSF10 Bryony Thompson Gene: igsf10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4725 IGSF10 Bryony Thompson Classified gene: IGSF10 as Amber List (moderate evidence)
Mendeliome v0.4725 IGSF10 Bryony Thompson Gene: igsf10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4724 IGSF10 Bryony Thompson gene: IGSF10 was added
gene: IGSF10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IGSF10 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: IGSF10 were set to 27137492; 31042289
Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency
Review for gene: IGSF10 was set to AMBER
Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance.
Sources: Literature
Mendeliome v0.4723 KPTN Melanie Marty reviewed gene: KPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24239382, 32358097, 32808430; Phenotypes: Mental retardation, autosomal recessive 41 (MIM#615637); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4723 PFN1 Zornitza Stark Gene: pfn1 has been classified as Green List (High Evidence).
Mendeliome v0.4722 PFN1 Zornitza Stark Phenotypes for gene: PFN1 were changed from to Amyotrophic lateral sclerosis 18 (MIM# 614808); Paget’s disease of bone
Mendeliome v0.4720 PFN1 Zornitza Stark reviewed gene: PFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31802421, 31611772, 31401564, 30203378, 28040732, 22801503; Phenotypes: Amyotrophic lateral sclerosis 18, MIM# 614808; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4720 PCDH15 Zornitza Stark Gene: pcdh15 has been classified as Green List (High Evidence).
Mendeliome v0.4720 PCDH15 Zornitza Stark Phenotypes for gene: PCDH15 were changed from to Usher syndrome, type 1F, MIM# 602083; Deafness, autosomal recessive 23, MIM# 609533
Mendeliome v0.4717 PCDH15 Zornitza Stark reviewed gene: PCDH15: Rating: GREEN; Mode of pathogenicity: None; Publications: 11398101, 11487575, 11138007, 12782354, 16260500, 14570705, 25930172, 28281779; Phenotypes: Usher syndrome, type 1F, MIM# 602083, Deafness, autosomal recessive 23, MIM# 609533; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4717 WHRN Zornitza Stark Gene: whrn has been classified as Green List (High Evidence).
Mendeliome v0.4717 WHRN Zornitza Stark Phenotypes for gene: WHRN were changed from to Usher syndrome, type 2D, MIM# 611383; Deafness, autosomal recessive 31, MIM# 607084
Mendeliome v0.4714 WHRN Zornitza Stark reviewed gene: WHRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 17171570, 21738389, 22147658, 26338283, 12833159, 20502675, 28254438, 27117407, 12833159, 29270100, 15841483; Phenotypes: Usher syndrome, type 2D, MIM# 611383, Deafness, autosomal recessive 31, MIM# 607084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4714 PFN1 Ain Roesley reviewed gene: PFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23141414, 22801503, 25499087, 24309268, 22801503, 26908597; Phenotypes: Amyotrophic lateral sclerosis 18 (MIM# 614808); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4714 OTOGL Zornitza Stark Gene: otogl has been classified as Green List (High Evidence).
Mendeliome v0.4714 OTOGL Zornitza Stark Phenotypes for gene: OTOGL were changed from to Deafness, autosomal recessive 84B, MIM# 614944
Mendeliome v0.4711 OTOGL Zornitza Stark reviewed gene: OTOGL: Rating: GREEN; Mode of pathogenicity: None; Publications: 23122586, 23850727, 25829320, ​25719458, 28426234; Phenotypes: Deafness, autosomal recessive 84B, MIM# 614944; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4711 RDX Zornitza Stark Gene: rdx has been classified as Green List (High Evidence).
Mendeliome v0.4711 RDX Zornitza Stark Phenotypes for gene: RDX were changed from to Deafness, autosomal recessive 24, MIM# 611022
Mendeliome v0.4708 RDX Zornitza Stark reviewed gene: RDX: Rating: GREEN; Mode of pathogenicity: None; Publications: 17226784, 19215054, 22567349, 26226137, 15314067; Phenotypes: Deafness, autosomal recessive 24, MIM# 611022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4708 OTOA Zornitza Stark Gene: otoa has been classified as Green List (High Evidence).
Mendeliome v0.4708 OTOA Zornitza Stark Phenotypes for gene: OTOA were changed from to Deafness, autosomal recessive 22, MIM# 607039
Mendeliome v0.4705 OTOA Zornitza Stark reviewed gene: OTOA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11972037, 19888295, 23173898, 16460646, 26029705, 26969326, 23129639; Phenotypes: Deafness, autosomal recessive 22, MIM# 607039; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4705 MYO7A Zornitza Stark Gene: myo7a has been classified as Green List (High Evidence).
Mendeliome v0.4705 MYO7A Zornitza Stark Phenotypes for gene: MYO7A were changed from to Deafness, autosomal dominant 11, MIM# 601317; Deafness, autosomal recessive 2, 600060; Usher syndrome, type 1B, MIM# 276900
Mendeliome v0.4702 MYO7A Zornitza Stark reviewed gene: MYO7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 9354784, 15300860, 15121790, 15221449, 16449806, 21150918, 23451214, 23383098, 28802369, 29400105, 23559863, 18181211, 25211151; Phenotypes: Deafness, autosomal dominant 11, MIM# 601317, Deafness, autosomal recessive 2, 600060, Usher syndrome, type 1B, MIM# 276900; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4702 SMPX Zornitza Stark Gene: smpx has been classified as Green List (High Evidence).
Mendeliome v0.4699 MYO6 Zornitza Stark Gene: myo6 has been classified as Green List (High Evidence).
Mendeliome v0.4699 MYO6 Zornitza Stark Phenotypes for gene: MYO6 were changed from to Deafness, autosomal dominant 22, MIM# 606346; Deafness, autosomal recessive 37, MIM# 607821
Mendeliome v0.4696 MYO6 Zornitza Stark reviewed gene: MYO6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24105371, 11468689, 25999546, 25227905, 18348273, 27171474; Phenotypes: Deafness, autosomal dominant 22, MIM# 606346, Deafness, autosomal recessive 37, MIM# 607821; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4696 MYO15A Zornitza Stark Gene: myo15a has been classified as Green List (High Evidence).
Mendeliome v0.4696 MYO15A Zornitza Stark Phenotypes for gene: MYO15A were changed from to Deafness, autosomal recessive 3, MIM# 600316
Mendeliome v0.4693 MYO15A Zornitza Stark reviewed gene: MYO15A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27375115, 26226137, 23208854, 19309289, 9603735, 10915760; Phenotypes: Deafness, autosomal recessive 3, MIM# 600316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4693 MYH9 Zornitza Stark Gene: myh9 has been classified as Green List (High Evidence).
Mendeliome v0.4693 MYH9 Zornitza Stark Phenotypes for gene: MYH9 were changed from to Deafness, autosomal dominant 17, MIM# 603622; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100; MYH9-related disorders
Mendeliome v0.4690 MYH9 Zornitza Stark reviewed gene: MYH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 9390828, 24890873, 17146397, 25505834, 16630581, 16162639, 23976996, 21908426; Phenotypes: Deafness, autosomal dominant 17, MIM# 603622, Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100, MYH9-related disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4690 MARVELD2 Zornitza Stark Gene: marveld2 has been classified as Green List (High Evidence).
Mendeliome v0.4690 MARVELD2 Zornitza Stark Phenotypes for gene: MARVELD2 were changed from to Deafness, autosomal recessive 49, MIM# 610153
Mendeliome v0.4687 MARVELD2 Zornitza Stark reviewed gene: MARVELD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17186462, 18084694, 22903915, 27344577, 26677943, 23979167; Phenotypes: Deafness, autosomal recessive 49, MIM# 610153; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4687 RPL9 Zornitza Stark Gene: rpl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4686 RPL9 Zornitza Stark Classified gene: RPL9 as Amber List (moderate evidence)
Mendeliome v0.4686 RPL9 Zornitza Stark Gene: rpl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4685 RPL9 Arina Puzriakova changed review comment from: PMID: 31799629 (2020) - One individual diagnosed with Diamond Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype.; to: PMID: 31799629 (2020) - Female infant diagnosed with Diamond-Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Phenotypic overlap can be seen with the previously reported case with the same variant, including colitis, thumb anomaly, and microcephaly. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype.
Mendeliome v0.4685 LRTOMT Zornitza Stark Gene: lrtomt has been classified as Green List (High Evidence).
Mendeliome v0.4685 LRTOMT Zornitza Stark Phenotypes for gene: LRTOMT were changed from to Deafness, autosomal recessive 63, MIM# 611451
Mendeliome v0.4682 LRTOMT Zornitza Stark reviewed gene: LRTOMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 18953341, 18794526, 21739586, 18794526; Phenotypes: Deafness, autosomal recessive 63, MIM# 611451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4682 LHFPL5 Zornitza Stark Gene: lhfpl5 has been classified as Green List (High Evidence).
Mendeliome v0.4682 LHFPL5 Zornitza Stark Phenotypes for gene: LHFPL5 were changed from to Deafness, autosomal recessive 67, MIM# 610265
Mendeliome v0.4679 LHFPL5 Zornitza Stark reviewed gene: LHFPL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 16459341, 16752389, 21816241, 19888295, 26437881, 26029705, 15905332, 19102128, 25550511; Phenotypes: Deafness, autosomal recessive 67, MIM# 610265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4679 GYS1 Zornitza Stark Gene: gys1 has been classified as Green List (High Evidence).
Mendeliome v0.4676 PIGT Zornitza Stark Gene: pigt has been classified as Green List (High Evidence).
Mendeliome v0.4672 ALG13 Zornitza Stark Gene: alg13 has been classified as Green List (High Evidence).
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Gene: bloc1s5 has been classified as Green List (High Evidence).
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Classified gene: BLOC1S5 as Green List (high evidence)
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Gene: bloc1s5 has been classified as Green List (High Evidence).
Mendeliome v0.4668 BLOC1S5 Zornitza Stark gene: BLOC1S5 was added
gene: BLOC1S5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S5 were set to 32565547
Phenotypes for gene: BLOC1S5 were set to Hermansky–Pudlak syndrome
Review for gene: BLOC1S5 was set to GREEN
Added comment: 2 unrelated patients with mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Identified distinct homozygous variants in the BLOC1S5 gene (patient 1: deletion of exons 3 and 4, patient 2: 1-bp deletion in exon 4). Parental segregation confirmatory in patient 1, quantitative PCR analysis confirmatory in patient 2). Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele. Pathogenic variants in the genes encoding three other BLOC-1 subunits (DTNBP1, BLOC1S3, and BLOC1S6) underlie HPS types 7, 8, and 9 respectively.
Sources: Literature
Mendeliome v0.4667 FOXL2 Zornitza Stark Gene: foxl2 has been classified as Green List (High Evidence).
Mendeliome v0.4667 FOXL2 Zornitza Stark Phenotypes for gene: FOXL2 were changed from to Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100)
Mendeliome v0.4664 FOXL2 Ain Roesley changed review comment from: PMID: 31077882; 19x probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161); to: PMID: 31077882; >100 probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161)
Mendeliome v0.4664 FOXL2 Ain Roesley reviewed gene: FOXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31077882, 18642388, 17089161; Phenotypes: Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4664 ILDR1 Zornitza Stark Gene: ildr1 has been classified as Green List (High Evidence).
Mendeliome v0.4664 ILDR1 Zornitza Stark Phenotypes for gene: ILDR1 were changed from to Deafness, autosomal recessive 42, MIM# 609646
Mendeliome v0.4661 ILDR1 Zornitza Stark reviewed gene: ILDR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21255762, 23226338, 22903915, 27344577, 21255762, 23239027, 25822906, 25819842, 24990150; Phenotypes: Deafness, autosomal recessive 42, MIM# 609646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4661 HOXA2 Zornitza Stark Gene: hoxa2 has been classified as Green List (High Evidence).
Mendeliome v0.4658 GRXCR1 Zornitza Stark Gene: grxcr1 has been classified as Green List (High Evidence).
Mendeliome v0.4658 GRXCR1 Zornitza Stark Phenotypes for gene: GRXCR1 were changed from to Deafness, autosomal recessive 25, MIM# 613285
Mendeliome v0.4655 GRXCR1 Zornitza Stark reviewed gene: GRXCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20137778, 25802247, 26226137, 26445815, 26969326, 20137774; Phenotypes: Deafness, autosomal recessive 25, MIM# 613285; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4655 GPSM2 Zornitza Stark Gene: gpsm2 has been classified as Green List (High Evidence).
Mendeliome v0.4652 GIPC3 Zornitza Stark Gene: gipc3 has been classified as Green List (High Evidence).
Mendeliome v0.4652 GIPC3 Zornitza Stark Phenotypes for gene: GIPC3 were changed from to Deafness, autosomal recessive 15, MIM# 601869
Mendeliome v0.4649 GIPC3 Zornitza Stark reviewed gene: GIPC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21326233, 21660509; Phenotypes: Deafness, autosomal recessive 15, MIM# 601869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4649 COCH Zornitza Stark Phenotypes for gene: COCH were changed from Deafness, autosomal dominant 9, MIM# 601369 to Deafness, autosomal dominant 9, MIM# 601369; Deafness, autosomal recessive 110, MIM# 618094
Mendeliome v0.4647 COCH Zornitza Stark changed review comment from: Over 50 affected individuals from more than 10 families reported, mouse model. Single family with two siblings reported with bi-allelic variants in this gene and deafness (homozygous LOF) in PMID 29449721, evidence for bi-allelic disease is limited.; to: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.
Mendeliome v0.4647 COCH Zornitza Stark edited their review of gene: COCH: Changed phenotypes: Deafness, autosomal dominant 9, MIM# 601369, Deafness, autosomal recessive 110, MIM# 618094
Mendeliome v0.4647 CNOT1 Zornitza Stark Phenotypes for gene: CNOT1 were changed from Holoprosencephaly 12, with or without pancreatic agenesis; OMIM# 618500 to Vissers-Bodmer syndrome, MIM#619033; Holoprosencephaly 12, with or without pancreatic agenesis; OMIM# 618500
Mendeliome v0.4643 GATA3 Zornitza Stark Gene: gata3 has been classified as Green List (High Evidence).
Mendeliome v0.4643 GATA3 Zornitza Stark Phenotypes for gene: GATA3 were changed from to Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255
Mendeliome v0.4640 GATA3 Zornitza Stark reviewed gene: GATA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10935639, 11389161, 21120445, 26316437, 25771973, 27387476, 30396722; Phenotypes: Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4639 FGF3 Zornitza Stark reviewed gene: FGF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21480479, 21306635, 18435799, 17236138, 21306635, 18701883, 8223243, 26995070, 29902227, 30504125; Phenotypes: Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM# 610706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4636 ESPN Zornitza Stark Gene: espn has been classified as Green List (High Evidence).
Mendeliome v0.4636 ESPN Zornitza Stark Phenotypes for gene: ESPN were changed from to Deafness, autosomal recessive 36, MIM# 609006; Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006
Mendeliome v0.4633 ESPN Zornitza Stark reviewed gene: ESPN: Rating: GREEN; Mode of pathogenicity: None; Publications: 15286153, 18973245, 26445815, 28281779, 10975527, 15930085; Phenotypes: Deafness, autosomal recessive 36, MIM# 609006, Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4633 DFNB59 Zornitza Stark Gene: dfnb59 has been classified as Green List (High Evidence).
Mendeliome v0.4633 DFNB59 Zornitza Stark Phenotypes for gene: DFNB59 were changed from to Deafness, autosomal recessive 59, MIM# 610220
Mendeliome v0.4630 DFNB59 Zornitza Stark reviewed gene: DFNB59: Rating: GREEN; Mode of pathogenicity: None; Publications: 16804542, 26166082, 22617256, 28964305, 17373699, 25631766, 28209736; Phenotypes: Deafness, autosomal recessive 59, MIM# 610220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4630 DFNA5 Zornitza Stark Gene: dfna5 has been classified as Green List (High Evidence).
Mendeliome v0.4627 RIC3 Bryony Thompson Gene: ric3 has been classified as Red List (Low Evidence).
Mendeliome v0.4627 RIC3 Bryony Thompson Classified gene: RIC3 as Red List (low evidence)
Mendeliome v0.4627 RIC3 Bryony Thompson Gene: ric3 has been classified as Red List (Low Evidence).
Mendeliome v0.4626 PRIMPOL Zornitza Stark Classified gene: PRIMPOL as Red List (low evidence)
Mendeliome v0.4626 PRIMPOL Zornitza Stark Gene: primpol has been classified as Red List (Low Evidence).
Mendeliome v0.4625 MIEF2 Zornitza Stark Phenotypes for gene: MIEF2 were changed from Progressive muscle weakness; Exercise intolerance; Ragged red and COX negative fibres; Complex I and IV deficiency to Combined oxidative phosphorylation deficiency 49, MIM# 619024; Progressive muscle weakness; Exercise intolerance; Ragged red and COX negative fibres; Complex I and IV deficiency
Mendeliome v0.4624 MRPS25 Zornitza Stark Phenotypes for gene: MRPS25 were changed from Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum to Combined oxidative phosphorylation deficiency 50, MIM# 619025; Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum
Mendeliome v0.4623 MRPS25 Zornitza Stark edited their review of gene: MRPS25: Changed phenotypes: Combined oxidative phosphorylation deficiency 50, MIM# 619025, Dyskinetic cerebral palsy, Mitochondrial myopathy, Partial agenesis of the corpus callosum
Mendeliome v0.4623 MIEF2 Zornitza Stark edited their review of gene: MIEF2: Changed phenotypes: Combined oxidative phosphorylation deficiency 49, MIM# 619024, Progressive muscle weakness, Exercise intolerance, Ragged red and COX negative fibres, Complex I and IV deficiency
Mendeliome v0.4623 COL4A5 Zornitza Stark Gene: col4a5 has been classified as Green List (High Evidence).
Mendeliome v0.4621 COCH Zornitza Stark Gene: coch has been classified as Green List (High Evidence).
Mendeliome v0.4618 CLRN1 Zornitza Stark Gene: clrn1 has been classified as Green List (High Evidence).
Mendeliome v0.4615 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Mendeliome v0.4612 CLDN14 Zornitza Stark Gene: cldn14 has been classified as Green List (High Evidence).
Mendeliome v0.4612 CLDN14 Zornitza Stark Phenotypes for gene: CLDN14 were changed from to Deafness, autosomal recessive 29, MIM# 614035
Mendeliome v0.4609 CLDN14 Zornitza Stark reviewed gene: CLDN14: Rating: GREEN; Mode of pathogenicity: None; Publications: 11163249, 20811388, 22246673, 23235333, 27870113, 27838790, 12913076; Phenotypes: Deafness, autosomal recessive 29, MIM# 614035; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4609 CIB2 Zornitza Stark Gene: cib2 has been classified as Green List (High Evidence).
Mendeliome v0.4609 CIB2 Zornitza Stark Phenotypes for gene: CIB2 were changed from to Deafness, autosomal recessive 48, MIM# 609439
Mendeliome v0.4606 CIB2 Zornitza Stark reviewed gene: CIB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23023331, 23023331, 26173970, 26473954, 27344577, 26226137, 26445815; Phenotypes: Deafness, autosomal recessive 48, MIM# 609439; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4606 GCM2 Zornitza Stark Gene: gcm2 has been classified as Green List (High Evidence).
Mendeliome v0.4602 SECISBP2 Zornitza Stark Gene: secisbp2 has been classified as Green List (High Evidence).
Mendeliome v0.4599 UBA1 Zornitza Stark Gene: uba1 has been classified as Green List (High Evidence).
Mendeliome v0.4596 TRIP4 Zornitza Stark Gene: trip4 has been classified as Green List (High Evidence).
Mendeliome v0.4593 EXOSC9 Zornitza Stark Gene: exosc9 has been classified as Green List (High Evidence).
Mendeliome v0.4593 EXOSC9 Zornitza Stark Phenotypes for gene: EXOSC9 were changed from to Pontocerebellar hypoplasia, type 1D, MIM# 618065
Mendeliome v0.4590 EXOSC9 Zornitza Stark reviewed gene: EXOSC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30690203, 29727687; Phenotypes: Pontocerebellar hypoplasia, type 1D, MIM# 618065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4590 SLC7A14 Zornitza Stark Gene: slc7a14 has been classified as Red List (Low Evidence).
Mendeliome v0.4587 SLC7A14 Zornitza Stark Classified gene: SLC7A14 as Red List (low evidence)
Mendeliome v0.4587 SLC7A14 Zornitza Stark Gene: slc7a14 has been classified as Red List (Low Evidence).
Mendeliome v0.4586 ATP6V1B1 Zornitza Stark Gene: atp6v1b1 has been classified as Green List (High Evidence).
Mendeliome v0.4586 ATP6V1B1 Zornitza Stark Phenotypes for gene: ATP6V1B1 were changed from to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300
Mendeliome v0.4583 ATP6V1B1 Zornitza Stark reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916796, 12414817, 16611712, 18798332; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4583 ATP2B2 Zornitza Stark reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30535804, 15829536; Phenotypes: Dominant progressive sensorineural deafness, {Deafness, autosomal recessive 12, modifier of}, MIM# 601386; Mode of inheritance: None
Mendeliome v0.4581 ALB Zornitza Stark Gene: alb has been classified as Green List (High Evidence).
Mendeliome v0.4578 TREM2 Zornitza Stark Gene: trem2 has been classified as Green List (High Evidence).
Mendeliome v0.4578 TREM2 Zornitza Stark Phenotypes for gene: TREM2 were changed from to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193
Mendeliome v0.4575 TREM2 Zornitza Stark reviewed gene: TREM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12080485, 15883308; Phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4575 SPG21 Zornitza Stark Gene: spg21 has been classified as Green List (High Evidence).
Mendeliome v0.4572 LMX1A Zornitza Stark Gene: lmx1a has been classified as Green List (High Evidence).
Mendeliome v0.4569 RPS20 Bryony Thompson Gene: rps20 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4569 RPS20 Bryony Thompson Classified gene: RPS20 as Amber List (moderate evidence)
Mendeliome v0.4569 RPS20 Bryony Thompson Gene: rps20 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4568 RPS20 Bryony Thompson gene: RPS20 was added
gene: RPS20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS20 were set to 32790018
Phenotypes for gene: RPS20 were set to Diamond Blackfan anaemia
Mode of pathogenicity for gene: RPS20 was set to Other
Review for gene: RPS20 was set to AMBER
Added comment: Two unrelated cases where a de novo variant involving Ile84 (Ile84Ser and Ile84Asn), and reduce the RPS20 protein level in patient cells. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. Loss of function may not be the mechanism of disease, because loss of function variants appear to be exclusively associated with familial colorectal cancer without the DBA phenotype.
Sources: Literature
Mendeliome v0.4566 SPAST Zornitza Stark Gene: spast has been classified as Green List (High Evidence).
Mendeliome v0.4563 TRRAP Zornitza Stark Gene: trrap has been classified as Green List (High Evidence).
Mendeliome v0.4560 UPF3B Zornitza Stark Gene: upf3b has been classified as Green List (High Evidence).
Mendeliome v0.4557 XPR1 Zornitza Stark Gene: xpr1 has been classified as Green List (High Evidence).
Mendeliome v0.4554 VPS13C Zornitza Stark Gene: vps13c has been classified as Green List (High Evidence).
Mendeliome v0.4551 KIAA1161 Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome to Basal ganglia calcification, idiopathic, 7, MIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome
Mendeliome v0.4548 KIAA1161 Zornitza Stark edited their review of gene: KIAA1161: Added comment: In a cohort study comprising 435 individuals with primary brain calcification, 38 individuals identified with mono-allelic variants in this gene, in addition to 14 with bi-allelic variants. Clinical and imaging penetrance of individuals with bi-allelic variants were 100%, whereas among individuals with heterozygous variants, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG variants, individuals with heterozygous variants had brain calcifications with much lower calcification scores (P < 2e-16). HGNC approved name is MYORG.; Changed publications: 30656188, 30649222, 30460687, 29910000, 31951047; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4548 ALG14 Zornitza Stark Gene: alg14 has been classified as Green List (High Evidence).
Mendeliome v0.4545 TCF12 Zornitza Stark Gene: tcf12 has been classified as Green List (High Evidence).
Mendeliome v0.4545 TCF12 Zornitza Stark Phenotypes for gene: TCF12 were changed from to Craniosynostosis 3, MIM# 615314; Kallman syndrome
Mendeliome v0.4542 TCF12 Zornitza Stark reviewed gene: TCF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 23354436, 32620954; Phenotypes: Craniosynostosis 3, MIM# 615314, Kallman syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4542 RP1L1 Zornitza Stark Gene: rp1l1 has been classified as Green List (High Evidence).
Mendeliome v0.4539 CYP11B2 Zornitza Stark Gene: cyp11b2 has been classified as Green List (High Evidence).
Mendeliome v0.4536 HPS5 Zornitza Stark Gene: hps5 has been classified as Green List (High Evidence).
Mendeliome v0.4533 IBA57 Zornitza Stark Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, MIM#615330 to Multiple mitochondrial dysfunctions syndrome 3, MIM#615330; Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark changed review comment from: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.; to: MMDS3: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.

SPG74: Three families with spastic paraparesis as a feature of the condition.
Mendeliome v0.4531 IBA57 Zornitza Stark edited their review of gene: IBA57: Changed phenotypes: Multiple mitochondrial dysfunctions syndrome 3, MIM#615330, Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark Gene: iba57 has been classified as Green List (High Evidence).
Mendeliome v0.4525 PAX7 Zornitza Stark Gene: pax7 has been classified as Green List (High Evidence).
Mendeliome v0.4525 PAX7 Zornitza Stark Phenotypes for gene: PAX7 were changed from to Myopathy, congenital, progressive, with scoliosis, MIM# 618578
Mendeliome v0.4522 PAX7 Zornitza Stark reviewed gene: PAX7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31092906, 11030621, 24065826, 31092906, 8631261, 11030621, 24065826; Phenotypes: Myopathy, congenital, progressive, with scoliosis, MIM# 618578; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4521 MADD Zornitza Stark edited their review of gene: MADD: Added comment: OMIM have assigned two disease entities to this gene.

DEEAH syndrome: 12 families.
NEDDISH syndrome: 8 families.; Changed phenotypes: DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities), Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005
Mendeliome v0.4520 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Added comment: Monoallelic :
DD/ID was a feature in >= 6 individuals with monoallelic de novo SLC12A2. An individual with an exon 22 truncating variant was reported to have normal milestones and cognitive function. Exon 21 variants have been described in individuals with rather isolated hearing impairment (possibly some associated motor delay, but normal cognition). Hearing impairment was also reported in 2/6 patients with variants in other exons (1 missense / 1 frameshift).

Biallelic :
DD/ID was reported in at least 3 individuals in literature. Hearing impairment has been reported on 2 occasions (although this was not probably evaluated in all subjects).

---

Monoallelic SLC12A2 mutations :

► Individuals with de novo mutations and developmental disorder were first identified by the DDD study (2017 - PMID: 28135719). 5 of them have been reported in detail by McNeill et al (below).

► McNeill et al (2020 - PMID: 32658972) report on 6 individuals with neurodevelopmental disorder due to de novo SLC12A2 mutation. All presented DD or ID ranging from mild to severe. ASD was reported in 3/6. Sensorineural hearing loss was a feature in 2/6 with the remaining having normal formal evaluations. Brain, cardiac and/or additional malformations were reported in a single individual. Following non-diagnostic prior work-up (CMA, FMR1 or other investigations) trio exome sequencing revealed missense (4/6) or truncating variants (2/6).

Three additional individuals (incl. a father and his son) with missense variants in exon 21 (NM_001046.3 / p.Glu979Lys and p.Glu980Lys) presented with bilateral sensorineural hearing loss. Speech and/or motor delay reported in these cases were attributed to the hearing impairment/vestibular arreflexia (cognitive abilities not tested).

SLC12A2 encodes sodium-potassium-chloride transporter 1 (also NKCC1).

The GTEx project has identified 8 isoforms. In brain both exon 21-containing/deleted isoforms are expressed (cited Morita et al 2014 - PMID: 24695712). As the authors discuss, RNA-seq of the developing mouse cochlea suggests that the exon 21 containing isoform is the single transcript expressed. Evidence from RNA-seq data (BrainSpan project) and literature suggests that the significant amounts of exon 21 lacking isoforms in fetal brain compensate for the deleterious effects of exon 21 variants and explain the lack of NDD in relevant patients.

Slc12a2 (NKCC1) null mouse model has demonstrated that the transporter plays a role in accumulation of the potassium rich endolymph in the inner ear, with NKCC1 absence causing sensorineural deafness and imbalance. Slc12a2 display cochlear malformations, loss of hair cells and hearing impairment (cited Delpire et al 1999 - PMID: 10369265). The brain phenotype has not been studied extensively, although loss of Slc12a2 has been shown to inhibit neurogenesis (cited: Magalhães and Rivera et al. - PMID: 27582690).

Slc12a2 null zebrafish display a collapse of the otic vesicle and reduced endolymph (Abbas and Whitfield, 2009 - PMID: 19633174) relevant to the human hearing disorder.

In vitro assessment of NKCC1 ion transporter function in Xenopus laevis, supported the deleterious effect of the identified variants (significant reduction in K+ influx). Using available single cell RNA-seq data the authors further demonstrated that SLC12A2 expressing cells display transcriptomic profiles reflective of active neurogenesis.

► Delpire et al (2016 - PMID: 27900370 - not reviewed in detail) described a 13 y.o. girl harboring a de novo 11-bp deletion in SLC12A2 exon 22. This individual reached developmental milestones on time and had a NORMAL cognitive function. Hearing was seemingly normal. Features included orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency and multiorgan failure incl. gut and bladder. Exome in the proband, parents and 3 unaffected sibs suggested SLC12A2 as the only candidate for her phenotype. Functional analyses in Xenopus laevis oocytes suggested that a non functional transporter was expressed and trafficked to the membrane as the wt. Detection of the truncated protein at higher molecular sizes suggested either enhanced dimerization or misfolded aggregate. There was no dominant-negative effect of mutant NKCC1. In patient fibroblasts a reduced total and NKCC1-mediated K+ influx.

► Mutai et al (2020 - PMID: 32294086) report on several individuals from 4 families, harboring variants within exon 21 or - in one case - at it's 3' splice-site (leading to skipping oe this exon at the mRNA level). All subjects were investigated for severe/profound hearing loss (in line with the role of exon 21-included isoforms in cochlea. The variant segregated with hearing impairment in 3 generations of a family while in all other subjects the variant had occured as de novo event. Despite motor delays (e.g. the subject from fam2 could not hold head or sit at the age of 10m / the proband in Fam3 was able to hold his head and walk at 6 and 20 m respectively) behavior and cognition were commented to be within normal range.


-----

Biallelic SLC12A2 mutations:

► Anazi et al (2017 - PMID: 29288388) briefly reported on a 3 y.o. boy (17DG0776) with central hypotonia, neonatal respiratory distress, failure to thrive, global DD and microcephaly and a skeletal survey suggestive of osteopenia. After non-diagnostic prior investigations (CMA revealing a 1p duplication classified as VUS, extensive metabolic workup), WES revealed a homozygous SLC12A2 splicing variant [NM_001046.2:c.2617-2A>G].

► Macnamara et al (2019 - PMID: 30740830) described a 5.5 y.o. male with sensorineural hearing loss, profound delays in all developmental areas among several other features (choanal atresia, failure to thrive, respiratory problems, absent sweat and tear production or salivation, GI abnormalities). Genetic testing for several disorders considered (cystic fibrosis, spinal muscular atrophy, sequencing and del/dup analysis of mtDNA) was normal. CMA revealed paternal uniparental isodisomy for chr. 5 and WGS a homozygous 22kb deletion in SLC12A2. This was followed by confirmation of homozygosity in the proband, heterozygosity of the unaffected father, delineation of breakpoints (chr5:127441491-127471419). mRNA studies in patient fibroblasts confirmed deletion of ex2-7, splicing of ex1 directly to ex8 and introduction of a premature stop codon in ex9. qRT-PCR confirmed that mRNA is likely subjected to NMD (expression ~80% of control). Western blot confirmed absence of the protein in the patient's fibroblasts. Again mouse models are thought to recapitulate the hearing defect but also the deficient saliva production (cited Evans et al 2000 - PMID: 10831596). Again the authors speculate a role of SLC12A2 in brain development based on evidence from murine models (migration, dendritic growth, increse in neuron density through regulation of GABAergic signalling (Young et al 2012 - PMID: 23015452). Hypotheses are also made on a regulatory relationship between NKCC1 and CFTR based on mRNA data from the ko mouse model.

► Stödberg et al (2020 - PMID: 32754646) reported 2 sibs with a complex neurodevelopmental disorder due to compound heterozygosity for a frameshift SLC12A2 variant and a splicing one (NM_001046:c.1431delT and c.2006-1G>A). Both presented hypotonia, neonatal S. aureus parotitis and respiratory problems (incl. apneas). While the older sib died at the age of 22 days, the younger one had persistent respiratory issues incl. a dry respiratory mucosa motivating metabolic, immunology investigations and testing for CF. She displayed microcephaly (OFC -2.5 SD, H was also -3.5SD), severe intellectual disability. MRI was suggestive of white matter and basal ganglia abnormalities. Other features incl. hearing impairment, and lack of tears,saliva and sweat, constipation and intestinal malrotation. There was facial dysmorphism. The variants were the only retained following WGS of the 2 affected sisters, parents and an unaffected brother. The splicing variant was shown to result in skipping of exon 13, while the indel in NMD. Again the authors discuss that the deficient saliva production, impaired hearing and GI problems are recapitulated in the mouse model (several refs provided).; Changed rating: GREEN; Changed publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Changed phenotypes: Kilquist syndrome, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4520 VPS37A Zornitza Stark Gene: vps37a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4520 VPS37A Zornitza Stark Phenotypes for gene: VPS37A were changed from to Spastic paraplegia 53, autosomal recessive, MIM# 614898
Mendeliome v0.4517 VPS37A Zornitza Stark Classified gene: VPS37A as Amber List (moderate evidence)
Mendeliome v0.4517 VPS37A Zornitza Stark Gene: vps37a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4516 VPS37A Zornitza Stark reviewed gene: VPS37A: Rating: AMBER; Mode of pathogenicity: None; Publications: 22717650; Phenotypes: Spastic paraplegia 53, autosomal recessive, MIM# 614898; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4516 TECPR2 Zornitza Stark Gene: tecpr2 has been classified as Green List (High Evidence).
Mendeliome v0.4516 TECPR2 Zornitza Stark Phenotypes for gene: TECPR2 were changed from to Spastic paraplegia 49, autosomal recessive, MIM# 615031; Autonomic-sensory neuropathy
Mendeliome v0.4513 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, MIM# 615031, Autonomic-sensory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4513 SMOC2 Zornitza Stark Gene: smoc2 has been classified as Green List (High Evidence).
Mendeliome v0.4513 SMOC2 Zornitza Stark Phenotypes for gene: SMOC2 were changed from to Dentin dysplasia, type I, with microdontia and misshapen teeth, MIM# 125400
Mendeliome v0.4510 SMOC2 Zornitza Stark reviewed gene: SMOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22152679, 23317772, 32908163; Phenotypes: Dentin dysplasia, type I, with microdontia and misshapen teeth, MIM# 125400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4510 MAG Zornitza Stark Gene: mag has been classified as Green List (High Evidence).
Mendeliome v0.4510 MAG Zornitza Stark Phenotypes for gene: MAG were changed from to Spastic paraplegia 75, autosomal recessive, MIM# 616680
Mendeliome v0.4507 MAG Zornitza Stark reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 26179919, 31402626, 32629324; Phenotypes: Spastic paraplegia 75, autosomal recessive, MIM# 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4507 DSTYK Zornitza Stark Gene: dstyk has been classified as Green List (High Evidence).
Mendeliome v0.4504 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Mendeliome v0.4504 ZMYM2 Zornitza Stark Classified gene: ZMYM2 as Green List (high evidence)
Mendeliome v0.4504 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Mendeliome v0.4503 ZMYM2 Zornitza Stark gene: ZMYM2 was added
gene: ZMYM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Congenital anomalies of kidney and urinary tract; Neurodevelopmental disorder
Review for gene: ZMYM2 was set to GREEN
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants.

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Mendeliome v0.4502 MTX2 Zornitza Stark Gene: mtx2 has been classified as Green List (High Evidence).
Mendeliome v0.4502 MTX2 Zornitza Stark Classified gene: MTX2 as Green List (high evidence)
Mendeliome v0.4502 MTX2 Zornitza Stark Gene: mtx2 has been classified as Green List (High Evidence).
Mendeliome v0.4501 MTX2 Zornitza Stark gene: MTX2 was added
gene: MTX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Review for gene: MTX2 was set to GREEN
Added comment: Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation.
Sources: Literature
Mendeliome v0.4500 RREB1 Zornitza Stark Gene: rreb1 has been classified as Red List (Low Evidence).
Mendeliome v0.4500 RREB1 Zornitza Stark gene: RREB1 was added
gene: RREB1 was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: RREB1.
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to 32938917
Phenotypes for gene: RREB1 were set to Noonan syndrome-like disorder
Review for gene: RREB1 was set to RED
Added comment: Single individual reported with Noonan syndrome-like features and a deletion encompassing RREB1. Overlapping deletions in publicly reported databases examined, and RREB1 postulated to be the key gene. Rreb1 hemizygous mice display orbital hypertelorism and age dependent cardiac hypertrophy. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes.

In summary, single well phenotyped individual with a CNV and experimental data to support gene-disease association.
Sources: Literature
Mendeliome v0.4499 FNIP1 Zornitza Stark Gene: fnip1 has been classified as Green List (High Evidence).
Mendeliome v0.4499 FNIP1 Zornitza Stark Classified gene: FNIP1 as Green List (high evidence)
Mendeliome v0.4499 FNIP1 Zornitza Stark Gene: fnip1 has been classified as Green List (High Evidence).
Mendeliome v0.4498 NEMF Zornitza Stark Gene: nemf has been classified as Green List (High Evidence).
Mendeliome v0.4498 NEMF Zornitza Stark Classified gene: NEMF as Green List (high evidence)
Mendeliome v0.4498 NEMF Zornitza Stark Gene: nemf has been classified as Green List (High Evidence).
Mendeliome v0.4497 NEMF Zornitza Stark gene: NEMF was added
gene: NEMF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEMF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225
Phenotypes for gene: NEMF were set to Intellectual disability; neuropathy
Review for gene: NEMF was set to GREEN
Added comment: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature
Mendeliome v0.4496 TAOK1 Zornitza Stark Gene: taok1 has been classified as Green List (High Evidence).
Mendeliome v0.4493 CSF1R Zornitza Stark Gene: csf1r has been classified as Green List (High Evidence).
Mendeliome v0.4493 CSF1R Zornitza Stark Phenotypes for gene: CSF1R were changed from to Brain abnormalities, neurodegeneration, and dysosteosclerosis, (MIM#618476); Leukoencephalopathy, diffuse hereditary, with spheroids, (MIM#221820)
Mendeliome v0.4489 L2HGDH Zornitza Stark Gene: l2hgdh has been classified as Green List (High Evidence).
Mendeliome v0.4486 CSF1R Elena Savva reviewed gene: CSF1R: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31330095, 24336230; Phenotypes: Brain abnormalities, neurodegeneration, and dysosteosclerosis, (MIM#618476), Leukoencephalopathy, diffuse hereditary, with spheroids, (MIM#221820); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4486 LMNB1 Zornitza Stark Gene: lmnb1 has been classified as Green List (High Evidence).
Mendeliome v0.4483 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from to 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 v0.4482 LMNB1 Zornitza Stark reviewed gene: LMNB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32910914, 16951681, 19151023; Phenotypes: 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; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4482 MAPK8 Zornitza Stark reviewed gene: MAPK8: Rating: AMBER; Mode of pathogenicity: None; Publications: 31784499; Phenotypes: Chronic mucocutaneous candidiasis, Connective tissue disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4482 MAPK8 Zornitza Stark Gene: mapk8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4482 MAPK8 Zornitza Stark Classified gene: MAPK8 as Amber List (moderate evidence)
Mendeliome v0.4482 MAPK8 Zornitza Stark Gene: mapk8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4481 CTNNBL1 Zornitza Stark Gene: ctnnbl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4481 CTNNBL1 Zornitza Stark Classified gene: CTNNBL1 as Amber List (moderate evidence)
Mendeliome v0.4481 CTNNBL1 Zornitza Stark Gene: ctnnbl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4480 MAPK8 Arina Puzriakova gene: MAPK8 was added
gene: MAPK8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK8 were set to 31784499
Phenotypes for gene: MAPK8 were set to Chronic mucocutaneous candidiasis; Connective tissue disorders
Added comment: PMID: 31784499 (2020) - Three cases in a single family with chronic mucocutaneous candidiasis and a connective tissue disorder that clinically overlaps with hEDS. WES revealed a splice-site variant (c.311+1G>A) in the MAPK8 gene that segregated with the disorder. Includes supportive functional data using patient-derived fibroblasts, showing that the variant impairs IL-17A/F immunity and the development of Th17 cells.
Sources: Literature
Mendeliome v0.4480 CTNNBL1 Arina Puzriakova gene: CTNNBL1 was added
gene: CTNNBL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTNNBL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNBL1 were set to 32484799
Phenotypes for gene: CTNNBL1 were set to Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency
Added comment: PMID: 32484799 (2020) - One patient with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC), associated with a homozygous missense M466V variant in the CTNNBL1 gene. Functional studies showed that the variant impaired interaction with AID, in turn disrupting AID-mediated antibody diversification in activated B-cells.
Sources: Literature
Mendeliome v0.4480 PDIA5 Zornitza Stark Gene: pdia5 has been classified as Red List (Low Evidence).
Mendeliome v0.4480 PDIA5 Zornitza Stark Classified gene: PDIA5 as Red List (low evidence)
Mendeliome v0.4480 PDIA5 Zornitza Stark Gene: pdia5 has been classified as Red List (Low Evidence).
Mendeliome v0.4479 TNNI2 Zornitza Stark Gene: tnni2 has been classified as Green List (High Evidence).
Mendeliome v0.4479 TNNI2 Zornitza Stark Phenotypes for gene: TNNI2 were changed from to Arthrogryposis, distal, type 2B1 (MIM#601680)
Mendeliome v0.4475 TNNI2 Michelle Torres reviewed gene: TNNI2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 17194691, 25340332; Phenotypes: Arthrogryposis, distal, type 2B1 (MIM#601680); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4475 MMP23A Bryony Thompson Gene: mmp23a has been classified as Red List (Low Evidence).
Mendeliome v0.4475 MMP23A Bryony Thompson Classified gene: MMP23A as Red List (low evidence)
Mendeliome v0.4475 MMP23A Bryony Thompson Gene: mmp23a has been classified as Red List (Low Evidence).
Mendeliome v0.4474 MMP23A Bryony Thompson reviewed gene: MMP23A: Rating: RED; Mode of pathogenicity: None; Publications: 15483646, 18924166; Phenotypes: Craniosynostosis; Mode of inheritance: Unknown
Mendeliome v0.4473 TAF2 Elena Savva reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24084144, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4473 VPS11 Zornitza Stark Gene: vps11 has been classified as Green List (High Evidence).
Mendeliome v0.4470 GGT1 Zornitza Stark Gene: ggt1 has been classified as Red List (Low Evidence).
Mendeliome v0.4467 GGT1 Zornitza Stark Classified gene: GGT1 as Red List (low evidence)
Mendeliome v0.4467 GGT1 Zornitza Stark Gene: ggt1 has been classified as Red List (Low Evidence).
Mendeliome v0.4466 GGT1 Elena Savva edited their review of gene: GGT1: Added comment: PMID: 29483667 - 1 family (2 sibs) w/ a homozygous 16.9kb deletion spanning part of the gene and no others. Carrier parents were normal.

PMID: 23615310 - homozygous mutant mouse model have dwarfism, cataracts and coat colour abnormalities. Protein activity reduced to 4% of wildtype. Noted it was for use as a GGT deficiency model.

PMID: 31520399 - 2 families with AD inheritance showing GGT1 deficiency but NO clinical symptoms. Authors call GGTemia a benign condition.; Changed publications: PMID: 29483667, 23615310, 31520399
Mendeliome v0.4466 NAXE Zornitza Stark Gene: naxe has been classified as Green List (High Evidence).
Mendeliome v0.4466 NAXE Zornitza Stark Phenotypes for gene: NAXE were changed from to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186
Mendeliome v0.4463 NAXE Zornitza Stark changed review comment from: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.; to: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.
Mendeliome v0.4463 NAXE Zornitza Stark reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27122014, 27616477, 31758406; Phenotypes: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4463 NAXD Zornitza Stark Gene: naxd has been classified as Green List (High Evidence).
Mendeliome v0.4463 NAXD Zornitza Stark Phenotypes for gene: NAXD were changed from to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Mendeliome v0.4460 NAXD Zornitza Stark reviewed gene: NAXD: Rating: GREEN; Mode of pathogenicity: None; Publications: 30576410, 31755961, 32462209; Phenotypes: Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4460 ISCA2 Zornitza Stark Gene: isca2 has been classified as Green List (High Evidence).
Mendeliome v0.4457 PRIMPOL Zornitza Stark Gene: primpol has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4454 PRIMPOL Zornitza Stark Classified gene: PRIMPOL as Amber List (moderate evidence)
Mendeliome v0.4454 PRIMPOL Zornitza Stark Gene: primpol has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4453 KCNN4 Zornitza Stark Gene: kcnn4 has been classified as Green List (High Evidence).
Mendeliome v0.4453 KCNN4 Zornitza Stark Classified gene: KCNN4 as Green List (high evidence)
Mendeliome v0.4453 KCNN4 Zornitza Stark Gene: kcnn4 has been classified as Green List (High Evidence).
Mendeliome v0.4452 KCNN4 Zornitza Stark gene: KCNN4 was added
gene: KCNN4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN4 were set to 26148990; 26198474; 26178367
Phenotypes for gene: KCNN4 were set to Dehydrated hereditary stomatocytosis 2, MIM# 616689
Review for gene: KCNN4 was set to GREEN
Added comment: At least three families reported.
Sources: Expert list
Mendeliome v0.4451 C15orf41 Zornitza Stark Gene: c15orf41 has been classified as Green List (High Evidence).
Mendeliome v0.4451 C15orf41 Zornitza Stark Classified gene: C15orf41 as Green List (high evidence)
Mendeliome v0.4451 C15orf41 Zornitza Stark Gene: c15orf41 has been classified as Green List (High Evidence).
Mendeliome v0.4449 XRCC2 Zornitza Stark Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4446 XRCC2 Zornitza Stark Classified gene: XRCC2 as Amber List (moderate evidence)
Mendeliome v0.4446 XRCC2 Zornitza Stark Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4445 TSR2 Zornitza Stark Gene: tsr2 has been classified as Red List (Low Evidence).
Mendeliome v0.4445 TSR2 Zornitza Stark Phenotypes for gene: TSR2 were changed from to Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, MIM# 300946
Mendeliome v0.4442 TSR2 Zornitza Stark Classified gene: TSR2 as Red List (low evidence)
Mendeliome v0.4442 TSR2 Zornitza Stark Gene: tsr2 has been classified as Red List (Low Evidence).
Mendeliome v0.4441 TSR2 Zornitza Stark reviewed gene: TSR2: Rating: RED; Mode of pathogenicity: None; Publications: 24942156; Phenotypes: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, MIM# 300946; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4441 SRP72 Zornitza Stark Gene: srp72 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4438 SRP72 Zornitza Stark Classified gene: SRP72 as Amber List (moderate evidence)
Mendeliome v0.4438 SRP72 Zornitza Stark Gene: srp72 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4437 SLC25A38 Zornitza Stark Gene: slc25a38 has been classified as Green List (High Evidence).
Mendeliome v0.4437 SLC25A38 Zornitza Stark Phenotypes for gene: SLC25A38 were changed from to Anemia, sideroblastic, 2, pyridoxine-refractory, MIM# 205950
Mendeliome v0.4434 SLC25A38 Zornitza Stark reviewed gene: SLC25A38: Rating: GREEN; Mode of pathogenicity: None; Publications: 19412178; Phenotypes: Anemia, sideroblastic, 2, pyridoxine-refractory, MIM# 205950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4434 SLC19A2 Zornitza Stark Gene: slc19a2 has been classified as Green List (High Evidence).
Mendeliome v0.4434 SLC19A2 Zornitza Stark Phenotypes for gene: SLC19A2 were changed from to Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270
Mendeliome v0.4431 SLC19A2 Zornitza Stark reviewed gene: SLC19A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10391221, 10978358; Phenotypes: Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4431 SEC23B Zornitza Stark Gene: sec23b has been classified as Green List (High Evidence).
Mendeliome v0.4428 RPS27 Zornitza Stark Gene: rps27 has been classified as Red List (Low Evidence).
Mendeliome v0.4425 RPS27 Zornitza Stark Classified gene: RPS27 as Red List (low evidence)
Mendeliome v0.4425 RPS27 Zornitza Stark Gene: rps27 has been classified as Red List (Low Evidence).
Mendeliome v0.4424 RPS17 Zornitza Stark Gene: rps17 has been classified as Green List (High Evidence).
Mendeliome v0.4421 RPL9 Zornitza Stark Gene: rpl9 has been classified as Red List (Low Evidence).
Mendeliome v0.4421 RPL9 Zornitza Stark gene: RPL9 was added
gene: RPL9 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPL9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL9 were set to 29114930; 20116044
Phenotypes for gene: RPL9 were set to Diamond Blackfan anaemia
Review for gene: RPL9 was set to RED
Added comment: PMID: 29114930, de novo splice site variant, c.-2+1G>C, functional impact of this variant is likely deleterious but not proven. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad.
Sources: Expert list
Mendeliome v0.4420 RPL31 Zornitza Stark Gene: rpl31 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4417 RPL31 Zornitza Stark Classified gene: RPL31 as Amber List (moderate evidence)
Mendeliome v0.4417 RPL31 Zornitza Stark Gene: rpl31 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4416 PUS1 Zornitza Stark Gene: pus1 has been classified as Green List (High Evidence).
Mendeliome v0.4416 PUS1 Zornitza Stark Phenotypes for gene: PUS1 were changed from to Myopathy, lactic acidosis, and sideroblastic anemia 1, MIM# 600462
Mendeliome v0.4413 PUS1 Zornitza Stark reviewed gene: PUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25227147, 17056637, 15108122, 32287105, 31641589, 28832011; Phenotypes: Myopathy, lactic acidosis, and sideroblastic anemia 1, MIM# 600462; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4413 OXSR1 Zornitza Stark Gene: oxsr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4413 OXSR1 Zornitza Stark Classified gene: OXSR1 as Red List (low evidence)
Mendeliome v0.4413 OXSR1 Zornitza Stark Gene: oxsr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4412 NHP2 Zornitza Stark Gene: nhp2 has been classified as Green List (High Evidence).
Mendeliome v0.4412 NHP2 Zornitza Stark Phenotypes for gene: NHP2 were changed from to Dyskeratosis congenita, autosomal recessive 2, MIM# 613987
Mendeliome v0.4409 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18523010, 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, MIM# 613987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4409 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Mendeliome v0.4406 HOXA11 Zornitza Stark Gene: hoxa11 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4406 HOXA11 Zornitza Stark Phenotypes for gene: HOXA11 were changed from to Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432
Mendeliome v0.4403 HOXA11 Zornitza Stark Classified gene: HOXA11 as Amber List (moderate evidence)
Mendeliome v0.4403 HOXA11 Zornitza Stark Gene: hoxa11 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4402 HOXA11 Zornitza Stark reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832, 16765069; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4402 TGM6 Zornitza Stark Gene: tgm6 has been classified as Red List (Low Evidence).
Mendeliome v0.4399 TGM6 Zornitza Stark Classified gene: TGM6 as Red List (low evidence)
Mendeliome v0.4399 TGM6 Zornitza Stark Gene: tgm6 has been classified as Red List (Low Evidence).
Mendeliome v0.4398 SVBP Zornitza Stark changed review comment from: 5 unrelated families with homozygous mutations in SVBP. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Literature; to: 5 unrelated families with homozygous mutations in SVBP. Some shared the same founder variant, p.Q28*. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Literature
Mendeliome v0.4398 SQSTM1 Zornitza Stark Gene: sqstm1 has been classified as Green List (High Evidence).
Mendeliome v0.4395 SQSTM1 Zornitza Stark changed review comment from: Four unrelated families, presenting feature of this progressive neurological disorder was ataxia.; to: Nine individuals from four unrelated families.
Mendeliome v0.4395 SLC25A46 Zornitza Stark Gene: slc25a46 has been classified as Green List (High Evidence).
Mendeliome v0.4392 SLC25A46 Zornitza Stark changed review comment from: Age of onset is variable, but childhood onset described. Ataxia is a feature.; to: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus.

At least 10 unrelated families reported, supportive functional data.
Mendeliome v0.4392 RORA Zornitza Stark Gene: rora has been classified as Green List (High Evidence).
Mendeliome v0.4389 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Mendeliome v0.4389 LARS2 Zornitza Stark Phenotypes for gene: LARS2 were changed from to Perrault syndrome 4; Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Leukodystrophy
Mendeliome v0.4386 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4386 LAMA1 Zornitza Stark Gene: lama1 has been classified as Green List (High Evidence).
Mendeliome v0.4383 KCNA2 Zornitza Stark Gene: kcna2 has been classified as Green List (High Evidence).
Mendeliome v0.4380 KCNA2 Zornitza Stark commented on gene: KCNA2: Review of 23 affected individuals in PMID 29050392: some variants are LoF and others GoF, and some genotype-phenotype correlations made. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalised and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations.
Mendeliome v0.4380 HARS2 Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence).
Mendeliome v0.4377 EBF3 Zornitza Stark Gene: ebf3 has been classified as Green List (High Evidence).
Mendeliome v0.4374 DOCK3 Zornitza Stark Gene: dock3 has been classified as Green List (High Evidence).
Mendeliome v0.4371 ATP8A2 Zornitza Stark Gene: atp8a2 has been classified as Green List (High Evidence).
Mendeliome v0.4368 ATP8A2 Zornitza Stark changed review comment from: Multiple individuals from unrelated families reported with bi-allelic variants in this gene and neurological phenotypes including intellectual disability.
Sources: Expert list; to: 10 individuals from six unrelated families reported with bi-allelic variants in this gene and neurological phenotypes including intellectual disability.
Sources: Expert list
Mendeliome v0.4368 ADPRHL2 Zornitza Stark Gene: adprhl2 has been classified as Green List (High Evidence).
Mendeliome v0.4368 CNGB3 Zornitza Stark Gene: cngb3 has been classified as Green List (High Evidence).
Mendeliome v0.4368 CNGB3 Zornitza Stark Phenotypes for gene: CNGB3 were changed from to Achromatopsia 3, MIM# 262300
Mendeliome v0.4365 CNGB3 Zornitza Stark reviewed gene: CNGB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17265047; Phenotypes: Achromatopsia 3, MIM# 262300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4365 CNGA3 Zornitza Stark Gene: cnga3 has been classified as Green List (High Evidence).
Mendeliome v0.4365 CNGA3 Zornitza Stark Phenotypes for gene: CNGA3 were changed from to Achromatopsia 2, MIM# 216900
Mendeliome v0.4362 CNGA3 Zornitza Stark reviewed gene: CNGA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9662398, 11536077, 17265047; Phenotypes: Achromatopsia 2, MIM# 216900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4362 SPRED1 Zornitza Stark Gene: spred1 has been classified as Green List (High Evidence).
Mendeliome v0.4355 SOS1 Zornitza Stark edited their review of gene: SOS1: Added comment: Over 50 individuals reported with SOS1 variants and a Noonan syndrome phenotype. Pulmonic stenosis tends to be more frequent compared to those with PTPN11 mutations, and atrial septal defect is relatively rare. Ectodermal features including keratosis pilaris and curly hair are significantly more prevalent compared with the general Noonan population. Height below the third percentile and learning disability are observed in fewer individuals compared with Noonan syndrome in general. In contrast, macrocephaly is overrepresented among those with SOS1 mutations.; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 17143285, 17143282, 28884940, 17586837; Changed phenotypes: Noonan syndrome 4, MIM# 610733; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4355 SHOC2 Zornitza Stark Gene: shoc2 has been classified as Green List (High Evidence).
Mendeliome v0.4351 RIT1 Zornitza Stark Gene: rit1 has been classified as Green List (High Evidence).
Mendeliome v0.4347 NRAS Zornitza Stark Gene: nras has been classified as Green List (High Evidence).
Mendeliome v0.4343 MAP2K2 Zornitza Stark Gene: map2k2 has been classified as Green List (High Evidence).
Mendeliome v0.4339 MAP2K1 Zornitza Stark Gene: map2k1 has been classified as Green List (High Evidence).
Mendeliome v0.4335 HRAS Zornitza Stark Gene: hras has been classified as Green List (High Evidence).
Mendeliome v0.4331 CBL Zornitza Stark Gene: cbl has been classified as Green List (High Evidence).
Mendeliome v0.4327 CSNK1D Zornitza Stark Gene: csnk1d has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4324 CSNK1D Zornitza Stark Classified gene: CSNK1D as Amber List (moderate evidence)
Mendeliome v0.4324 CSNK1D Zornitza Stark Gene: csnk1d has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4323 CACNA1E Zornitza Stark Gene: cacna1e has been classified as Green List (High Evidence).
Mendeliome v0.4320 ATAD1 Zornitza Stark Gene: atad1 has been classified as Green List (High Evidence).
Mendeliome v0.4317 ATAD1 Zornitza Stark changed review comment from: Severe progressive neurological disorder, severe/profound intellectual disability is a feature; to: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures. Severe progressive neurological disorder, severe/profound intellectual disability is a feature.
Mendeliome v0.4316 ADAT1 Zornitza Stark Gene: adat1 has been classified as Green List (High Evidence).
Mendeliome v0.4316 ADAT1 Zornitza Stark Classified gene: ADAT1 as Green List (high evidence)
Mendeliome v0.4316 ADAT1 Zornitza Stark Gene: adat1 has been classified as Green List (High Evidence).
Mendeliome v0.4315 ADAT1 Zornitza Stark gene: ADAT1 was added
gene: ADAT1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ADAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAT1 were set to 28180185; 29390050; 29659736
Phenotypes for gene: ADAT1 were set to Hyperekplexia 4, MIM#618011
Review for gene: ADAT1 was set to GREEN
Added comment: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures.
Sources: Expert list
Mendeliome v0.4312 OCA2 Zornitza Stark Gene: oca2 has been classified as Green List (High Evidence).
Mendeliome v0.4309 OCA2 Elena Savva changed review comment from: Single variant found causing AD OCA - p.G780S in two families (Lee, 2020) -> GOF suggested

Complete penetrance for oculocutaneous albininism but variable expressivity (PMID: 24518832). No variable expressivity or incomplete penetrance reported in GeneReviews.

Loss of function; to: Single variant found causing AD OCA - p.G780S in two families (Lee, 2020) -> GOF suggested

Complete penetrance for oculocutaneous albininism but variable expressivity (PMID: 24518832). No variable expressivity or incomplete penetrance reported in GeneReviews.

Loss of function

2.7kb deletion is very common in sub-Saharan African populations (GeneReviews)
Mendeliome v0.4309 ZSWIM6 Zornitza Stark changed review comment from: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X) identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp
Mendeliome v0.4309 ZSWIM6 Zornitza Stark changed review comment from: MIM #617865 A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671: recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp
Mendeliome v0.4309 SREBF1 Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016
Mendeliome v0.4308 SREBF1 Zornitza Stark reviewed gene: SREBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4308 VPS13D Zornitza Stark Gene: vps13d has been classified as Green List (High Evidence).
Mendeliome v0.4308 VPS13D Zornitza Stark Phenotypes for gene: VPS13D were changed from to Spinocerebellar ataxia, autosomal recessive 4, MIM# 607317
Mendeliome v0.4304 FARSA Zornitza Stark Gene: farsa has been classified as Red List (Low Evidence).
Mendeliome v0.4304 FARSA Zornitza Stark gene: FARSA was added
gene: FARSA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to Rajab interstitial lung disease with brain calcifications 2, MIM# 619013
Review for gene: FARSA was set to RED
Added comment: Autosomal recessive disorder characterized by growth delay, interstitial lung disease, liver disease, and abnormal brain MRI findings, including brain calcifications and periventricular cysts. Single affected individual reported, but FARSA interacts with FARSB, which causes a similar disorder.
Sources: Expert list
Mendeliome v0.4303 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Green List (High Evidence).
Mendeliome v0.4300 ANGPT2 Zornitza Stark Gene: angpt2 has been classified as Green List (High Evidence).
Mendeliome v0.4300 ANGPT2 Zornitza Stark Classified gene: ANGPT2 as Green List (high evidence)
Mendeliome v0.4300 ANGPT2 Zornitza Stark Gene: angpt2 has been classified as Green List (High Evidence).
Mendeliome v0.4298 UBR4 Zornitza Stark changed review comment from: Episodic ataxia reported in two families, but another molecular diagnosis present in the second, so suggested as a modifier. Only one individual reported with childhood-onset progressive neurological disorder as part of a large paper proposing multiple candidate genes.; to: Episodic ataxia reported in four families, but another molecular diagnosis present in the some, so suggested as a modifier. Variants are missense, with no supportive segregation or functional data, some are present at a low level in population databases. Only one individual reported with childhood-onset progressive neurological disorder as part of a large paper proposing multiple candidate genes.
Mendeliome v0.4298 SLC20A2 Zornitza Stark Gene: slc20a2 has been classified as Green List (High Evidence).
Mendeliome v0.4295 SLC16A2 Zornitza Stark Gene: slc16a2 has been classified as Green List (High Evidence).
Mendeliome v0.4289 HSP90B2P Bryony Thompson Gene: hsp90b2p has been classified as Red List (Low Evidence).
Mendeliome v0.4289 HSP90B2P Bryony Thompson Classified gene: HSP90B2P as Red List (low evidence)
Mendeliome v0.4289 HSP90B2P Bryony Thompson Gene: hsp90b2p has been classified as Red List (Low Evidence).
Mendeliome v0.4288 NOBOX Zornitza Stark Gene: nobox has been classified as Green List (High Evidence).
Mendeliome v0.4282 TET2 Zornitza Stark Classified gene: TET2 as Green List (high evidence)
Mendeliome v0.4282 TET2 Zornitza Stark Gene: tet2 has been classified as Green List (High Evidence).
Mendeliome v0.4281 TLR7 Zornitza Stark Gene: tlr7 has been classified as Green List (High Evidence).
Mendeliome v0.4278 EXOSC5 Zornitza Stark Gene: exosc5 has been classified as Green List (High Evidence).
Mendeliome v0.4278 EXOSC5 Zornitza Stark Phenotypes for gene: EXOSC5 were changed from to Short stature; Motor developmental delays; Cerebellar hypoplasia; Ataxia
Mendeliome v0.4275 EXOSC5 Arina Puzriakova changed review comment from: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.; to: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Mendeliome v0.4275 EXOSC5 Arina Puzriakova reviewed gene: EXOSC5: Rating: ; Mode of pathogenicity: None; Publications: 32504085, 29302074; Phenotypes: Short stature, Motor developmental delays, Cerebellar hypoplasia, Ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4275 SLC20A1 Zornitza Stark Gene: slc20a1 has been classified as Green List (High Evidence).
Mendeliome v0.4272 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Mendeliome v0.4272 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from to Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Mendeliome v0.4269 NR2F1 Zornitza Stark Gene: nr2f1 has been classified as Green List (High Evidence).
Mendeliome v0.4266 RAD50 Zornitza Stark Gene: rad50 has been classified as Green List (High Evidence).
Mendeliome v0.4262 KMT2D Zornitza Stark edited their review of gene: KMT2D: Added comment: Four further individuals with KMT2D-associated neurodevelopmental syndrome reported. Features include: athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. Two of the four individuals had severe interstitial lung disease.; Changed publications: 31949313, 32083401
Mendeliome v0.4261 CFAP58 Zornitza Stark Gene: cfap58 has been classified as Green List (High Evidence).
Mendeliome v0.4261 CFAP58 Zornitza Stark Classified gene: CFAP58 as Green List (high evidence)
Mendeliome v0.4261 CFAP58 Zornitza Stark Gene: cfap58 has been classified as Green List (High Evidence).
Mendeliome v0.4260 WASHC4 Zornitza Stark Gene: washc4 has been classified as Green List (High Evidence).
Mendeliome v0.4260 WASHC4 Zornitza Stark Classified gene: WASHC4 as Green List (high evidence)
Mendeliome v0.4260 WASHC4 Zornitza Stark Gene: washc4 has been classified as Green List (High Evidence).
Mendeliome v0.4259 WASHC4 Zornitza Stark gene: WASHC4 was added
gene: WASHC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC4 were set to 31953988; 21498477
Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817
Review for gene: WASHC4 was set to GREEN
Added comment: Three unrelated families reported.
Sources: Literature
Mendeliome v0.4258 DNAJC7 Seb Lunke Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4258 DNAJC7 Seb Lunke Classified gene: DNAJC7 as Amber List (moderate evidence)
Mendeliome v0.4258 DNAJC7 Seb Lunke Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4257 DNAJC7 Seb Lunke gene: DNAJC7 was added
gene: DNAJC7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJC7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DNAJC7 were set to 31768050
Phenotypes for gene: DNAJC7 were set to amyotrophic lateral sclerosis
Review for gene: DNAJC7 was set to AMBER
Added comment: Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. However gene described as risk factor, unclear why.

DOI: https://doi.org/10.1212/NXG.0000000000000503
Sources: Literature
Mendeliome v0.4256 SVIL Melanie Marty edited their review of gene: SVIL: Added comment: Four patients from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.; Changed rating: AMBER
Mendeliome v0.4256 HSPA9 Zornitza Stark Gene: hspa9 has been classified as Green List (High Evidence).
Mendeliome v0.4256 HSPA9 Zornitza Stark Phenotypes for gene: HSPA9 were changed from to Anemia, sideroblastic, 4, MIM# 182170; Even-plus syndrome, MIM#616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose
Mendeliome v0.4252 SVIL Zornitza Stark Gene: svil has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4252 SVIL Zornitza Stark Classified gene: SVIL as Amber List (moderate evidence)
Mendeliome v0.4252 SVIL Zornitza Stark Gene: svil has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4250 CFAP57 Zornitza Stark reviewed gene: CFAP57: Rating: AMBER; Mode of pathogenicity: None; Publications: 21574244, 32764743; Phenotypes: Van der Woude Syndrome, Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4250 SVIL Melanie Marty gene: SVIL was added
gene: SVIL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVIL were set to 32779703
Phenotypes for gene: SVIL were set to myopathy
Penetrance for gene: SVIL were set to unknown
Review for gene: SVIL was set to GREEN
Added comment: Four patients from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.
Sources: Literature
Mendeliome v0.4250 HSPA9 Zornitza Stark reviewed gene: HSPA9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Anemia, sideroblastic, 4, MIM# 182170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4249 MYT1L Zornitza Stark edited their review of gene: MYT1L: Added comment: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems.; Changed publications: 28859103, 32065501
Mendeliome v0.4249 ARID1A Zornitza Stark Gene: arid1a has been classified as Green List (High Evidence).
Mendeliome v0.4249 ARID1A Zornitza Stark Phenotypes for gene: ARID1A were changed from to Coffin-Siris syndrome 2 (MIM#614607)
Mendeliome v0.4246 PDE10A Zornitza Stark Gene: pde10a has been classified as Green List (High Evidence).
Mendeliome v0.4246 PDE10A Zornitza Stark Phenotypes for gene: PDE10A were changed from to Dyskinesia, limb and orofacial, infantile-onset, MIM#616921; Striatal degeneration, autosomal dominant, MIM# 616922
Mendeliome v0.4243 PDE10A Zornitza Stark reviewed gene: PDE10A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27058446, 27058447; Phenotypes: Dyskinesia, limb and orofacial, infantile-onset, MIM#616921, Striatal degeneration, autosomal dominant, MIM# 616922; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4242 PNPLA8 Kristin Rigbye reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29681094, 25512002; Phenotypes: Mitochondrial myopathy with lactic acidosis (MIM#251950), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4242 ARID1A Crystle Lee reviewed gene: ARID1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23929686, 22426308, 25168959; Phenotypes: Coffin-Siris syndrome 2 (MIM#614607); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4241 KIF1C Zornitza Stark Gene: kif1c has been classified as Green List (High Evidence).
Mendeliome v0.4241 KIF1C Zornitza Stark Phenotypes for gene: KIF1C were changed from to Spastic ataxia 2, autosomal recessive, MIM# 611302
Mendeliome v0.4238 KIF1C Zornitza Stark reviewed gene: KIF1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 24319291, 31413903, 29544888; Phenotypes: Spastic ataxia 2, autosomal recessive, MIM# 611302; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4238 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Green List (High Evidence).
Mendeliome v0.4235 GNB1 Zornitza Stark Gene: gnb1 has been classified as Green List (High Evidence).
Mendeliome v0.4232 NDUFB10 Zornitza Stark Phenotypes for gene: NDUFB10 were changed from fatal infantile lactic acidosis; cardiomyopathy to fatal infantile lactic acidosis; cardiomyopathy; Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Mendeliome v0.4231 NDUFB10 Zornitza Stark edited their review of gene: NDUFB10: Changed phenotypes: fatal infantile lactic acidosis, cardiomyopathy, Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Mendeliome v0.4230 MCM10 Zornitza Stark Gene: mcm10 has been classified as Red List (Low Evidence).
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Mono-allelic variants: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.
Mendeliome v0.4229 FDXR Zornitza Stark Gene: fdxr has been classified as Green List (High Evidence).
Mendeliome v0.4226 FDXR Zornitza Stark edited their review of gene: FDXR: Added comment: Four families reported with bi-allelic variants in FDXR causing an autosomal recessive neurologic disorder characterised by onset of visual and hearing impairment in the first or second decades. Two individuals described with a more severe progressive neurological phenotype. Mouse model exhibits neurodegeneration.; Changed rating: GREEN; Changed publications: 30250212, 28965846
Mendeliome v0.4226 EXOC7 Zornitza Stark Gene: exoc7 has been classified as Green List (High Evidence).
Mendeliome v0.4226 EXOC7 Zornitza Stark Classified gene: EXOC7 as Green List (high evidence)
Mendeliome v0.4226 EXOC7 Zornitza Stark Gene: exoc7 has been classified as Green List (High Evidence).
Mendeliome v0.4225 EIF2S3 Zornitza Stark Gene: eif2s3 has been classified as Green List (High Evidence).
Mendeliome v0.4220 TRAPPC6B Zornitza Stark Gene: trappc6b has been classified as Green List (High Evidence).
Mendeliome v0.4217 TRAPPC12 Zornitza Stark Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Mendeliome v0.4214 TRAPPC12 Zornitza Stark reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837, 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4214 TPRKB Zornitza Stark Gene: tprkb has been classified as Green List (High Evidence).
Mendeliome v0.4211 TP53RK Zornitza Stark Gene: tp53rk has been classified as Green List (High Evidence).
Mendeliome v0.4208 TBC1D20 Zornitza Stark Gene: tbc1d20 has been classified as Green List (High Evidence).
Mendeliome v0.4205 DHX34 Zornitza Stark Gene: dhx34 has been classified as Red List (Low Evidence).
Mendeliome v0.4205 DHX34 Zornitza Stark gene: DHX34 was added
gene: DHX34 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX34 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX34 were set to 31256877
Phenotypes for gene: DHX34 were set to Intellectual disability; congenital anomalies
Review for gene: DHX34 was set to RED
Added comment: Three families reported. Two with bi-allelic variants and ID/multiple congenital anomalies but another molecular diagnosis present in both (variants in established genes). Single de novo missense in another individual with ID and dysmorphism. No supporting functional data. Overall RED rating for both MOI.
Sources: Literature
Mendeliome v0.4204 DDX54 Zornitza Stark Gene: ddx54 has been classified as Red List (Low Evidence).
Mendeliome v0.4204 DDX54 Zornitza Stark gene: DDX54 was added
gene: DDX54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX54 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DDX54 were set to 31256877
Phenotypes for gene: DDX54 were set to Intellectual disability; congenital anomalies
Review for gene: DDX54 was set to RED
Added comment: Three individuals reported with different MOIs and different phenotypes. One with de novo variant and ID, another with bi-allelic variants and ID, and a third with bi-allelic variants and CAKUT. All variants are missense, no functional data. Overall, Red rating given inconsistent phenotypes and modes of inheritance, each one is essentially treated separately for now until further cases identified.
Sources: Literature
Mendeliome v0.4203 DHX16 Zornitza Stark Gene: dhx16 has been classified as Green List (High Evidence).
Mendeliome v0.4203 DHX16 Zornitza Stark Classified gene: DHX16 as Green List (high evidence)
Mendeliome v0.4203 DHX16 Zornitza Stark Gene: dhx16 has been classified as Green List (High Evidence).
Mendeliome v0.4202 DHX16 Zornitza Stark gene: DHX16 was added
gene: DHX16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, MIM# 618733
Review for gene: DHX16 was set to GREEN
Added comment: Four unrelated individuals reported with de novo missense variants in this gene. Three of the individuals died in infancy, so phenotypic spectrum difficult to discern. Two had seizures. Individual with long-term survival had a progressive course, evidence of myopathy, loss of hearing and vision, and normal IQ.
Sources: Literature
Mendeliome v0.4201 DHX37 Zornitza Stark Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS); Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Mendeliome v0.4198 DHX37 Zornitza Stark changed review comment from: Seventeen individuals with 46,XY gonadal dysgenesis reported in two studies.
Sources: Literature; to: Mono-allelic disease: Seventeen individuals with 46,XY gonadal dysgenesis reported in two studies.
Sources: Literature
Mendeliome v0.4198 DHX37 Zornitza Stark edited their review of gene: DHX37: Added comment: Bi-allelic disease: 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype, which also includes congenital anomalies particularly affecting the vertebrae and heart, but also some with microcephaly, brain anomalies.; Changed publications: 31337883, 31745530, 26539891, 31256877; Changed phenotypes: 46,XY gonadal dysgenesis, testicular regression syndrome (TRS), Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4198 CFL2 Zornitza Stark Gene: cfl2 has been classified as Green List (High Evidence).
Mendeliome v0.4198 CFL2 Zornitza Stark Phenotypes for gene: CFL2 were changed from to Nemaline myopathy 7, autosomal recessive, MIM# 610687
Mendeliome v0.4195 CFL2 Zornitza Stark reviewed gene: CFL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17160903, 22560515, 32697999, 29457652, 24610938; Phenotypes: Nemaline myopathy 7, autosomal recessive, MIM# 610687; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4195 TDRD7 Zornitza Stark Gene: tdrd7 has been classified as Green List (High Evidence).
Mendeliome v0.4195 TDRD7 Zornitza Stark Phenotypes for gene: TDRD7 were changed from Cataract 36 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis to Cataract 36, 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis
Mendeliome v0.4193 PAK3 Zornitza Stark Gene: pak3 has been classified as Green List (High Evidence).
Mendeliome v0.4190 CLTC Zornitza Stark Gene: cltc has been classified as Green List (High Evidence).
Mendeliome v0.4187 SLC1A4 Zornitza Stark reviewed gene: SLC1A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25930971, 26138499, 26041762, 27193218, 29989513; Phenotypes: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4187 RPL10 Zornitza Stark Gene: rpl10 has been classified as Green List (High Evidence).
Mendeliome v0.4184 IFT122 Zornitza Stark Gene: ift122 has been classified as Green List (High Evidence).
Mendeliome v0.4184 IFT122 Zornitza Stark Phenotypes for gene: IFT122 were changed from to Cranioectodermal dysplasia 1, MIM# MIM#218330
Mendeliome v0.4181 IFT122 Zornitza Stark reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: None; Publications: 26792575, 28370949, 29037998; Phenotypes: Cranioectodermal dysplasia 1, MIM# MIM#218330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4181 JAK1 Zornitza Stark edited their review of gene: JAK1: Changed phenotypes: Eosinophilia, Eosinophilic enteritis, Thyroid disease, Poor growth, Viral infections, Susceptibility to mycobacteria and viruses, Autoinflammation, immunde dysregulation, and eosinophilia, MIM# 618999
Mendeliome v0.4181 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Relapsing HLH to Relapsing HLH; Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v0.4180 RC3H1 Zornitza Stark edited their review of gene: RC3H1: Changed phenotypes: Relapsing HLH, Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v0.4180 KIAA0319 Zornitza Stark Gene: kiaa0319 has been classified as Red List (Low Evidence).
Mendeliome v0.4179 KIAA0319 Zornitza Stark Classified gene: KIAA0319 as Red List (low evidence)
Mendeliome v0.4179 KIAA0319 Zornitza Stark Gene: kiaa0319 has been classified as Red List (Low Evidence).
Mendeliome v0.4178 RARS2 Zornitza Stark Gene: rars2 has been classified as Green List (High Evidence).
Mendeliome v0.4178 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from Pontocerebellar hypoplasia, type 6, MIM# 611523 to Pontocerebellar hypoplasia, type 6, MIM# 611523; early onset cerebellar ataxia
Mendeliome v0.4176 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from to Pontocerebellar hypoplasia, type 6, MIM# 611523
Mendeliome v0.4172 RAB3GAP2 Zornitza Stark Gene: rab3gap2 has been classified as Green List (High Evidence).
Mendeliome v0.4169 RAB3GAP1 Zornitza Stark Gene: rab3gap1 has been classified as Green List (High Evidence).
Mendeliome v0.4166 RAB18 Zornitza Stark Gene: rab18 has been classified as Green List (High Evidence).
Mendeliome v0.4163 PTPN23 Zornitza Stark Gene: ptpn23 has been classified as Green List (High Evidence).
Mendeliome v0.4160 PRUNE1 Zornitza Stark Gene: prune1 has been classified as Green List (High Evidence).
Mendeliome v0.4157 POGZ Zornitza Stark Gene: pogz has been classified as Green List (High Evidence).
Mendeliome v0.4154 POC1A Zornitza Stark Gene: poc1a has been classified as Green List (High Evidence).
Mendeliome v0.4154 POC1A Zornitza Stark Phenotypes for gene: POC1A were changed from to Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, MIM# 614813
Mendeliome v0.4151 POC1A Zornitza Stark reviewed gene: POC1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22840364, 22840363, 26374189, 26162852, 26791357; Phenotypes: Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, MIM# 614813; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4151 PLK4 Zornitza Stark Gene: plk4 has been classified as Green List (High Evidence).
Mendeliome v0.4151 PLK4 Zornitza Stark Phenotypes for gene: PLK4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171
Mendeliome v0.4148 PLK4 Zornitza Stark reviewed gene: PLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25344692, 25320347, 27650967; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4148 PIGH Zornitza Stark Gene: pigh has been classified as Green List (High Evidence).
Mendeliome v0.4148 PIGH Zornitza Stark Phenotypes for gene: PIGH were changed from to Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010
Mendeliome v0.4145 PIGH Zornitza Stark reviewed gene: PIGH: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573052, 29603516; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4145 PCYT2 Zornitza Stark Gene: pcyt2 has been classified as Green List (High Evidence).
Mendeliome v0.4145 PCYT2 Zornitza Stark Phenotypes for gene: PCYT2 were changed from to Spastic paraplegia 82, autosomal recessive 618770; global developmental delay; regression; spastic parapesis or tetraparesis; epilepsy; progressive cerebral and cerebellar atrophy
Mendeliome v0.4143 PCYT2 Zornitza Stark reviewed gene: PCYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31637422; Phenotypes: Spastic paraplegia 82, autosomal recessive 618770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4143 TRAPPC2L Zornitza Stark Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4143 TRAPPC2L Zornitza Stark Classified gene: TRAPPC2L as Amber List (moderate evidence)
Mendeliome v0.4143 TRAPPC2L Zornitza Stark Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4141 TIMM8A Zornitza Stark Gene: timm8a has been classified as Green List (High Evidence).
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Red List (Low Evidence).
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Classified gene: TOGARAM1 as Red List (low evidence)
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Red List (Low Evidence).
Mendeliome v0.4138 DPP6 Zornitza Stark Gene: dpp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4135 DPP6 Zornitza Stark Classified gene: DPP6 as Amber List (moderate evidence)
Mendeliome v0.4135 DPP6 Zornitza Stark Gene: dpp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4134 TRAPPC2L Arina Puzriakova changed review comment from: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature; to: Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Amber as additional cases required to delineate the genotype-phenotype relationship.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.

Sources: Literature
Mendeliome v0.4134 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Mendeliome v0.4134 TOGARAM1 Arina Puzriakova gene: TOGARAM1 was added
gene: TOGARAM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439
Phenotypes for gene: TOGARAM1 were set to Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus
Added comment: PMID: 32747439 (2020) - Novel gene-disease association. In two sibling fetuses with a malformation disorder characterised by microcephaly, severe cleft lip and palate, microphthalmia, and brain anomalies, WES revealed compound heterozygous variants ([c.1102C>T, p.Arg368Trp] and [c.3619C>T, p.Arg1207*]) in the TOGARAM1 gene.

Functional analysis of the missense variant in a C. elegans model showed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. In vitro analysis revealed faster microtubule polymerisation compared to wild-type, suggesting aberrant tubulin binding.
Sources: Literature
Mendeliome v0.4134 PCGF2 Zornitza Stark Gene: pcgf2 has been classified as Green List (High Evidence).
Mendeliome v0.4131 TRIT1 Zornitza Stark Gene: trit1 has been classified as Green List (High Evidence).
Mendeliome v0.4128 CRIPT Zornitza Stark Gene: cript has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4128 CRIPT Zornitza Stark Classified gene: CRIPT as Amber List (moderate evidence)
Mendeliome v0.4128 CRIPT Zornitza Stark Gene: cript has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4125 CRIPT Ain Roesley gene: CRIPT was added
gene: CRIPT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRIPT were set to 24389050; 27250922
Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies (MIM#615789)
Penetrance for gene: CRIPT were set to unknown
Review for gene: CRIPT was set to AMBER
Added comment: PMID: 24389050
- 2 unrelated probands homozygous for PTVs. However 1 was deceased and DNA was unavailable therefore parents were sequenced

PMID: 27250922
- 1x proband
- het for a missense which was maternally inherited. Because the father was negative for SNVs, they did CMA and found a small heterozygous deletion 1.6kb in size encompassing exon 1 of CRIPT. This deletion was paternally inherited

*did not find new reports since
Sources: Literature
Mendeliome v0.4125 DIAPH1 Zornitza Stark Gene: diaph1 has been classified as Green List (High Evidence).
Mendeliome v0.4123 UFC1 Seb Lunke Gene: ufc1 has been classified as Green List (High Evidence).
Mendeliome v0.4122 UFC1 Seb Lunke Classified gene: UFC1 as Green List (high evidence)
Mendeliome v0.4122 UFC1 Seb Lunke Gene: ufc1 has been classified as Green List (High Evidence).
Mendeliome v0.4121 UFC1 Paul De Fazio gene: UFC1 was added
gene: UFC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFC1 were set to 29868776; 30552426
Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth (MIM#618076)
Review for gene: UFC1 was set to GREEN
gene: UFC1 was marked as current diagnostic
Added comment: PMID 29868776: 8 affected individuals from 4 families reported. 7 were described to be postnatally microcephalic (at or below 3rd percentile). One was -5.1SD and one was -3.6SD. SD values for the others weren't provided.

The following head circumference measurements were provided for 6 of the affecteds:

51cm at 16yo; 50cm at 19yo; 42.5cm at 12mo, 45cm at 28mo, 45.2cm at 7yo; 45cm at 4yo.

3 of the families were consanguineous Saudi families with the same homozygous missense variant.

In vitro functional expression studies showed that both mutations caused impaired thioester binding with UFM1. Patient cells also showed decreased UFC1 intermediate formation with UFM1. The decrease in function was consistent with a hypomorphic allele, and the authors suggested that complete loss of function would be embryonic lethal.

PMID 30552426: 1 more individual with epileptic encephalopathy reported with a different homozygous missense variant in UFC1. The patient had microcephaly <3rd percentile.
Sources: Literature
Mendeliome v0.4121 CENPE Seb Lunke Gene: cenpe has been classified as Red List (Low Evidence).
Mendeliome v0.4121 CENPE Seb Lunke Phenotypes for gene: CENPE were changed from to Microcephaly 13, primary, autosomal recessive (MIM#616051)
Mendeliome v0.4118 CENPE Seb Lunke Classified gene: CENPE as Red List (low evidence)
Mendeliome v0.4118 CENPE Seb Lunke Gene: cenpe has been classified as Red List (Low Evidence).
Mendeliome v0.4117 CENPE Ain Roesley reviewed gene: CENPE: Rating: RED; Mode of pathogenicity: None; Publications: 24748105, 30086807; Phenotypes: Microcephaly 13, primary, autosomal recessive (MIM#616051); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4117 CDC6 Seb Lunke Gene: cdc6 has been classified as Red List (Low Evidence).
Mendeliome v0.4114 CDC6 Seb Lunke Classified gene: CDC6 as Red List (low evidence)
Mendeliome v0.4114 CDC6 Seb Lunke Gene: cdc6 has been classified as Red List (Low Evidence).
Mendeliome v0.4113 CTNND1 Zornitza Stark Gene: ctnnd1 has been classified as Green List (High Evidence).
Mendeliome v0.4109 RIPOR2 Zornitza Stark Phenotypes for gene: RIPOR2 were changed from Deafness, autosomal recessive 104, MIM# 616515 to Deafness, autosomal recessive 104, MIM# 616515; Deafness, autosomal dominant
Mendeliome v0.4108 RIPOR2 Zornitza Stark changed review comment from: Single family and animal model data.
Sources: Expert list; to: Single family with bi-allelic variants and animal model data.
Sources: Expert list
Mendeliome v0.4108 RIPOR2 Zornitza Stark Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4106 NOTCH3 Zornitza Stark Classified gene: NOTCH3 as No list
Mendeliome v0.4102 ZFYVE19 Zornitza Stark Gene: zfyve19 has been classified as Green List (High Evidence).
Mendeliome v0.4102 ZFYVE19 Zornitza Stark Classified gene: ZFYVE19 as Green List (high evidence)
Mendeliome v0.4102 ZFYVE19 Zornitza Stark Gene: zfyve19 has been classified as Green List (High Evidence).
Mendeliome v0.4101 TRPM7 Zornitza Stark Phenotypes for gene: TRPM7 were changed from {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500 to {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500; Cardiac arrhythmia, stillbirth
Mendeliome v0.4098 TRPM7 Zornitza Stark Classified gene: TRPM7 as Amber List (moderate evidence)
Mendeliome v0.4098 TRPM7 Zornitza Stark Gene: trpm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4097 TRPM7 Zornitza Stark edited their review of gene: TRPM7: Added comment: Ion channel expressed in the nervous and cardiac systems. The variant associated with ALS/dementia in the Guam population, p.Thr1482Ile is present in >23,000 hets in gnomad, which is out of keeping for a rare Mendelian disorder. Note recent publication associating missense variants with cardiac arrhythmia and stillbirth, with some functional data provided to substantiate effect of variant on protein function but not necessarily establish gene-disease association.; Changed rating: AMBER; Changed publications: 32503408, 31423533; Changed phenotypes: {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500, Cardiac arrhythmia, stillbirth; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4097 CHCHD10 Zornitza Stark Gene: chchd10 has been classified as Green List (High Evidence).
Mendeliome v0.4097 CHCHD10 Zornitza Stark Phenotypes for gene: CHCHD10 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911; Spinal muscular atrophy, Jokela type 615048; Myopathy, isolated mitochondrial, autosomal dominant 616209
Mendeliome v0.4093 CHCHD10 Zornitza Stark reviewed gene: CHCHD10: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24934289, 25428574, 25193783, 32042922, 31690696, 30877432, 30874923; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911, Spinal muscular atrophy, Jokela type 615048, Myopathy, isolated mitochondrial, autosomal dominant 616209; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4091 NOTCH3 Eleanor Williams gene: NOTCH3 was added
gene: NOTCH3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NOTCH3 were set to 31960911
Phenotypes for gene: NOTCH3 were set to CADASIL
Review for gene: NOTCH3 was set to AMBER
Added comment: PMID: 31960911 - Gravesteijn et al 2020 - describe a family with a unique cysteine-altering NOTCH3 variant in exon 9 in 5 individuals, which is predicted to cause natural exon 9 skipping. This mimics the therapeutic NOTCH3 cysteine correction approach and allows the effect of cysteine corrective exon skipping on NOTCH3 protein aggregation and disease severity in humans to be studied. In this family the CADASIL phenotype was mild.

Note this gene is rated green on the Neurodegenerative disorders - adult onset panel in the Genomics England instance of PanelApp https://panelapp.genomicsengland.co.uk/panels/474/gene/NOTCH3/
Sources: Literature
Mendeliome v0.4091 TRPM7 Eleanor Williams commented on gene: TRPM7: PMID: 31423533 - Cartwright et al 2020 - functional studies on four heterozygous nonsynonymous variants that were observed in TRPM7 in four individual cases of unexplained still birth which were screened for variants in 35 candidate genes in PMID: 29874177 (Munroe et al 2018). TRPM7 is a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. They found two variants in TRPM7, p.G179V and p.T860M, reduce ion channel current expression, which in the case of p.T860M is likely due to rapid degradation mediated by the proteasome. In addition, the p.R494Q TRPM7 variant significantly increases TRPM7 ion channel current, in a cell-type specific manner. They believe that TRPM7 may play a key role in ensuring correct cardiac development of the fetus.
Mendeliome v0.4091 ZFYVE19 Arina Puzriakova gene: ZFYVE19 was added
gene: ZFYVE19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFYVE19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE19 were set to 32737136
Phenotypes for gene: ZFYVE19 were set to Cholestasis
Review for gene: ZFYVE19 was set to GREEN
Added comment: PMID: 32737136 (2020) - Nine Han Chinese children from seven families with biallelic, predicted complete LoF variants in ZFYVE19. All patients had high-GGT intrahepatic cholestasis, portal hypertension, and histopathological features of the ductal plate malformation/congenital hepatic fibrosis.

ZFYVE19 depletion in cultured cells from one patient yielded centriolar and axonemal abnormalities, and immunostaining for two ciliary proteins DCDC2 and ACALT showed abnormal localisation in patient cholangiocytes, indicating this as a novel ciliopathy disorder.
Sources: Literature
Mendeliome v0.4091 SRD5A3 Zornitza Stark Gene: srd5a3 has been classified as Green List (High Evidence).
Mendeliome v0.4088 KIF14 Zornitza Stark Gene: kif14 has been classified as Green List (High Evidence).
Mendeliome v0.4088 KIF14 Zornitza Stark Phenotypes for gene: KIF14 were changed from to Microcephaly 20, primary, autosomal recessive, MIM# 617914; Meckel syndrome 12, MIM# 616258
Mendeliome v0.4085 KIF14 Zornitza Stark reviewed gene: KIF14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28892560, 29343805, 24128419; Phenotypes: Microcephaly 20, primary, autosomal recessive, MIM# 617914, Meckel syndrome 12, MIM# 616258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4085 KIF1BP Zornitza Stark Gene: kif1bp has been classified as Green List (High Evidence).
Mendeliome v0.4082 TRIP11 Zornitza Stark Gene: trip11 has been classified as Green List (High Evidence).
Mendeliome v0.4082 TRIP11 Zornitza Stark Phenotypes for gene: TRIP11 were changed from to Osteochondrodysplasia, 184260; Achondrogenesis, type IA, 200600
Mendeliome v0.4079 PRF1 Zornitza Stark Gene: prf1 has been classified as Green List (High Evidence).
Mendeliome v0.4079 PRF1 Zornitza Stark Phenotypes for gene: PRF1 were changed from to Aplastic anemia 609135; Hemophagocytic lymphohistiocytosis, familial, 2 603553; Lymphoma, non-Hodgkin 605027
Mendeliome v0.4076 HLCS Zornitza Stark Gene: hlcs has been classified as Green List (High Evidence).
Mendeliome v0.4073 CA5A Zornitza Stark Gene: ca5a has been classified as Green List (High Evidence).
Mendeliome v0.4067 OSR1 Zornitza Stark Gene: osr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4067 OSR1 Zornitza Stark Classified gene: OSR1 as Red List (low evidence)
Mendeliome v0.4067 OSR1 Zornitza Stark Gene: osr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4066 KDM1A Zornitza Stark Gene: kdm1a has been classified as Green List (High Evidence).
Mendeliome v0.4063 TRIP11 Elena Savva reviewed gene: TRIP11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31903676, 30728324; Phenotypes: Osteochondrodysplasia, 184260, Achondrogenesis, type IA, 200600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4063 COL11A1 Zornitza Stark Gene: col11a1 has been classified as Green List (High Evidence).
Mendeliome v0.4063 COL11A1 Zornitza Stark Phenotypes for gene: COL11A1 were changed from to Fibrochondrogenesis 1 (MIM#228520); Marshall syndrome (MIM#154780); Stickler syndrome, type II (MIM#604841)
Mendeliome v0.4061 PRF1 Elena Savva reviewed gene: PRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19487666; Phenotypes: Aplastic anemia 609135, Hemophagocytic lymphohistiocytosis, familial, 2 603553, Lymphoma, non-Hodgkin 605027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4059 COL11A1 Elena Savva reviewed gene: COL11A1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 25073711, 30245514, 32427345, 27081569, 21035103; Phenotypes: Fibrochondrogenesis 1 (MIM#228520), Marshall syndrome (MIM#154780), Stickler syndrome, type II (MIM#604841), {Lumbar disc herniation, susceptibility to}, (MIM#603932), ?Deafness, autosomal dominant 37, (MIM#618533); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4059 YRDC Zornitza Stark Gene: yrdc has been classified as Green List (High Evidence).
Mendeliome v0.4059 YRDC Zornitza Stark Classified gene: YRDC as Green List (high evidence)
Mendeliome v0.4059 YRDC Zornitza Stark Gene: yrdc has been classified as Green List (High Evidence).
Mendeliome v0.4057 GON7 Zornitza Stark Gene: gon7 has been classified as Green List (High Evidence).
Mendeliome v0.4057 GON7 Zornitza Stark Classified gene: GON7 as Green List (high evidence)
Mendeliome v0.4057 GON7 Zornitza Stark Gene: gon7 has been classified as Green List (High Evidence).
Mendeliome v0.4055 LAGE3 Zornitza Stark Gene: lage3 has been classified as Green List (High Evidence).
Mendeliome v0.4052 LINGO1 Zornitza Stark Gene: lingo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4052 LINGO1 Zornitza Stark Phenotypes for gene: LINGO1 were changed from to Mental retardation, autosomal recessive 64, MIM# 618103
Mendeliome v0.4049 LINGO1 Zornitza Stark Classified gene: LINGO1 as Amber List (moderate evidence)
Mendeliome v0.4049 LINGO1 Zornitza Stark Gene: lingo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4048 LINGO1 Zornitza Stark reviewed gene: LINGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31668702; Phenotypes: Mental retardation, autosomal recessive 64, MIM# 618103; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4048 OSGEP Zornitza Stark Gene: osgep has been classified as Green List (High Evidence).
Mendeliome v0.4045 NUP107 Zornitza Stark Gene: nup107 has been classified as Green List (High Evidence).
Mendeliome v0.4042 NSD2 Zornitza Stark Gene: nsd2 has been classified as Green List (High Evidence).
Mendeliome v0.4039 NSD2 Zornitza Stark changed review comment from: Microcephaly reported in 6 of 7 individuals with LOF variants in this gene.; to: 7 individuals with LOF variants in this gene, gene thought to be responsible for key features of Wolf-Hirschorn syndrome.
Mendeliome v0.4039 NCAPH Zornitza Stark Gene: ncaph has been classified as Red List (Low Evidence).
Mendeliome v0.4039 NCAPH Zornitza Stark Phenotypes for gene: NCAPH were changed from to Microcephaly 23, primary, autosomal recessive 617985
Mendeliome v0.4036 NCAPH Zornitza Stark Classified gene: NCAPH as Red List (low evidence)
Mendeliome v0.4036 NCAPH Zornitza Stark Gene: ncaph has been classified as Red List (Low Evidence).
Mendeliome v0.4035 NCAPH Zornitza Stark reviewed gene: NCAPH: Rating: RED; Mode of pathogenicity: None; Publications: 27737959; Phenotypes: Microcephaly 23, primary, autosomal recessive 617985; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4035 ATRIP Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence).
Mendeliome v0.4035 ATRIP Zornitza Stark Classified gene: ATRIP as Red List (low evidence)
Mendeliome v0.4035 ATRIP Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence).
Mendeliome v0.4034 ATRIP Ain Roesley gene: ATRIP was added
gene: ATRIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATRIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATRIP were set to 23144622
Phenotypes for gene: ATRIP were set to Seckel Syndrome
Penetrance for gene: ATRIP were set to unknown
Review for gene: ATRIP was set to RED
Added comment: PMID: 23144622;
- 1x proband from a consanguineous family
- progressive severe microcephaly (-9 to -10SD)
- cHet for a nonsense and a splice
Sources: Literature
Mendeliome v0.4034 AP4E1 Zornitza Stark Gene: ap4e1 has been classified as Green List (High Evidence).
Mendeliome v0.4034 AP4E1 Zornitza Stark Phenotypes for gene: AP4E1 were changed from to Spastic paraplegia 51, autosomal recessive, MIM# 613744
Mendeliome v0.4031 AP4E1 Zornitza Stark reviewed gene: AP4E1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20972249, 21620353, 21937992; Phenotypes: Spastic paraplegia 51, autosomal recessive, MIM# 613744; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4031 AP4B1 Zornitza Stark Gene: ap4b1 has been classified as Green List (High Evidence).
Mendeliome v0.4031 AP4B1 Zornitza Stark Phenotypes for gene: AP4B1 were changed from to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Mendeliome v0.4028 AP4B1 Zornitza Stark reviewed gene: AP4B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 22290197, 24700674, 24781758; Phenotypes: Spastic paraplegia 47, autosomal recessive, MIM# 614066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4028 ANKLE2 Zornitza Stark reviewed gene: ANKLE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25259927, 30214071, 31735666; Phenotypes: Microcephaly 16, primary, autosomal recessive, MIM# 616681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4028 TSEN2 Zornitza Stark Gene: tsen2 has been classified as Green List (High Evidence).
Mendeliome v0.4028 TSEN2 Zornitza Stark Phenotypes for gene: TSEN2 were changed from to Pontocerebellar hypoplasia type 2B, MIM# 612389
Mendeliome v0.4025 TSEN2 Zornitza Stark edited their review of gene: TSEN2: Added comment: At least 3 unrelated families reported.; Changed rating: GREEN; Changed publications: 23562994, 20952379; Changed phenotypes: Pontocerebellar hypoplasia type 2B, MIM# 612389
Mendeliome v0.4025 ZSWIM6 Zornitza Stark Gene: zswim6 has been classified as Green List (High Evidence).
Mendeliome v0.4025 ZSWIM6 Zornitza Stark Phenotypes for gene: ZSWIM6 were changed from to Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features, MIM# 617865; Acromelic frontonasal dysostosis, MIM# 603671
Mendeliome v0.4022 ZSWIM6 Zornitza Stark reviewed gene: ZSWIM6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29198722, 25105228, 26706854; Phenotypes: Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features, MIM# 617865, Acromelic frontonasal dysostosis, MIM# 603671; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4022 ABCB11 Zornitza Stark Gene: abcb11 has been classified as Green List (High Evidence).
Mendeliome v0.4022 ABCB11 Zornitza Stark Phenotypes for gene: ABCB11 were changed from to Cholestasis, progressive familial intrahepatic 2, MIM# 601847; Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479
Mendeliome v0.4019 ABCB11 Zornitza Stark reviewed gene: ABCB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 16871584, 23141890, 9806540, 15300568, 11172067; Phenotypes: Cholestasis, progressive familial intrahepatic 2, MIM# 601847, Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4019 ABCB1 Zornitza Stark Gene: abcb1 has been classified as Red List (Low Evidence).
Mendeliome v0.4016 ABCB1 Zornitza Stark Classified gene: ABCB1 as Red List (low evidence)
Mendeliome v0.4016 ABCB1 Zornitza Stark Gene: abcb1 has been classified as Red List (Low Evidence).
Mendeliome v0.4015 ABCA3 Zornitza Stark Gene: abca3 has been classified as Green List (High Evidence).
Mendeliome v0.4012 ABCA12 Zornitza Stark Gene: abca12 has been classified as Green List (High Evidence).
Mendeliome v0.4012 ABCA12 Zornitza Stark Phenotypes for gene: ABCA12 were changed from to Ichthyosis, congenital, autosomal recessive 4A (MIM#601277); Ichthyosis, congenital, autosomal recessive 4B (harlequin) (MIM#242500)
Mendeliome v0.4009 ABCA12 Zornitza Stark reviewed gene: ABCA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31168818, 19664001, 31489029; Phenotypes: Ichthyosis, congenital, autosomal recessive 4A (MIM#601277), Ichthyosis, congenital, autosomal recessive 4B (harlequin) (MIM#242500); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4006 AASS Zornitza Stark Gene: aass has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4006 AASS Zornitza Stark Phenotypes for gene: AASS were changed from to Hyperlysinemia, MIM# 238700
Mendeliome v0.4003 AASS Zornitza Stark Classified gene: AASS as Amber List (moderate evidence)
Mendeliome v0.4003 AASS Zornitza Stark Gene: aass has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4002 AASS Zornitza Stark changed review comment from: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. Hyperlysinemia is generally considered to be a benign metabolic variant rather than a disease entity.; to: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity.
Mendeliome v0.4002 AASS Zornitza Stark reviewed gene: AASS: Rating: RED; Mode of pathogenicity: None; Publications: 23570448; Phenotypes: Hyperlysinemia, MIM# 238700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4002 AARS2 Zornitza Stark Gene: aars2 has been classified as Green List (High Evidence).
Mendeliome v0.4002 AARS2 Zornitza Stark Phenotypes for gene: AARS2 were changed from to Combined oxidative phosphorylation deficiency 8 MIM#614096; Leukoencephalopathy, progressive, with ovarian failure MIM#615889; MONDO:0013570
Mendeliome v0.3999 AARS2 Zornitza Stark edited their review of gene: AARS2: Changed phenotypes: Combined oxidative phosphorylation deficiency 8 MIM#614096, Leukoencephalopathy, progressive, with ovarian failure MIM#615889, MONDO:0013570
Mendeliome v0.3999 AARS2 Zornitza Stark reviewed gene: AARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30706699, 27839525, 21549344, 25058219, 24808023; Phenotypes: Combined oxidative phosphorylation deficiency 8 MIM#614096, Leukoencephalopathy, progressive, with ovarian failure MIM#615889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3999 AARS Zornitza Stark Gene: aars has been classified as Green List (High Evidence).
Mendeliome v0.3996 AAGAB Zornitza Stark Gene: aagab has been classified as Green List (High Evidence).
Mendeliome v0.3993 A4GALT Zornitza Stark Gene: a4galt has been classified as Red List (Low Evidence).
Mendeliome v0.3992 A4GALT Zornitza Stark Classified gene: A4GALT as Red List (low evidence)
Mendeliome v0.3992 A4GALT Zornitza Stark Gene: a4galt has been classified as Red List (Low Evidence).
Mendeliome v0.3991 PAFAH1B1 Zornitza Stark Gene: pafah1b1 has been classified as Green List (High Evidence).
Mendeliome v0.3988 LAMB1 Zornitza Stark Gene: lamb1 has been classified as Green List (High Evidence).
Mendeliome v0.3985 TMEM5 Zornitza Stark Gene: tmem5 has been classified as Green List (High Evidence).
Mendeliome v0.3982 KIF5C Zornitza Stark Gene: kif5c has been classified as Green List (High Evidence).
Mendeliome v0.3982 KIF5C Zornitza Stark Phenotypes for gene: KIF5C were changed from to Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282
Mendeliome v0.3979 KIF5C Zornitza Stark reviewed gene: KIF5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 23033978, 32562872; Phenotypes: Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3979 KIF2A Zornitza Stark Gene: kif2a has been classified as Green List (High Evidence).
Mendeliome v0.3979 KIF2A Zornitza Stark Phenotypes for gene: KIF2A were changed from to Cortical dysplasia, complex, with other brain malformations 3, MIM# 615411
Mendeliome v0.3976 KIF2A Zornitza Stark reviewed gene: KIF2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 27896282, 27747449, 29077851, 31919497; Phenotypes: Cortical dysplasia, complex, with other brain malformations 3, MIM# 615411; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3976 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Mendeliome v0.3973 DCX Zornitza Stark Gene: dcx has been classified as Green List (High Evidence).
Mendeliome v0.3970 ASPRV1 Zornitza Stark Phenotypes for gene: ASPRV1 were changed from palmoplantar keratoderma; lamellar ichthyosis to Ichthyosis, lamellar, autosomal dominant, MIM# 146750; palmoplantar keratoderma; lamellar ichthyosis
Mendeliome v0.3969 ASPRV1 Zornitza Stark reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis, lamellar, autosomal dominant, MIM# 146750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3969 MRPL44 Zornitza Stark Gene: mrpl44 has been classified as Green List (High Evidence).
Mendeliome v0.3966 KBTBD13 Zornitza Stark Gene: kbtbd13 has been classified as Green List (High Evidence).
Mendeliome v0.3962 NDUFA13 Zornitza Stark Classified gene: NDUFA13 as Amber List (moderate evidence)
Mendeliome v0.3962 NDUFA13 Zornitza Stark Gene: ndufa13 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3961 LAMA2 Zornitza Stark Gene: lama2 has been classified as Green List (High Evidence).
Mendeliome v0.3961 LAMA2 Zornitza Stark Phenotypes for gene: LAMA2 were changed from to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855; Muscular dystrophy, limb-girdle, autosomal recessive 23, MIM# 618138
Mendeliome v0.3958 LAMA2 Zornitza Stark reviewed gene: LAMA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30055037; Phenotypes: Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855, Muscular dystrophy, limb-girdle, autosomal recessive 23, MIM# 618138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3958 GRIN2B Zornitza Stark Gene: grin2b has been classified as Green List (High Evidence).
Mendeliome v0.3955 GRIN1 Zornitza Stark Gene: grin1 has been classified as Green List (High Evidence).
Mendeliome v0.3955 GRIN1 Zornitza Stark Phenotypes for gene: GRIN1 were changed from to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Mendeliome v0.3952 GRIN1 Zornitza Stark reviewed gene: GRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29365063, 27164704, 27164704, 28051072; Phenotypes: Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254, Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3952 BCLAF1 Zornitza Stark Gene: bclaf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3952 BCLAF1 Zornitza Stark Classified gene: BCLAF1 as Red List (low evidence)
Mendeliome v0.3952 BCLAF1 Zornitza Stark Gene: bclaf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3951 ALG12 Zornitza Stark Gene: alg12 has been classified as Green List (High Evidence).
Mendeliome v0.3950 SEC61A1 Zornitza Stark Gene: sec61a1 has been classified as Green List (High Evidence).
Mendeliome v0.3945 ALG11 Zornitza Stark Gene: alg11 has been classified as Green List (High Evidence).
Mendeliome v0.3942 NPRL2 Zornitza Stark Gene: nprl2 has been classified as Green List (High Evidence).
Mendeliome v0.3942 NPRL2 Zornitza Stark Phenotypes for gene: NPRL2 were changed from to Epilepsy, familial focal, with variable foci 2, MIM# 617116; focal seizures; frontal lobe epilepsy; nocturnal frontal lobe epilepsy; temporal lobe epilepsy; focal cortical dysplasia
Mendeliome v0.3939 NPRL2 Dean Phelan reviewed gene: NPRL2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26505888, 27173016, 28199897, 31594065; Phenotypes: focal seizures, frontal lobe epilepsy, nocturnal frontal lobe epilepsy, temporal lobe epilepsy, focal cortical dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3939 PDE2A Zornitza Stark Gene: pde2a has been classified as Green List (High Evidence).
Mendeliome v0.3939 PDE2A Zornitza Stark Classified gene: PDE2A as Green List (high evidence)
Mendeliome v0.3939 PDE2A Zornitza Stark Gene: pde2a has been classified as Green List (High Evidence).
Mendeliome v0.3938 PDE2A Zornitza Stark gene: PDE2A was added
gene: PDE2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE2A were set to 32467598; 32196122; 29392776
Phenotypes for gene: PDE2A were set to Paroxysmal dyskinesia
Review for gene: PDE2A was set to GREEN
Added comment: Four unrelated families reported with childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy. One of the reports characterises the disorder as 'Rett-like'.
Sources: Literature
Mendeliome v0.3937 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
Mendeliome v0.3937 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099
Mendeliome v0.3934 OTULIN Zornitza Stark reviewed gene: OTULIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 27523608, 27559085; Phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3933 RRAGC Zornitza Stark Gene: rragc has been classified as Red List (Low Evidence).
Mendeliome v0.3931 RRAGC Zornitza Stark Classified gene: RRAGC as Red List (low evidence)
Mendeliome v0.3931 RRAGC Zornitza Stark Gene: rragc has been classified as Red List (Low Evidence).
Mendeliome v0.3930 RANBP17 Zornitza Stark Gene: ranbp17 has been classified as Red List (Low Evidence).
Mendeliome v0.3930 RANBP17 Zornitza Stark Classified gene: RANBP17 as Red List (low evidence)
Mendeliome v0.3930 RANBP17 Zornitza Stark Gene: ranbp17 has been classified as Red List (Low Evidence).
Mendeliome v0.3929 MICA Zornitza Stark Gene: mica has been classified as Red List (Low Evidence).
Mendeliome v0.3929 MICA Zornitza Stark Classified gene: MICA as Red List (low evidence)
Mendeliome v0.3929 MICA Zornitza Stark Gene: mica has been classified as Red List (Low Evidence).
Mendeliome v0.3928 CRADD Zornitza Stark Gene: cradd has been classified as Green List (High Evidence).
Mendeliome v0.3928 CRADD Zornitza Stark Phenotypes for gene: CRADD were changed from to Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499
Mendeliome v0.3925 CRADD Zornitza Stark reviewed gene: CRADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27773430; Phenotypes: Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3925 TDGF1 Zornitza Stark Gene: tdgf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3922 TDGF1 Zornitza Stark Classified gene: TDGF1 as Red List (low evidence)
Mendeliome v0.3922 TDGF1 Zornitza Stark Gene: tdgf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3921 GABRA6 Zornitza Stark Gene: gabra6 has been classified as Red List (Low Evidence).
Mendeliome v0.3920 TMTC3 Zornitza Stark Gene: tmtc3 has been classified as Green List (High Evidence).
Mendeliome v0.3917 ARFGEF2 Zornitza Stark Gene: arfgef2 has been classified as Green List (High Evidence).
Mendeliome v0.3914 SLC6A3 Zornitza Stark Gene: slc6a3 has been classified as Green List (High Evidence).
Mendeliome v0.3911 MAOA Zornitza Stark Gene: maoa has been classified as Green List (High Evidence).
Mendeliome v0.3905 GLRB Zornitza Stark Gene: glrb has been classified as Green List (High Evidence).
Mendeliome v0.3901 GLRA1 Zornitza Stark Gene: glra1 has been classified as Green List (High Evidence).
Mendeliome v0.3898 GABRG2 Zornitza Stark Gene: gabrg2 has been classified as Green List (High Evidence).
Mendeliome v0.3895 GABRB3 Zornitza Stark Gene: gabrb3 has been classified as Green List (High Evidence).
Mendeliome v0.3892 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
Mendeliome v0.3889 DBH Zornitza Stark Gene: dbh has been classified as Green List (High Evidence).
Mendeliome v0.3886 ARHGEF9 Zornitza Stark Gene: arhgef9 has been classified as Green List (High Evidence).
Mendeliome v0.3883 STAT5B Zornitza Stark Gene: stat5b has been classified as Green List (High Evidence).
Mendeliome v0.3883 STAT5B Zornitza Stark Phenotypes for gene: STAT5B were changed from to Growth hormone insensitivity with immunodeficiency, MIM# 245590
Mendeliome v0.3879 STAT5B Zornitza Stark reviewed gene: STAT5B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29844444; Phenotypes: Growth hormone insensitivity with immunodeficiency, MIM# 245590; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3879 ALDH5A1 Zornitza Stark Gene: aldh5a1 has been classified as Green List (High Evidence).
Mendeliome v0.3876 ABAT Zornitza Stark Gene: abat has been classified as Green List (High Evidence).
Mendeliome v0.3874 ABAT Zornitza Stark edited their review of gene: ABAT: Added comment: Bi-allelic variants in ABAT are associated with a neurotransmitter disorder. However, there are also reports of families with encephalomyopathic MDS caused by bi-allelic variants in ABAT resulting in elevated GABA in subjects' brains as well as decreased mtDNA levels in subjects' fibroblasts. Nucleoside rescue and co-IP experiments demonstrate that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Unclear whether this a distinct disorder or part of a continuum caused by the enzyme being part of two pathways.; Changed publications: 25738457, 27903293, 28411234, 27596361, 20052547, 10407778, 6148708; Changed phenotypes: GABA-transaminase deficiency, MIM# 613163, mtDNA depletion syndrome (MDS)
Mendeliome v0.3873 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Mendeliome v0.3873 LMBRD2 Zornitza Stark Classified gene: LMBRD2 as Green List (high evidence)
Mendeliome v0.3873 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Mendeliome v0.3872 LMBRD2 Zornitza Stark gene: LMBRD2 was added
gene: LMBRD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to GREEN
Added comment: 13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies.

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants. Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific). All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity. 5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect. There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H). The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely. As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation. It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Mendeliome v0.3867 KAT5 Zornitza Stark Classified gene: KAT5 as Green List (high evidence)
Mendeliome v0.3867 KAT5 Zornitza Stark Gene: kat5 has been classified as Green List (High Evidence).
Mendeliome v0.3866 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Green List (High Evidence).
Mendeliome v0.3866 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from to Spastic ataxia 5, autosomal recessive (MIM#614487); Spinocerebellar ataxia 28 (MIM#610246); Optic atrophy 12, MIM# 618977
Mendeliome v0.3863 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29181157, 26539208, 30252181, 30389403, 32219868, 32600459, 32548275; Phenotypes: Spastic ataxia 5, autosomal recessive (MIM#614487), Spinocerebellar ataxia 28 (MIM#610246), Optic atrophy 12, MIM# 618977; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3863 MYOD1 Zornitza Stark Gene: myod1 has been classified as Green List (High Evidence).
Mendeliome v0.3863 MYOD1 Zornitza Stark Classified gene: MYOD1 as Green List (high evidence)
Mendeliome v0.3863 MYOD1 Zornitza Stark Gene: myod1 has been classified as Green List (High Evidence).
Mendeliome v0.3861 TMEM237 Zornitza Stark Gene: tmem237 has been classified as Green List (High Evidence).
Mendeliome v0.3859 NOD2 Zornitza Stark Gene: nod2 has been classified as Green List (High Evidence).
Mendeliome v0.3856 PAX3 Zornitza Stark Gene: pax3 has been classified as Green List (High Evidence).
Mendeliome v0.3850 ESRRB Zornitza Stark Gene: esrrb has been classified as Green List (High Evidence).
Mendeliome v0.3850 ESRRB Zornitza Stark Phenotypes for gene: ESRRB were changed from to Deafness, autosomal recessive 35, MIM#608565
Mendeliome v0.3847 ESRRB Zornitza Stark reviewed gene: ESRRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 18179891, 31389194, 32681043; Phenotypes: Deafness, autosomal recessive 35, MIM#608565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3847 HNRNPA2B1 Zornitza Stark Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3847 HNRNPA2B1 Zornitza Stark Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Mendeliome v0.3847 HNRNPA2B1 Zornitza Stark Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3846 HNRNPA2B1 Zornitza Stark gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPA2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPA2B1 were set to 23455423; 30279180; 29358076; 26744327; 23635965
Phenotypes for gene: HNRNPA2B1 were set to Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422
Review for gene: HNRNPA2B1 was set to AMBER
Added comment: One family reported that segregates cognitive impairment as part of the phenotype, and extensive functional analysis of protein, including a drosophila model.
Sources: Literature
Mendeliome v0.3845 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3845 PSMC3 Zornitza Stark Classified gene: PSMC3 as Amber List (moderate evidence)
Mendeliome v0.3845 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3844 PSMC3 Zornitza Stark gene: PSMC3 was added
gene: PSMC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to Deafness; cataract
Review for gene: PSMC3 was set to AMBER
Added comment: Three affected individuals from a single consanguineous family reported with homozygous intronic variant. Animal model.
Sources: Literature
Mendeliome v0.3843 SOS2 Zornitza Stark Gene: sos2 has been classified as Green List (High Evidence).
Mendeliome v0.3838 RAI1 Zornitza Stark Gene: rai1 has been classified as Green List (High Evidence).
Mendeliome v0.3835 TAF1C Zornitza Stark Gene: taf1c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3835 TAF1C Zornitza Stark Classified gene: TAF1C as Amber List (moderate evidence)
Mendeliome v0.3835 TAF1C Zornitza Stark Gene: taf1c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3834 TAF1C Zornitza Stark gene: TAF1C was added
gene: TAF1C was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants. Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual). Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1). The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele. TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit. RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs). A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data). The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).
Sources: Expert list
Mendeliome v0.3833 KALRN Zornitza Stark Gene: kalrn has been classified as Red List (Low Evidence).
Mendeliome v0.3830 KALRN Zornitza Stark Classified gene: KALRN as Red List (low evidence)
Mendeliome v0.3830 KALRN Zornitza Stark Gene: kalrn has been classified as Red List (Low Evidence).
Mendeliome v0.3829 KRT6C Zornitza Stark Gene: krt6c has been classified as Green List (High Evidence).
Mendeliome v0.3826 KRT6B Zornitza Stark Gene: krt6b has been classified as Green List (High Evidence).
Mendeliome v0.3823 KRT2 Zornitza Stark Gene: krt2 has been classified as Green List (High Evidence).
Mendeliome v0.3823 KRT2 Zornitza Stark Phenotypes for gene: KRT2 were changed from to Superficial epidermolytic ichthyosis (SEI) (MIM#146800)
Mendeliome v0.3820 KRT2 Zornitza Stark reviewed gene: KRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26581228, 22612346; Phenotypes: Superficial epidermolytic ichthyosis (SEI) (MIM#146800); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3820 KRT17 Zornitza Stark Gene: krt17 has been classified as Green List (High Evidence).
Mendeliome v0.3817 KRT17 Zornitza Stark changed review comment from: Also known as Jackson-Lawler type, the main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. PMID: 31823354; - cohort of 815 individuals, 134 patients had variants in KRT17 - approx 61.8% presented with palmar keratoderma and approx 82.8% with plantar keratoderma; to: Also known as Jackson-Lawler type, the main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. PMID: 31823354; - cohort of 815 individuals, 134 patients had variants in KRT17 - approx 61.8% presented with palmar keratoderma and approx 82.8% with plantar keratoderma. Steatocystoma multiplex is an allelic disorder.
Mendeliome v0.3817 SERPINB7 Zornitza Stark Gene: serpinb7 has been classified as Green List (High Evidence).
Mendeliome v0.3814 SLURP1 Zornitza Stark Gene: slurp1 has been classified as Green List (High Evidence).
Mendeliome v0.3811 SLURP1 Zornitza Stark changed review comment from: Over 10 families reported with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities.; to: Over 10 families reported with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities. Note single report of manifesting carriers.
Mendeliome v0.3811 ACTN4 Zornitza Stark Gene: actn4 has been classified as Green List (High Evidence).
Mendeliome v0.3811 ACTN4 Zornitza Stark Phenotypes for gene: ACTN4 were changed from to Glomerulosclerosis, focal segmental, 1, MIM#603278
Mendeliome v0.3806 VKORC1 Zornitza Stark reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14765194, 21900891, 28198005; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, MIM# 607473, Warfarin resistance, MIM# 122700; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3806 ACTN4 Elena Savva reviewed gene: ACTN4: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 26740551, 22351778, 10700177, 26301083; Phenotypes: Glomerulosclerosis, focal segmental, 1, 603278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3806 TPM4 Zornitza Stark Gene: tpm4 has been classified as Green List (High Evidence).
Mendeliome v0.3806 TPM4 Zornitza Stark Classified gene: TPM4 as Green List (high evidence)
Mendeliome v0.3806 TPM4 Zornitza Stark Gene: tpm4 has been classified as Green List (High Evidence).
Mendeliome v0.3804 THPO Zornitza Stark Gene: thpo has been classified as Green List (High Evidence).
Mendeliome v0.3799 TBXAS1 Zornitza Stark Gene: tbxas1 has been classified as Green List (High Evidence).
Mendeliome v0.3797 SRC Zornitza Stark Gene: src has been classified as Green List (High Evidence).
Mendeliome v0.3797 SRC Zornitza Stark Classified gene: SRC as Green List (high evidence)
Mendeliome v0.3797 SRC Zornitza Stark Gene: src has been classified as Green List (High Evidence).
Mendeliome v0.3795 SLFN14 Zornitza Stark Gene: slfn14 has been classified as Green List (High Evidence).
Mendeliome v0.3795 SLFN14 Zornitza Stark Classified gene: SLFN14 as Green List (high evidence)
Mendeliome v0.3795 SLFN14 Zornitza Stark Gene: slfn14 has been classified as Green List (High Evidence).
Mendeliome v0.3793 PTPRJ Zornitza Stark Gene: ptprj has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3793 PTPRJ Zornitza Stark Classified gene: PTPRJ as Amber List (moderate evidence)
Mendeliome v0.3793 PTPRJ Zornitza Stark Gene: ptprj has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3792 PTPRJ Zornitza Stark gene: PTPRJ was added
gene: PTPRJ was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PTPRJ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPRJ were set to 30591527
Phenotypes for gene: PTPRJ were set to Thrombocytopaenia
Review for gene: PTPRJ was set to AMBER
Added comment: Two siblings reported with nonsyndromic thrombocytopenia characterised by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. Supportive zebrafish model.
Sources: Expert list
Mendeliome v0.3791 PTGS1 Zornitza Stark Gene: ptgs1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3791 PTGS1 Zornitza Stark Classified gene: PTGS1 as Amber List (moderate evidence)
Mendeliome v0.3791 PTGS1 Zornitza Stark Gene: ptgs1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3790 PTGS1 Zornitza Stark gene: PTGS1 was added
gene: PTGS1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PTGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTGS1 were set to 32299908; 11442478; 27629384; 8562397
Phenotypes for gene: PTGS1 were set to Platelet dysfunction; bleeding
Review for gene: PTGS1 was set to AMBER
Added comment: Single molecularly characterised family reported. However, note at least two previous older reports where deficiency was identified at protein rather than gene level.
Sources: Expert list
Mendeliome v0.3789 PRKACG Zornitza Stark Gene: prkacg has been classified as Red List (Low Evidence).
Mendeliome v0.3789 PRKACG Zornitza Stark gene: PRKACG was added
gene: PRKACG was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PRKACG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRKACG were set to 25061177; 30819905
Phenotypes for gene: PRKACG were set to Bleeding disorder, platelet-type, 19, MIM# 616176
Review for gene: PRKACG was set to RED
Added comment: Single family reported only. A heterozygous VOUS reported in another individual in PMID 30819905 together with several other VOUS in same individual.
Sources: Expert list
Mendeliome v0.3788 PLAU Zornitza Stark Gene: plau has been classified as Green List (High Evidence).
Mendeliome v0.3788 PLAU Zornitza Stark Classified gene: PLAU as Green List (high evidence)
Mendeliome v0.3788 PLAU Zornitza Stark Gene: plau has been classified as Green List (High Evidence).
Mendeliome v0.3786 PLA2G4A Zornitza Stark Gene: pla2g4a has been classified as Green List (High Evidence).
Mendeliome v0.3786 PLA2G4A Zornitza Stark Classified gene: PLA2G4A as Green List (high evidence)
Mendeliome v0.3786 PLA2G4A Zornitza Stark Gene: pla2g4a has been classified as Green List (High Evidence).
Mendeliome v0.3784 MPIG6B Zornitza Stark Gene: mpig6b has been classified as Green List (High Evidence).
Mendeliome v0.3784 MPIG6B Zornitza Stark Classified gene: MPIG6B as Green List (high evidence)
Mendeliome v0.3784 MPIG6B Zornitza Stark Gene: mpig6b has been classified as Green List (High Evidence).
Mendeliome v0.3783 MPIG6B Zornitza Stark gene: MPIG6B was added
gene: MPIG6B was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MPIG6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPIG6B were set to 31276734; 29898956; 27743390
Phenotypes for gene: MPIG6B were set to Thrombocytopenia, anemia, and myelofibrosis, MIM# 617441
Review for gene: MPIG6B was set to GREEN
Added comment: Six families reported.
Sources: Expert list
Mendeliome v0.3782 MAT2A Zornitza Stark Gene: mat2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3779 MAT2A Zornitza Stark Classified gene: MAT2A as Amber List (moderate evidence)
Mendeliome v0.3779 MAT2A Zornitza Stark Gene: mat2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3778 LOX Zornitza Stark Gene: lox has been classified as Green List (High Evidence).
Mendeliome v0.3775 KDSR Zornitza Stark Gene: kdsr has been classified as Green List (High Evidence).
Mendeliome v0.3775 KDSR Zornitza Stark Phenotypes for gene: KDSR were changed from to Erythrokeratodermia variabilis et progressiva 4, MIM# 617526; severe thrombocytopaenia
Mendeliome v0.3772 KDSR Zornitza Stark reviewed gene: KDSR: Rating: GREEN; Mode of pathogenicity: None; Publications: 28774589, 30467204, 28575652; Phenotypes: Erythrokeratodermia variabilis et progressiva 4, MIM# 617526, severe thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3772 GGCX Zornitza Stark Gene: ggcx has been classified as Green List (High Evidence).
Mendeliome v0.3768 GPI Zornitza Stark Gene: gpi has been classified as Green List (High Evidence).
Mendeliome v0.3766 KANK2 Zornitza Stark Gene: kank2 has been classified as Green List (High Evidence).
Mendeliome v0.3763 FAM83G Zornitza Stark Gene: fam83g has been classified as Red List (Low Evidence).
Mendeliome v0.3763 FAM83G Zornitza Stark gene: FAM83G was added
gene: FAM83G was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FAM83G was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM83G were set to 29138053
Phenotypes for gene: FAM83G were set to Palmoplantar keratoderma, curly scalp hair and toenail dystrophy
Review for gene: FAM83G was set to RED
Added comment: PMID: 29138053; - 2 siblings born of consanguineous family presented with palmoplantar keratoderma and exuberant curly scalp hair - progressive development of yellowish thickened scaly skin affecting the palms and soles since 2 years of age, and toenail dystrophy in their teenage years > homozygous for a missense p.(Ala34Glu)
Sources: Expert list
Mendeliome v0.3762 LONP2 Zornitza Stark Gene: lonp2 has been classified as Red List (Low Evidence).
Mendeliome v0.3762 LONP2 Zornitza Stark Classified gene: LONP2 as Red List (low evidence)
Mendeliome v0.3762 LONP2 Zornitza Stark Gene: lonp2 has been classified as Red List (Low Evidence).
Mendeliome v0.3761 CAST Zornitza Stark Gene: cast has been classified as Green List (High Evidence).
Mendeliome v0.3758 CARD14 Zornitza Stark Gene: card14 has been classified as Green List (High Evidence).
Mendeliome v0.3758 CARD14 Zornitza Stark Phenotypes for gene: CARD14 were changed from to Pityriasis rubra pilaris (MIM#173200)
Mendeliome v0.3755 CARD14 Zornitza Stark reviewed gene: CARD14: Rating: GREEN; Mode of pathogenicity: None; Publications: 22703878, 27760266; Phenotypes: Pityriasis rubra pilaris (MIM#173200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3755 TRPV3 Zornitza Stark Gene: trpv3 has been classified as Green List (High Evidence).
Mendeliome v0.3752 EPHB2 Zornitza Stark Gene: ephb2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3749 EPHB2 Zornitza Stark Classified gene: EPHB2 as Amber List (moderate evidence)
Mendeliome v0.3749 EPHB2 Zornitza Stark Gene: ephb2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3748 ACTN1 Zornitza Stark Gene: actn1 has been classified as Green List (High Evidence).
Mendeliome v0.3745 DSG3 Zornitza Stark Gene: dsg3 has been classified as Red List (Low Evidence).
Mendeliome v0.3745 DSG3 Zornitza Stark gene: DSG3 was added
gene: DSG3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DSG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSG3 were set to 30528827
Phenotypes for gene: DSG3 were set to Mucosal blistering
Review for gene: DSG3 was set to RED
Added comment: One individual with recurrent blisters and erosions in the oral mucosa since birth homozygous for p(.R287*).
Sources: Expert list
Mendeliome v0.3744 ITGA9 Zornitza Stark Gene: itga9 has been classified as Red List (Low Evidence).
Mendeliome v0.3744 ITGA9 Zornitza Stark Classified gene: ITGA9 as Red List (low evidence)
Mendeliome v0.3744 ITGA9 Zornitza Stark Gene: itga9 has been classified as Red List (Low Evidence).
Mendeliome v0.3743 MADD Zornitza Stark Gene: madd has been classified as Green List (High Evidence).
Mendeliome v0.3740 UNC45A Zornitza Stark Gene: unc45a has been classified as Green List (High Evidence).
Mendeliome v0.3740 UNC45A Zornitza Stark Phenotypes for gene: UNC45A were changed from to Cholestasis; Diarrhoea; Bone fragility; Impaired hearing
Mendeliome v0.3737 UNC45A Zornitza Stark reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29429573; Phenotypes: Cholestasis, Diarrhoea, Bone fragility, Impaired hearing; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3737 SLC5A6 Zornitza Stark Phenotypes for gene: SLC5A6 were changed from Developmental delay; epilepsy; neurodegeneration to Developmental delay; epilepsy; neurodegeneration; Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Mendeliome v0.3736 SLC5A6 Zornitza Stark edited their review of gene: SLC5A6: Changed phenotypes: Developmental delay, epilepsy, neurodegeneration, Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Mendeliome v0.3736 SMO Zornitza Stark Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis; Curry-Jones syndrome, somatic mosaic 601707 to Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800; Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3735 SMO Zornitza Stark edited their review of gene: SMO: Changed phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800, Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3735 HFE2 Zornitza Stark Gene: hfe2 has been classified as Green List (High Evidence).
Mendeliome v0.3735 HFE2 Zornitza Stark Phenotypes for gene: HFE2 were changed from to Hemochromatosis, type 2A, MIM# 602390
Mendeliome v0.3733 HFE2 Zornitza Stark reviewed gene: HFE2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hemochromatosis, type 2A, MIM# 602390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3733 FAM50A Zornitza Stark Gene: fam50a has been classified as Green List (High Evidence).
Mendeliome v0.3733 FAM50A Zornitza Stark Classified gene: FAM50A as Green List (high evidence)
Mendeliome v0.3733 FAM50A Zornitza Stark Gene: fam50a has been classified as Green List (High Evidence).
Mendeliome v0.3732 FAM50A Zornitza Stark gene: FAM50A was added
gene: FAM50A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Review for gene: FAM50A was set to GREEN
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).
Sources: Literature
Mendeliome v0.3731 ADK Zornitza Stark Gene: adk has been classified as Green List (High Evidence).
Mendeliome v0.3731 ADK Zornitza Stark Phenotypes for gene: ADK were changed from to Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300
Mendeliome v0.3728 ADK Zornitza Stark reviewed gene: ADK: Rating: GREEN; Mode of pathogenicity: None; Publications: 21963049, 17120046; Phenotypes: Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3728 SGK3 Zornitza Stark gene: SGK3 was added
gene: SGK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SGK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGK3 were set to 31821448
Phenotypes for gene: SGK3 were set to Hypophosphatemic rickets
Review for gene: SGK3 was set to RED
Added comment: 5 individuals from one family where a splice site variant segregated with disease.
Sources: Literature
Mendeliome v0.3727 SEC24D Zornitza Stark Gene: sec24d has been classified as Green List (High Evidence).
Mendeliome v0.3724 P4HB Zornitza Stark Gene: p4hb has been classified as Green List (High Evidence).
Mendeliome v0.3721 MPDZ Zornitza Stark Gene: mpdz has been classified as Green List (High Evidence).
Mendeliome v0.3715 B3GNT2 Zornitza Stark Classified gene: B3GNT2 as Amber List (moderate evidence)
Mendeliome v0.3715 B3GNT2 Zornitza Stark Gene: b3gnt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3714 SOX6 Zornitza Stark Phenotypes for gene: SOX6 were changed from ADHD; Craniosynostosis; Osteochondromas to ADHD; Craniosynostosis; Osteochondromas; Tolchin-Le Caignec syndrome, MIM#618971
Mendeliome v0.3713 HYLS1 Melanie Marty changed review comment from: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774).

2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932).

No other variants have been reported as pathogenic in this gene.; to: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human cells have shown mislocalisation of the protein to the nucleus (PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774).

2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932).

No other variants have been reported as pathogenic in this gene.
Mendeliome v0.3713 CNTN2 Zornitza Stark Gene: cntn2 has been classified as Red List (Low Evidence).
Mendeliome v0.3713 CNTN2 Zornitza Stark gene: CNTN2 was added
gene: CNTN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNTN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN2 were set to 23518707
Phenotypes for gene: CNTN2 were set to Epilepsy
Review for gene: CNTN2 was set to RED
Added comment: Single family reported in 2013, supportive mouse model.
Sources: Literature
Mendeliome v0.3712 DNAH8 Zornitza Stark Classified gene: DNAH8 as Green List (high evidence)
Mendeliome v0.3712 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Green List (High Evidence).
Mendeliome v0.3711 DTNA Zornitza Stark Gene: dtna has been classified as Red List (Low Evidence).
Mendeliome v0.3708 DTNA Zornitza Stark Classified gene: DTNA as Red List (low evidence)
Mendeliome v0.3708 DTNA Zornitza Stark Gene: dtna has been classified as Red List (Low Evidence).
Mendeliome v0.3707 HYLS1 Zornitza Stark Gene: hyls1 has been classified as Green List (High Evidence).
Mendeliome v0.3702 RAC1 Zornitza Stark Gene: rac1 has been classified as Green List (High Evidence).
Mendeliome v0.3698 FANCD2 Zornitza Stark Gene: fancd2 has been classified as Green List (High Evidence).
Mendeliome v0.3696 BCOR Zornitza Stark Gene: bcor has been classified as Green List (High Evidence).
Mendeliome v0.3691 ARSE Zornitza Stark Gene: arse has been classified as Green List (High Evidence).
Mendeliome v0.3691 ARSE Zornitza Stark Phenotypes for gene: ARSE were changed from to Chondrodysplasia punctata, X-linked recessive, MIM# 302950
Mendeliome v0.3690 ARSE Zornitza Stark reviewed gene: ARSE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia punctata, X-linked recessive, MIM# 302950; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3690 TPP1 Zornitza Stark Gene: tpp1 has been classified as Green List (High Evidence).
Mendeliome v0.3690 TPP1 Zornitza Stark Phenotypes for gene: TPP1 were changed from to Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270
Mendeliome v0.3687 PSAT1 Zornitza Stark Gene: psat1 has been classified as Green List (High Evidence).
Mendeliome v0.3684 TPP1 Michelle Torres reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2 204500, Spinocerebellar ataxia, autosomal recessive 7 609270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3684 FBXO11 Zornitza Stark Gene: fbxo11 has been classified as Green List (High Evidence).
Mendeliome v0.3681 FRMD7 Zornitza Stark Gene: frmd7 has been classified as Green List (High Evidence).
Mendeliome v0.3678 AIFM1 Zornitza Stark Gene: aifm1 has been classified as Green List (High Evidence).
Mendeliome v0.3678 AIFM1 Zornitza Stark Phenotypes for gene: AIFM1 were changed from to Combined oxidative phosphorylation deficiency 6, 300816; Cowchock syndrome, 310490; Deafness, X-linked 5, 300614; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, 300232
Mendeliome v0.3675 AIFM1 Elena Savva reviewed gene: AIFM1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28842795; Phenotypes: Combined oxidative phosphorylation deficiency 6, 300816, Cowchock syndrome, 310490, Deafness, X-linked 5, 300614, Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, 300232; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3675 PIGQ Zornitza Stark edited their review of gene: PIGQ: Added comment: Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548).

Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362).

Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality.

PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis.

More than 10 variants have been reported to date (missense / pLoF).; Changed phenotypes: Epileptic encephalopathy, early infantile, 77, MIM# 618548
Mendeliome v0.3674 SEC61B Zornitza Stark Gene: sec61b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3674 SEC61B Zornitza Stark Classified gene: SEC61B as Amber List (moderate evidence)
Mendeliome v0.3674 SEC61B Zornitza Stark Gene: sec61b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3672 CHI3L1 Zornitza Stark Gene: chi3l1 has been classified as Red List (Low Evidence).
Mendeliome v0.3671 CHI3L1 Zornitza Stark Classified gene: CHI3L1 as Red List (low evidence)
Mendeliome v0.3671 CHI3L1 Zornitza Stark Gene: chi3l1 has been classified as Red List (Low Evidence).
Mendeliome v0.3670 C3orf52 Zornitza Stark Gene: c3orf52 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3670 C3orf52 Zornitza Stark Classified gene: C3orf52 as Amber List (moderate evidence)
Mendeliome v0.3670 C3orf52 Zornitza Stark Gene: c3orf52 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3669 C3orf52 Zornitza Stark gene: C3orf52 was added
gene: C3orf52 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C3orf52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C3orf52 were set to 32336749
Phenotypes for gene: C3orf52 were set to Localized hypotrichosis
Review for gene: C3orf52 was set to AMBER
Added comment: 2 families with 4 individuals with localised hypotrichosis and homozygous variants in C3ORF52. C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H–mediated 2-acyl-lysophosphatidic acid (LPA) biosynthesis. Same pathway as two other genes for localised hypotrichosis (LIPH and LPAR6)
Sources: Literature
Mendeliome v0.3668 NDUFA8 Zornitza Stark Gene: ndufa8 has been classified as Red List (Low Evidence).
Mendeliome v0.3668 NDUFA8 Zornitza Stark gene: NDUFA8 was added
gene: NDUFA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDUFA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA8 were set to 32385911
Phenotypes for gene: NDUFA8 were set to NDUFA8-related mitochondrial disease; Developmental delay; microcehaly; seizures
Review for gene: NDUFA8 was set to RED
Added comment: Single individual reported with homozygous variant, fibroblasts showed apparent biochemical defects in mitochondrial complex I.
Sources: Literature
Mendeliome v0.3667 DLG5 Zornitza Stark Gene: dlg5 has been classified as Green List (High Evidence).
Mendeliome v0.3667 DLG5 Zornitza Stark Classified gene: DLG5 as Green List (high evidence)
Mendeliome v0.3667 DLG5 Zornitza Stark Gene: dlg5 has been classified as Green List (High Evidence).
Mendeliome v0.3665 AHR Zornitza Stark Gene: ahr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3665 AHR Zornitza Stark Classified gene: AHR as Amber List (moderate evidence)
Mendeliome v0.3665 AHR Zornitza Stark Gene: ahr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3664 M1AP Zornitza Stark Gene: m1ap has been classified as Green List (High Evidence).
Mendeliome v0.3664 M1AP Zornitza Stark Classified gene: M1AP as Green List (high evidence)
Mendeliome v0.3664 M1AP Zornitza Stark Gene: m1ap has been classified as Green List (High Evidence).
Mendeliome v0.3662 RELN Zornitza Stark Gene: reln has been classified as Green List (High Evidence).
Mendeliome v0.3662 RELN Zornitza Stark Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), MIM# 257320; ankylosing spondylitis to Lissencephaly 2 (Norman-Roberts type), MIM# 257320; {Epilepsy, familial temporal lobe, 7}, MIM# 616436; ankylosing spondylitis
Mendeliome v0.3661 RELN Zornitza Stark Phenotypes for gene: RELN were changed from to Lissencephaly 2 (Norman-Roberts type), MIM# 257320; ankylosing spondylitis
Mendeliome v0.3658 CALCRL Zornitza Stark Gene: calcrl has been classified as Red List (Low Evidence).
Mendeliome v0.3658 CALCRL Zornitza Stark Classified gene: CALCRL as Red List (low evidence)
Mendeliome v0.3658 CALCRL Zornitza Stark Gene: calcrl has been classified as Red List (Low Evidence).
Mendeliome v0.3657 CALCRL Hazel Phillimore gene: CALCRL was added
gene: CALCRL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CALCRL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CALCRL were set to PMID: 30115739
Phenotypes for gene: CALCRL were set to ?Lymphatic malformation 8 (MIM# 618773); hydrops fetalis
Review for gene: CALCRL was set to RED
Added comment: Homozygous in-frame deletion (Val205del) in the CALCRL gene (Val205del) in a 22 week-old fetus with hydrops details due to lymphatic malformation. Consanguineous parents.
Heterozygosity of the variant was also suggested to be associated with spontaneous miscarriage and subfertility. Consanguineous family with 8 total miscarriages from 3 carrier women, and 2 of these were confirmed to be due to hydrops fetalis.
Note: possible association of a variant in ASAH1 gene that is associated with Farber lipogranulomatosis which can sometimes present with antenatal hydrops fetalis. (Homozygosity in one of the fetuses, fetus and heterozygosity in some of the family members).
In vitro biochemical assays indicated that the variant causes misfolding of the protein and reduced association with its chaperone, RAMP2, and reduced translocation to the plasma membrane. (PMID: 30115739; Mackie, DI. et al., 2018).
Sources: Literature
Mendeliome v0.3657 RELN Chern Lim reviewed gene: RELN: Rating: AMBER; Mode of pathogenicity: None; Publications: 32001840; Phenotypes: ankylosing spondylitis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3657 AHR Chern Lim gene: AHR was added
gene: AHR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AHR were set to 29726989; 31896775
Phenotypes for gene: AHR were set to ?Retinitis pigmentosa 85 MIM#618345; foveal hypoplasia and infantile nystagmus
Review for gene: AHR was set to AMBER
Added comment: - One reported homozygous splice variant in a consanguineous family & a mouse model (PMID: 29726989)

- A homozygous nonsense variant in 1 consanguineous family with foveal hypoplasia and infantile nystagmus (PMID:31896775).
Sources: Literature
Mendeliome v0.3657 CRY1 Zornitza Stark Gene: cry1 has been classified as Green List (High Evidence).
Mendeliome v0.3657 CRY1 Zornitza Stark Classified gene: CRY1 as Green List (high evidence)
Mendeliome v0.3657 CRY1 Zornitza Stark Gene: cry1 has been classified as Green List (High Evidence).
Mendeliome v0.3656 FBXL7 Zornitza Stark Gene: fbxl7 has been classified as Red List (Low Evidence).
Mendeliome v0.3656 FBXL7 Zornitza Stark Phenotypes for gene: FBXL7 were changed from Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. to Hennekam lymphangiectasia-lymphedema syndrome
Mendeliome v0.3655 FBXL7 Zornitza Stark Classified gene: FBXL7 as Red List (low evidence)
Mendeliome v0.3655 FBXL7 Zornitza Stark Gene: fbxl7 has been classified as Red List (Low Evidence).
Mendeliome v0.3654 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Progressive neurological disorder to Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.3653 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Mendeliome v0.3653 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Neurological disorder to Progressive neurological disorder
Mendeliome v0.3652 HPDL Zornitza Stark Classified gene: HPDL as Green List (high evidence)
Mendeliome v0.3652 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Mendeliome v0.3651 NCKAP1L Zornitza Stark Gene: nckap1l has been classified as Green List (High Evidence).
Mendeliome v0.3651 NCKAP1L Zornitza Stark Classified gene: NCKAP1L as Green List (high evidence)
Mendeliome v0.3651 NCKAP1L Zornitza Stark Gene: nckap1l has been classified as Green List (High Evidence).
Mendeliome v0.3650 PIGP Seb Lunke Classified gene: PIGP as Green List (high evidence)
Mendeliome v0.3650 PIGP Seb Lunke Gene: pigp has been classified as Green List (High Evidence).
Mendeliome v0.3649 MYLPF Zornitza Stark Gene: mylpf has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3649 MYLPF Zornitza Stark Classified gene: MYLPF as Amber List (moderate evidence)
Mendeliome v0.3649 MYLPF Zornitza Stark Gene: mylpf has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3648 FBXL7 Hazel Phillimore changed review comment from: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature; to: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature
Mendeliome v0.3648 SCAF4 Zornitza Stark Gene: scaf4 has been classified as Green List (High Evidence).
Mendeliome v0.3648 SCAF4 Zornitza Stark Classified gene: SCAF4 as Green List (high evidence)
Mendeliome v0.3648 SCAF4 Zornitza Stark Gene: scaf4 has been classified as Green List (High Evidence).
Mendeliome v0.3647 FBXL7 Hazel Phillimore gene: FBXL7 was added
gene: FBXL7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL7 were set to PMID: 31633297
Phenotypes for gene: FBXL7 were set to Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Review for gene: FBXL7 was set to AMBER
Added comment: Homozygous deletion of exon 3 of FBXL7 (predicted to be in-frame) in a 2-year old with novel form of Hennekam syndrome. Each parent was heterozygous.
Patient had lymphedema, protein‐losing enteropathy, dental anomalies, camptodactyly, microtia, small auditory canals, ductive hearing loss, middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae.
Sources: Literature
Mendeliome v0.3647 PJA1 Zornitza Stark Gene: pja1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3647 PJA1 Zornitza Stark Classified gene: PJA1 as Amber List (moderate evidence)
Mendeliome v0.3647 PJA1 Zornitza Stark Gene: pja1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3645 MYLPF Crystle Lee gene: MYLPF was added
gene: MYLPF was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MYLPF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLPF were set to 32707087
Phenotypes for gene: MYLPF were set to Distal arthrogryoposis
Review for gene: MYLPF was set to GREEN
Added comment: 2 different homozygous variants reported in 6 consanguineous families with DA and an additional 2 different dominantly inherited variants in 2 families, with supporting animal model.
Sources: Expert Review
Mendeliome v0.3645 NCKAP1L Michelle Torres gene: NCKAP1L was added
gene: NCKAP1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCKAP1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCKAP1L were set to 32647003
Phenotypes for gene: NCKAP1L were set to Immunodeficiency
Review for gene: NCKAP1L was set to GREEN
Added comment: 5 patients from 4 families with recurrent bacterial and viral skin infections, severe respiratory tract infections leading to pneumonia and bronchiectasis. Functional of the 4 missense reported were performed.
Sources: Literature
Mendeliome v0.3645 MCF2 Zornitza Stark Gene: mcf2 has been classified as Red List (Low Evidence).
Mendeliome v0.3645 MCF2 Zornitza Stark gene: MCF2 was added
gene: MCF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MCF2 were set to 31846234
Phenotypes for gene: MCF2 were set to Perisylvian polymicrogyria
Review for gene: MCF2 was set to RED
Added comment: Single individual reported, inherited missense variant from unaffected mother, some support from mouse model.
Sources: Literature
Mendeliome v0.3644 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Mendeliome v0.3644 NARS Zornitza Stark Classified gene: NARS as Green List (high evidence)
Mendeliome v0.3644 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Mendeliome v0.3643 NARS Zornitza Stark gene: NARS was added
gene: NARS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).
Sources: Literature
Mendeliome v0.3642 ZNF407 Zornitza Stark Gene: znf407 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3639 ZNF407 Zornitza Stark Classified gene: ZNF407 as Amber List (moderate evidence)
Mendeliome v0.3639 ZNF407 Zornitza Stark Gene: znf407 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3638 DDX58 Zornitza Stark Gene: ddx58 has been classified as Green List (High Evidence).
Mendeliome v0.3638 DDX58 Zornitza Stark Phenotypes for gene: DDX58 were changed from to Singleton-Merten syndrome 2, MIM# 616298
Mendeliome v0.3635 DDX58 Zornitza Stark changed review comment from: Singleton-Merten syndrome-2 is characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies.; to: Singleton-Merten syndrome-2 is characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies. At least 3 families reported.
Mendeliome v0.3635 DDX58 Zornitza Stark reviewed gene: DDX58: Rating: GREEN; Mode of pathogenicity: None; Publications: 25620203; Phenotypes: Singleton-Merten syndrome 2, MIM# 616298; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3635 IVNS1ABP Zornitza Stark Gene: ivns1abp has been classified as Green List (High Evidence).
Mendeliome v0.3632 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Mendeliome v0.3632 MAPK1 Zornitza Stark Classified gene: MAPK1 as Green List (high evidence)
Mendeliome v0.3632 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Mendeliome v0.3631 MAPK1 Zornitza Stark gene: MAPK1 was added
gene: MAPK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Review for gene: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).
Sources: Literature
Mendeliome v0.3630 ASPM Zornitza Stark Gene: aspm has been classified as Green List (High Evidence).
Mendeliome v0.3630 ASPM Zornitza Stark Phenotypes for gene: ASPM were changed from to Microcephaly 5, primary, autosomal recessive, MIM#608716
Mendeliome v0.3627 ASPM Elena Savva reviewed gene: ASPM: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:29243349; Phenotypes: Microcephaly 5, primary, autosomal recessive, 608716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3627 AMBRA1 Bryony Thompson Gene: ambra1 has been classified as Green List (High Evidence).
Mendeliome v0.3627 AMBRA1 Bryony Thompson Classified gene: AMBRA1 as Green List (high evidence)
Mendeliome v0.3627 AMBRA1 Bryony Thompson Gene: ambra1 has been classified as Green List (High Evidence).
Mendeliome v0.3625 ERLEC1 Bryony Thompson Classified gene: ERLEC1 as Green List (high evidence)
Mendeliome v0.3625 ERLEC1 Bryony Thompson Gene: erlec1 has been classified as Green List (High Evidence).
Mendeliome v0.3624 ERLEC1 Bryony Thompson gene: ERLEC1 was added
gene: ERLEC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERLEC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERLEC1 were set to 32442352
Phenotypes for gene: ERLEC1 were set to Class III malocclusion
Review for gene: ERLEC1 was set to GREEN
Added comment: A heterozygous missense variant was found to co-segregate with dentofacial deformity in a multi-generational Chinese pedigree (2 unaffected carriers & 11 affected carriers), and 3 additional missense variants were identified in 3 unrelated cases from a sporadic malocclusion cohort. Additional functional assays were conducted to demonstrate that the proper level of ERLEC1 expression is crucial for proper osteogenic differentiation. All identified missense variants were assessed using luciferase reporter assays, and altered activity.
Sources: Literature
Mendeliome v0.3623 RIMS2 Zornitza Stark Phenotypes for gene: RIMS2 were changed from nystagmus; retinal dysfunction; autism; night blindness to nystagmus; retinal dysfunction; autism; night blindness; Cone-rod synaptic disorder syndrome, congenital nonprogressive , MIM#618970
Mendeliome v0.3622 RIMS2 Zornitza Stark edited their review of gene: RIMS2: Changed phenotypes: nystagmus, retinal dysfunction, autism, night blindness, Cone-rod synaptic disorder syndrome, congenital nonprogressive , MIM#618970
Mendeliome v0.3622 WDR1 Zornitza Stark Gene: wdr1 has been classified as Green List (High Evidence).
Mendeliome v0.3619 KREMEN1 Bryony Thompson Gene: kremen1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3619 KREMEN1 Bryony Thompson Classified gene: KREMEN1 as Amber List (moderate evidence)
Mendeliome v0.3619 KREMEN1 Bryony Thompson Gene: kremen1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3618 KREMEN1 Bryony Thompson gene: KREMEN1 was added
gene: KREMEN1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KREMEN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KREMEN1 were set to 27049303; 27550540
Phenotypes for gene: KREMEN1 were set to Ectodermal dysplasia 13, hair/tooth type MIM#617392
Review for gene: KREMEN1 was set to AMBER
Added comment: 4 consanguineous Palestinian families segregating the same homozygous missense (Phe209Ser) with disease phenotype which includes hair abnormalities. Possible founder variant. There are also animal model functional assays that suggest the gene is involved in hair development.
Sources: Expert list
Mendeliome v0.3617 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from Impaired intestinal peristalsis; dysmorphic features to Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features
Mendeliome v0.3616 ANO1 Zornitza Stark Gene: ano1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3616 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from to Impaired intestinal peristalsis; dysmorphic features
Mendeliome v0.3615 ANO1 Zornitza Stark Classified gene: ANO1 as Amber List (moderate evidence)
Mendeliome v0.3615 ANO1 Zornitza Stark Gene: ano1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3614 TUBB2A Zornitza Stark Gene: tubb2a has been classified as Green List (High Evidence).
Mendeliome v0.3614 TUBB2A Zornitza Stark Phenotypes for gene: TUBB2A were changed from to Cortical dysplasia, complex, with other brain malformations 5 MIM#615763
Mendeliome v0.3611 TUBB2A Zornitza Stark reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, MIM# 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3611 PMP22 Zornitza Stark Gene: pmp22 has been classified as Green List (High Evidence).
Mendeliome v0.3611 PMP22 Zornitza Stark Phenotypes for gene: PMP22 were changed from to Charcot-Marie-Tooth disease, type 1A, MIM# 118220; Charcot-Marie-Tooth disease, type 1E, MIM# 118300; Dejerine-Sottas disease, MIM# 145900; Neuropathy, recurrent, with pressure palsies 162500; Roussy-Levy syndrome 180800
Mendeliome v0.3608 PMP22 Zornitza Stark reviewed gene: PMP22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, type 1A, MIM# 118220, Charcot-Marie-Tooth disease, type 1E, MIM# 118300, Dejerine-Sottas disease, MIM# 145900, Neuropathy, recurrent, with pressure palsies 162500, Roussy-Levy syndrome 180800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3608 OTX2 Zornitza Stark Gene: otx2 has been classified as Green List (High Evidence).
Mendeliome v0.3606 CDAN1 Zornitza Stark Gene: cdan1 has been classified as Green List (High Evidence).
Mendeliome v0.3603 NGLY1 Zornitza Stark Gene: ngly1 has been classified as Green List (High Evidence).
Mendeliome v0.3598 IMPG2 Zornitza Stark Gene: impg2 has been classified as Green List (High Evidence).
Mendeliome v0.3595 GNPNAT1 Zornitza Stark Gene: gnpnat1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3595 GNPNAT1 Zornitza Stark Classified gene: GNPNAT1 as Amber List (moderate evidence)
Mendeliome v0.3595 GNPNAT1 Zornitza Stark Gene: gnpnat1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3593 EEF1A2 Zornitza Stark Gene: eef1a2 has been classified as Green List (High Evidence).
Mendeliome v0.3590 ANO1 Arina Puzriakova changed review comment from: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature; to: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Mendeliome v0.3590 ANO1 Arina Puzriakova gene: ANO1 was added
gene: ANO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Mendeliome v0.3590 GNPNAT1 Arina Puzriakova changed review comment from: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1.
Sources: Literature
Mendeliome v0.3590 GNPNAT1 Arina Puzriakova gene: GNPNAT1 was added
gene: GNPNAT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNPNAT1 were set to 32591345
Phenotypes for gene: GNPNAT1 were set to Rhizomelic skeletal dysplasia
Review for gene: GNPNAT1 was set to RED
Added comment: Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature
Mendeliome v0.3590 PKD1L1 Zornitza Stark Gene: pkd1l1 has been classified as Green List (High Evidence).
Mendeliome v0.3587 IVNS1ABP Bryony Thompson Classified gene: IVNS1ABP as Green List (high evidence)
Mendeliome v0.3587 IVNS1ABP Bryony Thompson Gene: ivns1abp has been classified as Green List (High Evidence).
Mendeliome v0.3586 IVNS1ABP Bryony Thompson gene: IVNS1ABP was added
gene: IVNS1ABP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IVNS1ABP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IVNS1ABP were set to 32499645
Phenotypes for gene: IVNS1ABP were set to Primary immunodeficiency
Review for gene: IVNS1ABP was set to GREEN
Added comment: 3 unrelated families with putative loss of function variants. Case features and immunophenotyping of patient cells is suggestive of a combined immune deficiency, based on the ESID definitions of PID subtypes.
Sources: Literature
Mendeliome v0.3585 PTPN2 Bryony Thompson Gene: ptpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3585 PTPN2 Bryony Thompson Classified gene: PTPN2 as Amber List (moderate evidence)
Mendeliome v0.3585 PTPN2 Bryony Thompson Gene: ptpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3584 PTPN2 Bryony Thompson gene: PTPN2 was added
gene: PTPN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN2 were set to 32499645; 27658548
Phenotypes for gene: PTPN2 were set to Lupus; arthritis; common variable immunodeficiency
Review for gene: PTPN2 was set to AMBER
Added comment: A single family with a proband diagnosed with CVID and arthiritis (among other features) with an intronic expression quantitative trait loci (eQTL) rs2847297-G in trans with a stopgain variant. The stopgain variant was also identified in the proband's mother, who was diagnosed with lupus. A Ptpn2 deficient mouse model also demonstrates an autoimmune phenotype.
Sources: Literature
Mendeliome v0.3583 SOCS1 Bryony Thompson Gene: socs1 has been classified as Green List (High Evidence).
Mendeliome v0.3583 SOCS1 Bryony Thompson Classified gene: SOCS1 as Green List (high evidence)
Mendeliome v0.3583 SOCS1 Bryony Thompson Gene: socs1 has been classified as Green List (High Evidence).
Mendeliome v0.3581 MRPS23 Zornitza Stark Phenotypes for gene: MRPS23 were changed from Hepatic disease; Combined respiratory chain complex deficienciesHepatic disease; Combined respiratory chain complex deficiencies; Cardiomyopathy; Tubulopathy; Lactic acidosis; Structural brain abnormalities to Hepatic disease; Combined respiratory chain complex deficiencies; Hepatic disease; Combined respiratory chain complex deficiencies; Cardiomyopathy; Tubulopathy; Lactic acidosis; Structural brain abnormalities; Combined oxidative phosphorylation deficiency 45, MIM#618951
Mendeliome v0.3580 MRPS23 Zornitza Stark edited their review of gene: MRPS23: Changed phenotypes: Hepatic disease, Combined respiratory chain complex deficiencies, Cardiomyopathy, Tubulopathy, Lactic acidosis, Structural brain abnormalities, Combined oxidative phosphorylation deficiency 45, MIM#618951
Mendeliome v0.3578 OXCT1 Zornitza Stark Gene: oxct1 has been classified as Green List (High Evidence).
Mendeliome v0.3575 KCNJ1 Zornitza Stark Gene: kcnj1 has been classified as Green List (High Evidence).
Mendeliome v0.3572 ZFYVE27 Zornitza Stark Gene: zfyve27 has been classified as Red List (Low Evidence).
Mendeliome v0.3569 KLF10 Zornitza Stark Gene: klf10 has been classified as Red List (Low Evidence).
Mendeliome v0.3569 KLF10 Zornitza Stark Classified gene: KLF10 as Red List (low evidence)
Mendeliome v0.3569 KLF10 Zornitza Stark Gene: klf10 has been classified as Red List (Low Evidence).
Mendeliome v0.3568 MYOZ2 Zornitza Stark Gene: myoz2 has been classified as Red List (Low Evidence).
Mendeliome v0.3565 MYOZ2 Zornitza Stark Classified gene: MYOZ2 as Red List (low evidence)
Mendeliome v0.3565 MYOZ2 Zornitza Stark Gene: myoz2 has been classified as Red List (Low Evidence).
Mendeliome v0.3564 TRIM63 Zornitza Stark Gene: trim63 has been classified as Green List (High Evidence).
Mendeliome v0.3564 TRIM63 Zornitza Stark Classified gene: TRIM63 as Green List (high evidence)
Mendeliome v0.3564 TRIM63 Zornitza Stark Gene: trim63 has been classified as Green List (High Evidence).
Mendeliome v0.3563 PDLIM3 Zornitza Stark Gene: pdlim3 has been classified as Red List (Low Evidence).
Mendeliome v0.3563 PDLIM3 Zornitza Stark Classified gene: PDLIM3 as Red List (low evidence)
Mendeliome v0.3563 PDLIM3 Zornitza Stark Gene: pdlim3 has been classified as Red List (Low Evidence).
Mendeliome v0.3562 OBSCN Zornitza Stark Gene: obscn has been classified as Red List (Low Evidence).
Mendeliome v0.3562 OBSCN Zornitza Stark Classified gene: OBSCN as Red List (low evidence)
Mendeliome v0.3562 OBSCN Zornitza Stark Gene: obscn has been classified as Red List (Low Evidence).
Mendeliome v0.3561 TRIM63 Ain Roesley gene: TRIM63 was added
gene: TRIM63 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM63 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM63 were set to 30681346; 32451364
Phenotypes for gene: TRIM63 were set to Hypertrophic cardiomyopathy
Penetrance for gene: TRIM63 were set to unknown
Review for gene: TRIM63 was set to GREEN
Added comment: PMID: 30681346;
LIMITED by Clingen working group (last evaluated 2018)

PMID: 32451364
- 16 index cases with rare homozygous or compound heterozygous variants (15 HCM and one restrictive cardiomyopathy). None of these variants have homozygote counts in gnomAD.
- segregated in 3 families
- 1 index had another pathogenic truncating variant in MYBPC3
- 5 missense and 3 PTCs
- Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy
Sources: Literature
Mendeliome v0.3561 KLF10 Paul De Fazio gene: KLF10 was added
gene: KLF10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLF10 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KLF10 were set to 22234868
Phenotypes for gene: KLF10 were set to HCM
gene: KLF10 was marked as current diagnostic
Added comment: Curated by ClinGen and rated as limited evidence.

Misssense mutations reported in six unrelated individuals patients (two males/four females), with family history of HCM only reported for one individual (PMID: 22234868). No further reports in the literature.
Sources: Literature
Mendeliome v0.3561 KRT71 Bryony Thompson Gene: krt71 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3561 KRT71 Bryony Thompson Classified gene: KRT71 as Amber List (moderate evidence)
Mendeliome v0.3561 KRT71 Bryony Thompson Gene: krt71 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3560 KRT71 Bryony Thompson gene: KRT71 was added
gene: KRT71 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KRT71 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT71 were set to 14632181; 22592156; 19713490
Phenotypes for gene: KRT71 were set to ?Hypotrichosis 13, 615896
Review for gene: KRT71 was set to AMBER
Added comment: A single family with 3 affected members of a 3-generation Japanese family segregating a missense variant (F141C) with autosomal dominant woolly hair/hypotrichosis, with supporting functional assays and animal models.
Sources: Literature
Mendeliome v0.3559 ACADL Zornitza Stark Gene: acadl has been classified as Red List (Low Evidence).
Mendeliome v0.3556 ACADL Zornitza Stark Classified gene: ACADL as Red List (low evidence)
Mendeliome v0.3556 ACADL Zornitza Stark Gene: acadl has been classified as Red List (Low Evidence).
Mendeliome v0.3555 TWNK Zornitza Stark Gene: twnk has been classified as Green List (High Evidence).
Mendeliome v0.3555 TWNK Zornitza Stark Phenotypes for gene: TWNK were changed from to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) 271245; Perrault syndrome 5 616138; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 609286
Mendeliome v0.3551 TWNK Elena Savva reviewed gene: TWNK: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32234020, 18593709; Phenotypes: Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) 271245, Perrault syndrome 5 616138, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 609286; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3551 UBE2T Zornitza Stark Classified gene: UBE2T as Green List (high evidence)
Mendeliome v0.3551 UBE2T Zornitza Stark Gene: ube2t has been classified as Green List (High Evidence).
Mendeliome v0.3550 P2RX2 Zornitza Stark Gene: p2rx2 has been classified as Green List (High Evidence).
Mendeliome v0.3547 KCNQ4 Zornitza Stark Gene: kcnq4 has been classified as Green List (High Evidence).
Mendeliome v0.3544 FLCN Zornitza Stark Gene: flcn has been classified as Green List (High Evidence).
Mendeliome v0.3539 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Mendeliome v0.3539 KERA Zornitza Stark Gene: kera has been classified as Green List (High Evidence).
Mendeliome v0.3539 KERA Zornitza Stark Phenotypes for gene: KERA were changed from to Cornea plana 2, autosomal recessive, MIM# 217300
Mendeliome v0.3536 KERA Zornitza Stark reviewed gene: KERA: Rating: GREEN; Mode of pathogenicity: None; Publications: 23834557, 11726611, 10802664; Phenotypes: Cornea plana 2, autosomal recessive, MIM# 217300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3536 CTRC Zornitza Stark Gene: ctrc has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3533 CTRC Zornitza Stark Classified gene: CTRC as Amber List (moderate evidence)
Mendeliome v0.3533 CTRC Zornitza Stark Gene: ctrc has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3532 CPA1 Zornitza Stark Gene: cpa1 has been classified as Green List (High Evidence).
Mendeliome v0.3529 CLDN2 Zornitza Stark Gene: cldn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3526 CLDN2 Zornitza Stark Classified gene: CLDN2 as Amber List (moderate evidence)
Mendeliome v0.3526 CLDN2 Zornitza Stark Gene: cldn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3525 BMP10 Zornitza Stark Gene: bmp10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3525 BMP10 Zornitza Stark Classified gene: BMP10 as Amber List (moderate evidence)
Mendeliome v0.3525 BMP10 Zornitza Stark Gene: bmp10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3524 BMP10 Zornitza Stark gene: BMP10 was added
gene: BMP10 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: BMP10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP10 were set to 30578383
Phenotypes for gene: BMP10 were set to Pulmonary arterial hypertension
Review for gene: BMP10 was set to AMBER
Added comment: A truncating mutation and a predicted loss-of-function missense variant were identified in BMP10 in two severely affected sporadic PAH female patients.
Sources: Expert list
Mendeliome v0.3523 SMAD1 Zornitza Stark Gene: smad1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3523 SMAD1 Zornitza Stark Classified gene: SMAD1 as Amber List (moderate evidence)
Mendeliome v0.3523 SMAD1 Zornitza Stark Gene: smad1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3522 SMAD1 Zornitza Stark gene: SMAD1 was added
gene: SMAD1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SMAD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD1 were set to 21898662; 23478097
Phenotypes for gene: SMAD1 were set to Pulmonary arterial hypertension
Review for gene: SMAD1 was set to AMBER
Added comment: One missense variant identified in a PAH case. Mouse model is consistent with pulmonary hypertension.
Sources: Expert list
Mendeliome v0.3521 BRAP Zornitza Stark Gene: brap has been classified as Red List (Low Evidence).
Mendeliome v0.3521 BRAP Zornitza Stark gene: BRAP was added
gene: BRAP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: BRAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAP were set to 30703135
Phenotypes for gene: BRAP were set to Pulmonary arterial hypertension
Review for gene: BRAP was set to RED
Added comment: A single BRAP missense variant in a Japanese family with PAH, with in vitro functional assays suggesting a gain-of-function.
Sources: Expert list
Mendeliome v0.3520 KLF2 Zornitza Stark Gene: klf2 has been classified as Red List (Low Evidence).
Mendeliome v0.3520 KLF2 Zornitza Stark gene: KLF2 was added
gene: KLF2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KLF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLF2 were set to 28188237
Phenotypes for gene: KLF2 were set to Pulmonary arterial hypertension
Review for gene: KLF2 was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.3519 ATP13A3 Zornitza Stark Gene: atp13a3 has been classified as Green List (High Evidence).
Mendeliome v0.3519 ATP13A3 Zornitza Stark Classified gene: ATP13A3 as Green List (high evidence)
Mendeliome v0.3519 ATP13A3 Zornitza Stark Gene: atp13a3 has been classified as Green List (High Evidence).
Mendeliome v0.3518 ATP13A3 Zornitza Stark gene: ATP13A3 was added
gene: ATP13A3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATP13A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP13A3 were set to 31798832; 30679663; 29650961
Phenotypes for gene: ATP13A3 were set to Pulmonary arterial hypertension
Review for gene: ATP13A3 was set to GREEN
Added comment: Three heterozygous frameshift variants, three stop gained, two splice region variants in ATP13A3, which are predicted to lead to loss of ATPase catalytic activity identified in idiopathic/familial PAH cases. Also one case with putative recessive inheritance reported. ATP13A3 mRNA expression is confirmed in primary PASMCs and endothelial cells where its loss hindered proliferation and enhanced apoptosis of endothelial cells, which is known as the initiation event of PAH.
Sources: Expert list
Mendeliome v0.3517 SMARCA2 Zornitza Stark Gene: smarca2 has been classified as Green List (High Evidence).
Mendeliome v0.3517 SMARCA2 Zornitza Stark Phenotypes for gene: SMARCA2 were changed from to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome
Mendeliome v0.3513 SMARCA2 Zornitza Stark reviewed gene: SMARCA2: 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: 26468571, 32694869; Phenotypes: Nicolaides-Baraitser syndrome, MIM #601358, Blepharophimosis-intellectual disability syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3513 MORC2 Zornitza Stark Gene: morc2 has been classified as Green List (High Evidence).
Mendeliome v0.3510 DBT Zornitza Stark Gene: dbt has been classified as Green List (High Evidence).
Mendeliome v0.3507 PLCB3 Zornitza Stark Gene: plcb3 has been classified as Red List (Low Evidence).
Mendeliome v0.3507 PLCB3 Zornitza Stark gene: PLCB3 was added
gene: PLCB3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PLCB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCB3 were set to 29122926
Phenotypes for gene: PLCB3 were set to Spondylometaphyseal dysplasia with corneal dystrophy, MIM# 618961
Review for gene: PLCB3 was set to RED
Added comment: Single consanguineous family reported.
Sources: Expert list
Mendeliome v0.3506 ACOX1 Zornitza Stark Gene: acox1 has been classified as Green List (High Evidence).
Mendeliome v0.3502 MPL Zornitza Stark Gene: mpl has been classified as Green List (High Evidence).
Mendeliome v0.3502 MPL Zornitza Stark Phenotypes for gene: MPL were changed from to Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503; Thrombocythemia 2, MIM#601977, AD, SMu; Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR
Mendeliome v0.3499 SH2B3 Zornitza Stark Gene: sh2b3 has been classified as Green List (High Evidence).
Mendeliome v0.3499 SH2B3 Zornitza Stark Phenotypes for gene: SH2B3 were changed from to Predisposition to haematological malignancies
Mendeliome v0.3496 SH2B3 Zornitza Stark reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26457647, 23908464, 31102422, 31173385; Phenotypes: Predisposition to haematological malignancies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3496 MPL Chern Lim reviewed gene: MPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28955303, 26423830; Phenotypes: Myelofibrosis with myeloid metaplasia, somatic, MIM#2544503, Thrombocythemia 2, MIM#601977, AD, SMu, Thrombocytopenia, congenital amegakaryocytic, MIM#604498, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.3496 HPD Zornitza Stark Gene: hpd has been classified as Green List (High Evidence).
Mendeliome v0.3496 HPD Zornitza Stark Phenotypes for gene: HPD were changed from to Hawkinsinuria (MIM#140350), AD; Tyrosinemia type III (MIM#276710), AR
Mendeliome v0.3493 HPD Zornitza Stark reviewed gene: HPD: Rating: GREEN; Mode of pathogenicity: None; Publications: 10942115, 17560158; Phenotypes: Hawkinsinuria (MIM#140350), AD, Tyrosinemia type III (MIM#276710), AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.3493 FANCM Zornitza Stark Gene: fancm has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3490 FANCM Zornitza Stark Classified gene: FANCM as Amber List (moderate evidence)
Mendeliome v0.3490 FANCM Zornitza Stark Gene: fancm has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3489 HDAC8 Zornitza Stark Gene: hdac8 has been classified as Green List (High Evidence).
Mendeliome v0.3486 RBM8A Zornitza Stark Gene: rbm8a has been classified as Green List (High Evidence).
Mendeliome v0.3484 RPL15 Zornitza Stark Gene: rpl15 has been classified as Green List (High Evidence).
Mendeliome v0.3481 RPS28 Zornitza Stark Gene: rps28 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3481 RPS28 Zornitza Stark Phenotypes for gene: RPS28 were changed from to Diamond Blackfan anemia 15 with mandibulofacial dysostosis, MIM# 606164
Mendeliome v0.3478 RPS28 Zornitza Stark Classified gene: RPS28 as Amber List (moderate evidence)
Mendeliome v0.3478 RPS28 Zornitza Stark Gene: rps28 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3477 RPS28 Zornitza Stark reviewed gene: RPS28: Rating: AMBER; Mode of pathogenicity: None; Publications: 24942156; Phenotypes: Diamond Blackfan anemia 15 with mandibulofacial dysostosis, MIM# 606164; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3477 RPS29 Zornitza Stark Gene: rps29 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3474 RPS29 Zornitza Stark Classified gene: RPS29 as Amber List (moderate evidence)
Mendeliome v0.3474 RPS29 Zornitza Stark Gene: rps29 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3472 REN Zornitza Stark Gene: ren has been classified as Green List (High Evidence).
Mendeliome v0.3472 REN Zornitza Stark Phenotypes for gene: REN were changed from to Renal tubular dysgenesis, MIM# 267430; Autosomal dominant tubulointerstitial disease
Mendeliome v0.3469 REN Zornitza Stark reviewed gene: REN: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 31586593, 31406136, 28701203, 21473025; Phenotypes: Renal tubular dysgenesis, MIM# 267430, Autosomal dominant tubulointerstitial disease; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3467 UVSSA Zornitza Stark Gene: uvssa has been classified as Green List (High Evidence).
Mendeliome v0.3467 UVSSA Zornitza Stark Phenotypes for gene: UVSSA were changed from to UV-sensitive syndrome 3 (MIM#614640)
Mendeliome v0.3464 SEC23A Zornitza Stark Gene: sec23a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3464 SEC23A Zornitza Stark Phenotypes for gene: SEC23A were changed from to Craniolenticulosutural dysplasia (MIM# 607812)
Mendeliome v0.3461 SEC23A Zornitza Stark Classified gene: SEC23A as Amber List (moderate evidence)
Mendeliome v0.3461 SEC23A Zornitza Stark Gene: sec23a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3460 DACT1 Zornitza Stark Gene: dact1 has been classified as Red List (Low Evidence).
Mendeliome v0.3459 DACT1 Zornitza Stark Classified gene: DACT1 as Red List (low evidence)
Mendeliome v0.3459 DACT1 Zornitza Stark Gene: dact1 has been classified as Red List (Low Evidence).
Mendeliome v0.3458 VPS33A Zornitza Stark Gene: vps33a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3458 VPS33A Zornitza Stark Phenotypes for gene: VPS33A were changed from to Mucopolysaccharidosis-plus syndrome (MIM#617303)
Mendeliome v0.3455 VPS33A Zornitza Stark Classified gene: VPS33A as Amber List (moderate evidence)
Mendeliome v0.3455 VPS33A Zornitza Stark Gene: vps33a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3454 VPS33A Zornitza Stark reviewed gene: VPS33A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28013294, 27547915; Phenotypes: Mucopolysaccharidosis-plus syndrome (MIM#617303); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3454 COG2 Zornitza Stark Gene: cog2 has been classified as Red List (Low Evidence).
Mendeliome v0.3451 COG2 Zornitza Stark Classified gene: COG2 as Red List (low evidence)
Mendeliome v0.3451 COG2 Zornitza Stark Gene: cog2 has been classified as Red List (Low Evidence).
Mendeliome v0.3450 DACT1 Natalie Tan gene: DACT1 was added
gene: DACT1 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: DACT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DACT1 were set to PMID: 28054444; 22610794; 19701191
Phenotypes for gene: DACT1 were set to ?Townes-Brocks syndrome 2 (OMIM #617466)
Review for gene: DACT1 was set to RED
Added comment: Webb et al. (2017) reported 6 affected members of a 3-generation family with ?Townes-Brocks syndrome-2, identified heterozygosity for a nonsense mutation in the DACT1 gene that segregated with disease. Clinical features include imperforate anus, rectovaginal fistula, crossed fused renal ectopia, vesicoureteral reflux, unilateral microtia, overfolded helices and cupped ears. One family member (proband's mother) with scoliosis and spina bifida occulta. Neural tube defects reported in a study of human fetuses (PMID: 22610794) and a mouse model (PMID: 19701191). Listed in Decipher v10.0 for an individual with abnormalities of (i) head or neck (ii) nervous system (iii) skeletal system. Unlike the gene SALL1 that causes Townes-Brocks syndrome 1, there is no information specifically relating to DACT1 with radial dysplasia, as these were not observed in the family with ?Townes-Brocks syndrome 2 (PMID: 28054444).
Sources: NHS GMS
Mendeliome v0.3450 G6PC3 Zornitza Stark Gene: g6pc3 has been classified as Green List (High Evidence).
Mendeliome v0.3450 G6PC3 Zornitza Stark Phenotypes for gene: G6PC3 were changed from to Dursun syndrome 612541; Neutropenia, severe congenital 4, autosomal recessive 612541
Mendeliome v0.3447 POGLUT1 Zornitza Stark Gene: poglut1 has been classified as Green List (High Evidence).
Mendeliome v0.3447 POGLUT1 Zornitza Stark Phenotypes for gene: POGLUT1 were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 21 (MIM# 617232), Dowling-Degos disease 4 (MIM# 615696)
Mendeliome v0.3444 G6PC3 Belinda Chong reviewed gene: G6PC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21385794; Phenotypes: Dursun syndrome 612541, Neutropenia, severe congenital 4, autosomal recessive 612541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.3444 POGLUT1 Ain Roesley reviewed gene: POGLUT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807076, 24387993; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 21 (MIM# 617232), Dowling-Degos disease 4 (MIM# 615696); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3444 SEC23A Paul De Fazio reviewed gene: SEC23A: Rating: AMBER; Mode of pathogenicity: None; Publications: 16980979, 21039434, 16980978, 27148587; Phenotypes: Craniolenticulosutural dysplasia (MIM# 607812); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.3444 ARSG Zornitza Stark Gene: arsg has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3443 ARSG Zornitza Stark Classified gene: ARSG as Amber List (moderate evidence)
Mendeliome v0.3443 ARSG Zornitza Stark Gene: arsg has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3442 UVSSA Crystle Lee reviewed gene: UVSSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31421932; Phenotypes: UV-sensitive syndrome 3 (MIM#614640); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3441 FAM92A Zornitza Stark Gene: fam92a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3441 FAM92A Zornitza Stark Classified gene: FAM92A as Amber List (moderate evidence)
Mendeliome v0.3441 FAM92A Zornitza Stark Gene: fam92a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3440 FAM92A Zornitza Stark gene: FAM92A was added
gene: FAM92A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FAM92A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM92A were set to 30395363
Phenotypes for gene: FAM92A were set to Polydactyly, postaxial, type A9, MIM# 618219
Review for gene: FAM92A was set to AMBER
Added comment: Single family and a mouse model reported.
Sources: Expert list
Mendeliome v0.3439 KIAA0825 Zornitza Stark Gene: kiaa0825 has been classified as Green List (High Evidence).
Mendeliome v0.3439 KIAA0825 Zornitza Stark Classified gene: KIAA0825 as Green List (high evidence)
Mendeliome v0.3439 KIAA0825 Zornitza Stark Gene: kiaa0825 has been classified as Green List (High Evidence).
Mendeliome v0.3437 ZNF141 Zornitza Stark Gene: znf141 has been classified as Red List (Low Evidence).
Mendeliome v0.3434 ZNF141 Zornitza Stark Classified gene: ZNF141 as Red List (low evidence)
Mendeliome v0.3434 ZNF141 Zornitza Stark Gene: znf141 has been classified as Red List (Low Evidence).
Mendeliome v0.3433 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Green List (High Evidence).
Mendeliome v0.3433 NR0B1 Zornitza Stark Phenotypes for gene: NR0B1 were changed from Adrenal hypoplasia, congenital (MIM# 300200) to Adrenal hypoplasia, congenital (MIM# 300200); 46XY sex reversal 2, dosage-sensitive, MIM# 300018
Mendeliome v0.3432 NR0B1 Zornitza Stark Classified gene: NR0B1 as Green List (high evidence)
Mendeliome v0.3432 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Green List (High Evidence).
Mendeliome v0.3431 NR0B1 Zornitza Stark Classified gene: NR0B1 as Amber List (moderate evidence)
Mendeliome v0.3431 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3430 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Green List (High Evidence).
Mendeliome v0.3430 NR0B1 Zornitza Stark Phenotypes for gene: NR0B1 were changed from to Adrenal hypoplasia, congenital (MIM# 300200)
Mendeliome v0.3427 NSDHL Zornitza Stark Gene: nsdhl has been classified as Green List (High Evidence).
Mendeliome v0.3423 TFR2 Zornitza Stark Gene: tfr2 has been classified as Green List (High Evidence).
Mendeliome v0.3423 TFR2 Zornitza Stark Phenotypes for gene: TFR2 were changed from Hemochromatosis, type 3 (MIM#604250) to Haemochromatosis, type 3 (MIM#604250)
Mendeliome v0.3422 TFR2 Zornitza Stark Phenotypes for gene: TFR2 were changed from to Hemochromatosis, type 3 (MIM#604250)
Mendeliome v0.3419 ABCD3 Zornitza Stark Gene: abcd3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3419 ABCD3 Zornitza Stark Phenotypes for gene: ABCD3 were changed from to Bile acid synthesis defect, congenital, 5 (MIM#616278)
Mendeliome v0.3416 ABCD3 Zornitza Stark Classified gene: ABCD3 as Amber List (moderate evidence)
Mendeliome v0.3416 ABCD3 Zornitza Stark Gene: abcd3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3414 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Amber List (moderate evidence)
Mendeliome v0.3414 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3413 NR0B1 Ain Roesley reviewed gene: NR0B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19508677, 26030781; Phenotypes: Adrenal hypoplasia, congenital (MIM# 300200); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3413 TFR2 Teresa Zhao reviewed gene: TFR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24847265, 29743178; Phenotypes: Hemochromatosis, type 3 (MIM#604250); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3413 ORMDL3 Zornitza Stark Gene: ormdl3 has been classified as Red List (Low Evidence).
Mendeliome v0.3413 ORMDL3 Zornitza Stark Classified gene: ORMDL3 as Red List (low evidence)
Mendeliome v0.3413 ORMDL3 Zornitza Stark Gene: ormdl3 has been classified as Red List (Low Evidence).
Mendeliome v0.3412 ABCD3 Crystle Lee reviewed gene: ABCD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168382; Phenotypes: ?Bile acid synthesis defect, congenital, 5 (MIM#616278); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3412 NSMF Zornitza Stark Gene: nsmf has been classified as Red List (Low Evidence).
Mendeliome v0.3409 NSMF Zornitza Stark Classified gene: NSMF as Red List (low evidence)
Mendeliome v0.3409 NSMF Zornitza Stark Gene: nsmf has been classified as Red List (Low Evidence).
Mendeliome v0.3408 SPRY4 Zornitza Stark Gene: spry4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3405 SPRY4 Zornitza Stark Classified gene: SPRY4 as Amber List (moderate evidence)
Mendeliome v0.3405 SPRY4 Zornitza Stark Gene: spry4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3404 KISS1 Zornitza Stark Gene: kiss1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3401 KISS1 Zornitza Stark Classified gene: KISS1 as Amber List (moderate evidence)
Mendeliome v0.3401 KISS1 Zornitza Stark Gene: kiss1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3400 INSL3 Zornitza Stark Gene: insl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3397 INSL3 Zornitza Stark Classified gene: INSL3 as Amber List (moderate evidence)
Mendeliome v0.3397 INSL3 Zornitza Stark Gene: insl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3396 IL17RD Zornitza Stark Gene: il17rd has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3393 IL17RD Zornitza Stark Classified gene: IL17RD as Amber List (moderate evidence)
Mendeliome v0.3393 IL17RD Zornitza Stark Gene: il17rd has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3391 HS6ST1 Zornitza Stark Gene: hs6st1 has been classified as Red List (Low Evidence).
Mendeliome v0.3388 HS6ST1 Zornitza Stark Classified gene: HS6ST1 as Red List (low evidence)
Mendeliome v0.3388 HS6ST1 Zornitza Stark Gene: hs6st1 has been classified as Red List (Low Evidence).
Mendeliome v0.3387 GNRH1 Zornitza Stark Gene: gnrh1 has been classified as Green List (High Evidence).
Mendeliome v0.3384 KIF3B Zornitza Stark Phenotypes for gene: KIF3B were changed from hepatic fibrosis; retinitis pigmentosa; postaxial polydactyly to hepatic fibrosis; retinitis pigmentosa; postaxial polydactyly; Retinitis pigmentosa 89, MIM#618955
Mendeliome v0.3383 KIF3B Zornitza Stark edited their review of gene: KIF3B: Changed phenotypes: hepatic fibrosis, retinitis pigmentosa, postaxial polydactyly, Retinitis pigmentosa 89, MIM#618955
Mendeliome v0.3383 CUX2 Zornitza Stark Gene: cux2 has been classified as Green List (High Evidence).
Mendeliome v0.3380 DPM1 Zornitza Stark Gene: dpm1 has been classified as Green List (High Evidence).
Mendeliome v0.3377 GIPC1 Zornitza Stark Gene: gipc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3377 GIPC1 Zornitza Stark Classified gene: GIPC1 as Amber List (moderate evidence)
Mendeliome v0.3377 GIPC1 Zornitza Stark Gene: gipc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3376 GIPC1 Zornitza Stark gene: GIPC1 was added
gene: GIPC1 was added to Mendeliome. Sources: Literature
5'UTR, STR tags were added to gene: GIPC1.
Mode of inheritance for gene: GIPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIPC1 were set to 32413282
Phenotypes for gene: GIPC1 were set to Oculopharyngodistal myopathy-2 (OPDM2), MIM#618940
Review for gene: GIPC1 was set to AMBER
Added comment: 19 families reported with heterozygous trinucleotide repeat expansion in the 5-prime untranslated region and onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. Note this is unlikely to be tractable currently by most NGS assays.
Sources: Literature
Mendeliome v0.3375 SMC3 Zornitza Stark Gene: smc3 has been classified as Green List (High Evidence).
Mendeliome v0.3372 DEAF1 Zornitza Stark Gene: deaf1 has been classified as Green List (High Evidence).
Mendeliome v0.3372 DEAF1 Zornitza Stark Phenotypes for gene: DEAF1 were changed from to Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171; Vulto-van Silfout-de Vries syndrome 615828
Mendeliome v0.3368 DEAF1 Elena Savva reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 30923367, PMID 24726472; Phenotypes: Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171, Vulto-van Silfout-de Vries syndrome 615828; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3366 ABCC9 Zornitza Stark Gene: abcc9 has been classified as Green List (High Evidence).
Mendeliome v0.3366 ABCC9 Zornitza Stark Phenotypes for gene: ABCC9 were changed from to Hypertrichotic osteochondrodysplasia, MIM# 239850; Cantu syndrome; mild ID, similar facies, myopathy, cerebral white matter hyperintensities; cardiac systolic dysfunction
Mendeliome v0.3363 ABCC9 Zornitza Stark reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31575858, 22610116, 22608503; Phenotypes: Hypertrichotic osteochondrodysplasia, MIM# 239850, Cantu syndrome, mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3363 TSPYL1 Zornitza Stark Gene: tspyl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3363 TSPYL1 Zornitza Stark Phenotypes for gene: TSPYL1 were changed from to Sudden infant death with dysgenesis of the testes syndrome (MIM#608800)
Mendeliome v0.3360 TSPYL1 Zornitza Stark Classified gene: TSPYL1 as Amber List (moderate evidence)
Mendeliome v0.3360 TSPYL1 Zornitza Stark Gene: tspyl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3359 TSPYL1 Zornitza Stark reviewed gene: TSPYL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 15273283, 19463995, 22137496, 25449952, 16418600; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome (MIM#608800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3359 PIGM Zornitza Stark Gene: pigm has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3359 PIGM Zornitza Stark Phenotypes for gene: PIGM were changed from to Glycosylphosphatidylinositol deficiency, MIM# 610293; portal vein thrombosis; persistent absence seizures; macrocephaly; infantile-onset cerebrovascular thrombotic events
Mendeliome v0.3356 PIGM Zornitza Stark Classified gene: PIGM as Amber List (moderate evidence)
Mendeliome v0.3356 PIGM Zornitza Stark Gene: pigm has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3355 LEP Zornitza Stark Gene: lep has been classified as Green List (High Evidence).
Mendeliome v0.3355 LEP Zornitza Stark Phenotypes for gene: LEP were changed from to Obesity, morbid, due to leptin deficiency (MIM#614962)
Mendeliome v0.3352 LEPR Zornitza Stark Gene: lepr has been classified as Green List (High Evidence).
Mendeliome v0.3352 LEPR Zornitza Stark Phenotypes for gene: LEPR were changed from to Obesity, morbid, due to leptin receptor deficiency (MIM#614963)
Mendeliome v0.3349 FEZF1 Zornitza Stark Gene: fezf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3346 FEZF1 Zornitza Stark Classified gene: FEZF1 as Amber List (moderate evidence)
Mendeliome v0.3346 FEZF1 Zornitza Stark Gene: fezf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3345 ESR2 Zornitza Stark Gene: esr2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3345 ESR2 Zornitza Stark Phenotypes for gene: ESR2 were changed from to 46,XY disorder of sex development; Ovarian dysgenesis 8, MIM# 618187
Mendeliome v0.3342 ESR2 Zornitza Stark reviewed gene: ESR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29261182, 9861029, 30113650; Phenotypes: 46,XY disorder of sex development, Ovarian dysgenesis 8, MIM# 618187; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3342 PIGM Paul De Fazio reviewed gene: PIGM: Rating: AMBER; Mode of pathogenicity: None; Publications: 31445883, 16767100; Phenotypes: portal vein thrombosis, persistent absence seizures, macrocephaly, infantile-onset cerebrovascular thrombotic events; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.3342 LEP Crystle Lee reviewed gene: LEP: Rating: GREEN; Mode of pathogenicity: None; Publications: 26567097; Phenotypes: Obesity, morbid, due to leptin deficiency (MIM#614962); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3342 DMRT1 Zornitza Stark Gene: dmrt1 has been classified as Red List (Low Evidence).
Mendeliome v0.3339 DMRT1 Zornitza Stark Classified gene: DMRT1 as Red List (low evidence)
Mendeliome v0.3339 DMRT1 Zornitza Stark Gene: dmrt1 has been classified as Red List (Low Evidence).
Mendeliome v0.3338 CBX2 Zornitza Stark Gene: cbx2 has been classified as Red List (Low Evidence).
Mendeliome v0.3335 CBX2 Zornitza Stark Classified gene: CBX2 as Red List (low evidence)
Mendeliome v0.3335 CBX2 Zornitza Stark Gene: cbx2 has been classified as Red List (Low Evidence).
Mendeliome v0.3334 LEPR Crystle Lee reviewed gene: LEPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 17229951, 29545012; Phenotypes: Obesity, morbid, due to leptin receptor deficiency (MIM#614963); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3334 MCM5 Zornitza Stark Gene: mcm5 has been classified as Red List (Low Evidence).
Mendeliome v0.3333 MCM5 Zornitza Stark Classified gene: MCM5 as Red List (low evidence)
Mendeliome v0.3333 MCM5 Zornitza Stark Gene: mcm5 has been classified as Red List (Low Evidence).
Mendeliome v0.3332 ATF3 Zornitza Stark Gene: atf3 has been classified as Red List (Low Evidence).
Mendeliome v0.3332 ATF3 Zornitza Stark Classified gene: ATF3 as Red List (low evidence)
Mendeliome v0.3332 ATF3 Zornitza Stark Gene: atf3 has been classified as Red List (Low Evidence).
Mendeliome v0.3331 CNPY3 Zornitza Stark Gene: cnpy3 has been classified as Green List (High Evidence).
Mendeliome v0.3328 KIF21B Zornitza Stark Gene: kif21b has been classified as Green List (High Evidence).
Mendeliome v0.3328 KIF21B Zornitza Stark Classified gene: KIF21B as Green List (high evidence)
Mendeliome v0.3328 KIF21B Zornitza Stark Gene: kif21b has been classified as Green List (High Evidence).
Mendeliome v0.3327 KIF21B Zornitza Stark gene: KIF21B was added
gene: KIF21B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Mode of pathogenicity for gene: KIF21B 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: KIF21B was set to GREEN
Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Expert Review
Mendeliome v0.3326 TBC1D2B Zornitza Stark Gene: tbc1d2b has been classified as Green List (High Evidence).
Mendeliome v0.3326 TBC1D2B Zornitza Stark Classified gene: TBC1D2B as Green List (high evidence)
Mendeliome v0.3326 TBC1D2B Zornitza Stark Gene: tbc1d2b has been classified as Green List (High Evidence).
Mendeliome v0.3325 TBC1D2B Zornitza Stark gene: TBC1D2B was added
gene: TBC1D2B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Review for gene: TBC1D2B was set to GREEN
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants. Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations. All were born to non-consanguineous couples and additional investigations were performed in some. Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses. In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts. TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation. Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.
Sources: Expert Review
Mendeliome v0.3324 EXOC2 Zornitza Stark Gene: exoc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3324 EXOC2 Zornitza Stark Classified gene: EXOC2 as Amber List (moderate evidence)
Mendeliome v0.3324 EXOC2 Zornitza Stark Gene: exoc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3323 EXOC2 Zornitza Stark gene: EXOC2 was added
gene: EXOC2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: EXOC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC2 were set to 32639540
Phenotypes for gene: EXOC2 were set to Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology
Review for gene: EXOC2 was set to AMBER
Added comment: Van Bergen et al (2020 - PMID: 32639540) report on 3 individuals from 2 families, harboring biallelic EXOC2 mutations. Clinical presentation included DD, ID (severe in 2 subjects from fam1, borderline intellectual functioning in fam2), dysmorphic features and brain abnormalities. Cerebellar anomalies were common to all with a molar tooth sign observed in one (1/3). Other findings limited to subjects from one family included acquired microcephaly, congenital contractures, spastic quadriplegia (each observed 2/3). Previous investigations were in all cases non-diagnostic. WES identified biallelic EXOC2 mutations in all affected individuals. EXOC2 encodes an exocyst subunit. The latter is an octameric complex, component of the membrane transport machinery, required for tethering and fusion of vesicles at the plasma membrane. As discussed ,vesicle transport is important for the development of brain and the function of neurons and glia. Exocyst function is also important for delivery of Arl13b to the primary cilium (biallelic ARL13B mutations cause Joubert syndrome 8) and ciliogenesis. Affected subjects from a broader consanguineous family (fam1) were homozygous for a truncating variant. Fibroblast studies revealed mRNA levels compatible with NMD (further restored in presence of CHX) as well as reduced protein levels. The female belonging to the second non-consanguineous family was found to harbor 2 missense variants in trans configuration. An exocytosis defect was demonstrated in fibroblasts from individuals belonging to both families. Ciliogenesis appeared to be normal, however Arl13b localization/recruitment to the cilia was reduced compared with control cells with the defect rescued upon exogenous expression of wt EXOC2. Mutations in other genes encoding components of the exocyst complex have been previously reported in individuals with relevant phenotypes (e.g. EXOC8 in a boy with features of Joubert s. or EXOC4 in nephrotic syndrome). The authors discuss on the essential role of EXOC2 based on model organism studies (e.g. impaired neuronal membrane traffic, failure of neuronal polarization and neuromuscular junction expansion seen in Drosophila Sec5 (EXOC2) null mutants).
Sources: Expert Review
Mendeliome v0.3322 CCDC174 Zornitza Stark Gene: ccdc174 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3322 CCDC174 Zornitza Stark Classified gene: CCDC174 as Amber List (moderate evidence)
Mendeliome v0.3322 CCDC174 Zornitza Stark Gene: ccdc174 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3321 CCDC174 Zornitza Stark gene: CCDC174 was added
gene: CCDC174 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC174 were set to 26358778
Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816
Review for gene: CCDC174 was set to AMBER
Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816). Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype. Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports.
Sources: Expert Review
Mendeliome v0.3320 ACOX2 Zornitza Stark Classified gene: ACOX2 as Green List (high evidence)
Mendeliome v0.3320 ACOX2 Zornitza Stark Gene: acox2 has been classified as Green List (High Evidence).
Mendeliome v0.3319 ABCA2 Zornitza Stark Gene: abca2 has been classified as Green List (High Evidence).
Mendeliome v0.3319 ABCA2 Zornitza Stark Classified gene: ABCA2 as Green List (high evidence)
Mendeliome v0.3319 ABCA2 Zornitza Stark Gene: abca2 has been classified as Green List (High Evidence).
Mendeliome v0.3318 ABCA2 Zornitza Stark gene: ABCA2 was added
gene: ABCA2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808). There are 3 relevant publications (01-07-2020) : - Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations. - Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures. - Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype. All subjects harbored biallelic pLoF variants. N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency. Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Expert Review
Mendeliome v0.3317 HERC2 Zornitza Stark Gene: herc2 has been classified as Green List (High Evidence).
Mendeliome v0.3317 HERC2 Zornitza Stark Phenotypes for gene: HERC2 were changed from to Mental retardation, autosomal recessive 38 (MIM 615516)
Mendeliome v0.3314 HERC2 Zornitza Stark reviewed gene: HERC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23065719, 23243086, 30902390, 32571899, 27848944, 26077850, 27759030; Phenotypes: Mental retardation, autosomal recessive 38 (MIM 615516); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3314 ALOX12 Zornitza Stark Gene: alox12 has been classified as Red List (Low Evidence).
Mendeliome v0.3314 ALOX12 Zornitza Stark Classified gene: ALOX12 as Red List (low evidence)
Mendeliome v0.3314 ALOX12 Zornitza Stark Gene: alox12 has been classified as Red List (Low Evidence).
Mendeliome v0.3313 ETF1 Zornitza Stark Gene: etf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3313 ETF1 Zornitza Stark Classified gene: ETF1 as Red List (low evidence)
Mendeliome v0.3313 ETF1 Zornitza Stark Gene: etf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3309 SGMS2 Bryony Thompson Gene: sgms2 has been classified as Green List (High Evidence).
Mendeliome v0.3309 SGMS2 Bryony Thompson Classified gene: SGMS2 as Green List (high evidence)
Mendeliome v0.3309 SGMS2 Bryony Thompson Gene: sgms2 has been classified as Green List (High Evidence).
Mendeliome v0.3308 SGMS2 Bryony Thompson gene: SGMS2 was added
gene: SGMS2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGMS2 were set to 30779713; 32028018
Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia MIM#126550
Review for gene: SGMS2 was set to GREEN
Added comment: 12 patients from 6 unrelated families with the same stopgain variant (p.Arg50*), with osteoporosis that resembles osteogenesis imperfecta. In vitro over-expression assays of the variant demonstrate protein that was completely mislocalized in the cytosolic and nuclear compartments. 2 unrelated families were heterozygous for 2 missense (p.Ile62Ser, p.Met64Arg) with bone fragility and severe short stature, and spondylometaphyseal dysplasia. In vitro assays of each variant demonstrated an enhanced rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum.
Sources: Expert list
Mendeliome v0.3307 AKR1C4 Zornitza Stark Gene: akr1c4 has been classified as Red List (Low Evidence).
Mendeliome v0.3304 AKR1C4 Zornitza Stark Classified gene: AKR1C4 as Red List (low evidence)
Mendeliome v0.3304 AKR1C4 Zornitza Stark Gene: akr1c4 has been classified as Red List (Low Evidence).
Mendeliome v0.3303 PIP5K1C Zornitza Stark Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3300 PIP5K1C Zornitza Stark Classified gene: PIP5K1C as Amber List (moderate evidence)
Mendeliome v0.3300 PIP5K1C Zornitza Stark Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3299 ERBB3 Zornitza Stark Gene: erbb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3296 ERBB3 Zornitza Stark Classified gene: ERBB3 as Amber List (moderate evidence)
Mendeliome v0.3296 ERBB3 Zornitza Stark Gene: erbb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3295 DPM2 Zornitza Stark Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3292 DPM2 Zornitza Stark Classified gene: DPM2 as Amber List (moderate evidence)
Mendeliome v0.3292 DPM2 Zornitza Stark Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3291 C17orf62 Zornitza Stark Phenotypes for gene: C17orf62 were changed from Chronic granulomatous disease to Chronic granulomatous disease 5, autosomal recessive, MIM# 618935
Mendeliome v0.3290 C17orf62 Zornitza Stark edited their review of gene: C17orf62: Changed phenotypes: Chronic granulomatous disease 5, autosomal recessive, MIM# 618935
Mendeliome v0.3290 DYSF Zornitza Stark Gene: dysf has been classified as Green List (High Evidence).
Mendeliome v0.3290 DYSF Zornitza Stark Phenotypes for gene: DYSF were changed from to Miyoshi muscular dystrophy 1 254130; Muscular dystrophy, limb-girdle, autosomal recessive 2 253601; Myopathy, distal, with anterior tibial onset 606768
Mendeliome v0.3287 NEB Zornitza Stark Gene: neb has been classified as Green List (High Evidence).
Mendeliome v0.3287 NEB Zornitza Stark Phenotypes for gene: NEB were changed from to Nemaline myopathy 2, autosomal recessive 256030
Mendeliome v0.3284 MRPS34 Zornitza Stark Gene: mrps34 has been classified as Green List (High Evidence).
Mendeliome v0.3281 NEB Elena Savva reviewed gene: NEB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25205138; Phenotypes: Nemaline myopathy 2, autosomal recessive 256030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3281 DYSF Elena Savva reviewed gene: DYSF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27602406; Phenotypes: Miyoshi muscular dystrophy 1 254130, Muscular dystrophy, limb-girdle, autosomal recessive 2 253601, Myopathy, distal, with anterior tibial onset 606768; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3281 GLS Zornitza Stark Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328; Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Epileptic encephalopathy, early infantile, 71, MIM# 618328; Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412; Cataract
Mendeliome v0.3278 GLS Zornitza Stark edited their review of gene: GLS: Added comment: In addition, single individual also reported with de novo, GoF variant with profound ID, cataract.; Changed publications: 30575854, 30970188, 30239721
Mendeliome v0.3278 GLS Zornitza Stark edited their review of gene: GLS: Changed phenotypes: Epileptic encephalopathy, early infantile, 71, MIM# 618328, Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412, Catarct; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3278 PYCR1 Dean Phelan changed review comment from: Aortopathy/Connective tissue review

Variants in this gene are associated with Cutis Laxa:
Cutis laxa type 2 (ARCL2, [MIM 219200]) is an autosomal-recessive multisystem disorder with prominent connective-tissue features characterized by the appearance of premature aging, particularly wrinkled and lax skin with reduced elasticity.

GEL PanelApp: Green in EDS panel - clinical features overlapping EDS
Cutis laxa, autosomal recessive, type IIIB (ARCL3B) PMID: 19648921,4076251, 22052856
Cutis laxa, autosomal recessive, type IIB (ARCL2B) PMID: 19576563, 19648921, 9648921, 22052856, 28294978 AR

PMID: 27756598: a homozygous mutation in PYCR1 segregating in the family with the affected individuals with complex connective tissue disorder and severe intellectual disability.; to: Aortopathy/Connective tissue review

Variants in this gene are associated with Cutis Laxa:
Cutis laxa type 2 (ARCL2, [MIM 219200]) is an autosomal-recessive multisystem disorder with prominent connective-tissue features characterized by the appearance of premature aging, particularly wrinkled and lax skin with reduced elasticity.

GEL PanelApp: Green in EDS panel - clinical features overlapping EDS
Cutis laxa, autosomal recessive, type IIIB (ARCL3B) PMID: 19648921,4076251, 22052856
Cutis laxa, autosomal recessive, type IIB (ARCL2B) PMID: 19576563, 19648921, 9648921, 22052856, 28294978 AR

PMID: 27756598: a homozygous mutation in PYCR1 segregating in the family with the affected individuals with complex connective tissue disorder and severe intellectual disability.
Mendeliome v0.3278 PYCR1 Seb Lunke Gene: pycr1 has been classified as Green List (High Evidence).
Mendeliome v0.3275 PIGY Zornitza Stark Gene: pigy has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3275 PIGY Zornitza Stark Phenotypes for gene: PIGY were changed from to Hyperphosphatasia with mental retardation syndrome 6, MIM# 616809
Mendeliome v0.3272 PIGY Zornitza Stark Classified gene: PIGY as Amber List (moderate evidence)
Mendeliome v0.3272 PIGY Zornitza Stark Gene: pigy has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3271 MTMR14 Zornitza Stark Added comment: Comment when marking as ready: Single family and animal models; postulated to be a modifier in the other family.
Mendeliome v0.3271 MTMR14 Zornitza Stark Gene: mtmr14 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3271 MTMR14 Zornitza Stark Classified gene: MTMR14 as Amber List (moderate evidence)
Mendeliome v0.3271 MTMR14 Zornitza Stark Gene: mtmr14 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3270 MTMR14 Zornitza Stark Gene: mtmr14 has been classified as Red List (Low Evidence).
Mendeliome v0.3268 P4HA1 Zornitza Stark Gene: p4ha1 has been classified as Red List (Low Evidence).
Mendeliome v0.3268 P4HA1 Zornitza Stark gene: P4HA1 was added
gene: P4HA1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: P4HA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HA1 were set to 28419360
Phenotypes for gene: P4HA1 were set to Joint hypermobility; Contractures; Hypotonia; Mild skeletal dysplasia without bone fragility; High myopia
Review for gene: P4HA1 was set to RED
Added comment: Single family reported with two affected individuals.
Sources: Expert list
Mendeliome v0.3267 ROBO3 Ain Roesley reviewed gene: ROBO3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15105459, 32373565; Phenotypes: Gaze palsy, familial horizontal, with progressive scoliosis, 1 (MIM# 607313); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3267 PIGY Elena Savva reviewed gene: PIGY: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26293662; Phenotypes: Hyperphosphatasia with mental retardation syndrome 6, MIM# 616809; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3267 GGPS1 Zornitza Stark Gene: ggps1 has been classified as Green List (High Evidence).
Mendeliome v0.3267 GGPS1 Zornitza Stark Classified gene: GGPS1 as Green List (high evidence)
Mendeliome v0.3267 GGPS1 Zornitza Stark Gene: ggps1 has been classified as Green List (High Evidence).
Mendeliome v0.3265 DNMBP Seb Lunke Gene: dnmbp has been classified as Green List (High Evidence).
Mendeliome v0.3265 DNMBP Seb Lunke Classified gene: DNMBP as Green List (high evidence)
Mendeliome v0.3265 DNMBP Seb Lunke Gene: dnmbp has been classified as Green List (High Evidence).
Mendeliome v0.3263 CRYGA Zornitza Stark Gene: cryga has been classified as Red List (Low Evidence).
Mendeliome v0.3263 CRYGA Zornitza Stark gene: CRYGA was added
gene: CRYGA was added to Mendeliome. Sources: Expert list
refuted tags were added to gene: CRYGA.
Mode of inheritance for gene: CRYGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRYGA were set to 30450742; 28839118
Phenotypes for gene: CRYGA were set to Cataract
Review for gene: CRYGA was set to RED
Added comment: Reported as potentially disease causing in multiple individuals from two seperate families, but in both cases variant is present in the general population (20 Hets for one variant, >1000 hets and 9 homs in other variant)
Sources: Expert list
Mendeliome v0.3262 AKR1E2 Zornitza Stark Gene: akr1e2 has been classified as Red List (Low Evidence).
Mendeliome v0.3262 AKR1E2 Zornitza Stark gene: AKR1E2 was added
gene: AKR1E2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: AKR1E2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AKR1E2 were set to 26622071
Phenotypes for gene: AKR1E2 were set to congenital cataracts
Review for gene: AKR1E2 was set to RED
Added comment: Same family with homozygous canonical splice variants and 3 cases of congenital cataract described in 2012 (original) and 2015 (review). No other descriptions since.
Sources: Expert list
Mendeliome v0.3261 ADAMTSL4 Zornitza Stark Gene: adamtsl4 has been classified as Green List (High Evidence).
Mendeliome v0.3261 ADAMTSL4 Zornitza Stark Phenotypes for gene: ADAMTSL4 were changed from to Ectopia lentis, isolated, autosomal recessive, MIM# 225100
Mendeliome v0.3258 ADAMTSL4 Zornitza Stark reviewed gene: ADAMTSL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19200529, 20564469, 20141359, 21051722; Phenotypes: Ectopia lentis, isolated, autosomal recessive, MIM# 225100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3258 HIST1H4C Zornitza Stark Gene: hist1h4c has been classified as Green List (High Evidence).
Mendeliome v0.3255 SFTPA1 Zornitza Stark Gene: sftpa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3255 SFTPA1 Zornitza Stark Phenotypes for gene: SFTPA1 were changed from to Idiopathic pulmonary fibrosis
Mendeliome v0.3252 SFTPA1 Zornitza Stark Classified gene: SFTPA1 as Amber List (moderate evidence)
Mendeliome v0.3252 SFTPA1 Zornitza Stark Gene: sftpa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3251 SFTPA1 Zornitza Stark reviewed gene: SFTPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31601679, 30854216, 28869238, 26792177; Phenotypes: Idiopathic pulmonary fibrosis; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.3251 CFAP74 Zornitza Stark Gene: cfap74 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3251 CFAP74 Zornitza Stark Classified gene: CFAP74 as Amber List (moderate evidence)
Mendeliome v0.3251 CFAP74 Zornitza Stark Gene: cfap74 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3250 CFAP74 Zornitza Stark gene: CFAP74 was added
gene: CFAP74 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP74 were set to 32555313
Phenotypes for gene: CFAP74 were set to Primary ciliary dyskinesia; infertility
Review for gene: CFAP74 was set to AMBER
Added comment: Two unrelated individuals with compound het missense variants reported.
Sources: Literature
Mendeliome v0.3249 ASPRV1 Zornitza Stark Gene: asprv1 has been classified as Green List (High Evidence).
Mendeliome v0.3249 ASPRV1 Zornitza Stark Classified gene: ASPRV1 as Green List (high evidence)
Mendeliome v0.3249 ASPRV1 Zornitza Stark Gene: asprv1 has been classified as Green List (High Evidence).
Mendeliome v0.3248 ASPRV1 Ee Ming Wong gene: ASPRV1 was added
gene: ASPRV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASPRV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ASPRV1 were set to PMID: 32516568
Phenotypes for gene: ASPRV1 were set to palmoplantar keratoderma; lamellar ichthyosis
Review for gene: ASPRV1 was set to GREEN
gene: ASPRV1 was marked as current diagnostic
Added comment: -3 heterozygous missense variants identified across 4 unrelated kindreds
-mutant ASPRV1 expressed in human keratinocytes suggests impaired filaggrin processing
Sources: Literature
Mendeliome v0.3248 LGR4 Zornitza Stark Gene: lgr4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3246 SREBF1 Seb Lunke Gene: srebf1 has been classified as Green List (High Evidence).
Mendeliome v0.3246 SREBF1 Seb Lunke Classified gene: SREBF1 as Green List (high evidence)
Mendeliome v0.3246 SREBF1 Seb Lunke Gene: srebf1 has been classified as Green List (High Evidence).
Mendeliome v0.3245 BTG4 Seb Lunke Gene: btg4 has been classified as Green List (High Evidence).
Mendeliome v0.3245 BTG4 Seb Lunke Classified gene: BTG4 as Green List (high evidence)
Mendeliome v0.3245 BTG4 Seb Lunke Gene: btg4 has been classified as Green List (High Evidence).
Mendeliome v0.3244 TRIP13 Seb Lunke Gene: trip13 has been classified as Green List (High Evidence).
Mendeliome v0.3243 LGR4 Zornitza Stark Classified gene: LGR4 as Amber List (moderate evidence)
Mendeliome v0.3243 LGR4 Zornitza Stark Gene: lgr4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3242 SREBF1 Paul De Fazio gene: SREBF1 was added
gene: SREBF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SREBF1 were set to 32497488
Phenotypes for gene: SREBF1 were set to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome
Review for gene: SREBF1 was set to GREEN
gene: SREBF1 was marked as current diagnostic
Added comment: 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. 3 different msisense variants identified affecting the same region (residues 527, 528, and 530). Functional studies support impaired function (impaired nuclear translocation of the transcriptionally active form of SREBP1 resulting in lower expression of the SREBP1 variants). Increased keratinocyte apoptosis was observed in patient scalp samples.
Sources: Literature
Mendeliome v0.3242 RAP1GDS1 Zornitza Stark Gene: rap1gds1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3242 RAP1GDS1 Zornitza Stark Classified gene: RAP1GDS1 as Amber List (moderate evidence)
Mendeliome v0.3242 RAP1GDS1 Zornitza Stark Gene: rap1gds1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3241 KIAA1217 Zornitza Stark Gene: kiaa1217 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3241 KIAA1217 Zornitza Stark Classified gene: KIAA1217 as Amber List (moderate evidence)
Mendeliome v0.3241 KIAA1217 Zornitza Stark Gene: kiaa1217 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3239 LGR4 Elena Savva reviewed gene: LGR4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32493844; Phenotypes: {Bone mineral density, low, susceptibility to} 615311; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3239 RAP1GDS1 Zornitza Stark gene: RAP1GDS1 was added
gene: RAP1GDS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAP1GDS1 were set to 32431071
Phenotypes for gene: RAP1GDS1 were set to Intellectual disability; dysmorphic features
Review for gene: RAP1GDS1 was set to AMBER
Added comment: Four individuals from two consanguineous families, same homozygous splice site variant detected.
Sources: Literature
Mendeliome v0.3238 HOXD10 Zornitza Stark Gene: hoxd10 has been classified as Red List (Low Evidence).
Mendeliome v0.3235 HOXD10 Zornitza Stark Classified gene: HOXD10 as Red List (low evidence)
Mendeliome v0.3235 HOXD10 Zornitza Stark Gene: hoxd10 has been classified as Red List (Low Evidence).
Mendeliome v0.3234 ADPRHL2 Zornitza Stark Gene: adprhl2 has been classified as Green List (High Evidence).
Mendeliome v0.3231 ADPRHL2 Zornitza Stark changed review comment from: Ataxia is part of the phenotype.
Sources: Expert list; to: 14 families reported, onset is in the first years of life following normal early development. Patients have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy.
Sources: Expert list
Mendeliome v0.3231 GPR161 Zornitza Stark Gene: gpr161 has been classified as Green List (High Evidence).
Mendeliome v0.3231 GPR161 Zornitza Stark Classified gene: GPR161 as Green List (high evidence)
Mendeliome v0.3231 GPR161 Zornitza Stark Gene: gpr161 has been classified as Green List (High Evidence).
Mendeliome v0.3230 GPR161 Zornitza Stark gene: GPR161 was added
gene: GPR161 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPR161 were set to 31609649
Phenotypes for gene: GPR161 were set to Predisposition to paediatric medulloblastoma
Review for gene: GPR161 was set to GREEN
Added comment: 6 unrelated individuals reported with germline variants, 5 with truncating, one missense. Somatic second hit in tumour tissue.
Sources: Literature
Mendeliome v0.3229 SETD1B Zornitza Stark Gene: setd1b has been classified as Green List (High Evidence).
Mendeliome v0.3226 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Mendeliome v0.3226 ARF1 Zornitza Stark Classified gene: ARF1 as Green List (high evidence)
Mendeliome v0.3226 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Mendeliome v0.3223 MRAS Zornitza Stark Gene: mras has been classified as Green List (High Evidence).
Mendeliome v0.3223 MRAS Zornitza Stark Classified gene: MRAS as Green List (high evidence)
Mendeliome v0.3223 MRAS Zornitza Stark Gene: mras has been classified as Green List (High Evidence).
Mendeliome v0.3222 MRAS Zornitza Stark changed review comment from: Two unrelated individuals reported with de novo variants in this gene. Rated as LIMITED by ClinGen.
Sources: Expert list; to: Two unrelated individuals reported with de novo variants in this gene initially. Rated as LIMITED by ClinGen in 2018. Note 4 further individuals reported since.
Sources: Expert list
Mendeliome v0.3221 A2ML1 Zornitza Stark Gene: a2ml1 has been classified as Red List (Low Evidence).
Mendeliome v0.3218 A2ML1 Zornitza Stark Classified gene: A2ML1 as Red List (low evidence)
Mendeliome v0.3218 A2ML1 Zornitza Stark Gene: a2ml1 has been classified as Red List (Low Evidence).
Mendeliome v0.3217 NRG1 Bryony Thompson Gene: nrg1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3217 NRG1 Bryony Thompson Classified gene: NRG1 as Amber List (moderate evidence)
Mendeliome v0.3217 NRG1 Bryony Thompson Gene: nrg1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3215 FLRT3 Zornitza Stark Gene: flrt3 has been classified as Red List (Low Evidence).
Mendeliome v0.3212 FLRT3 Zornitza Stark Classified gene: FLRT3 as Red List (low evidence)
Mendeliome v0.3212 FLRT3 Zornitza Stark Gene: flrt3 has been classified as Red List (Low Evidence).
Mendeliome v0.3211 CCDC32 Zornitza Stark Added comment: Comment when marking as ready: Three affected individuals from two unrelated families, supportive animal model and other functional data consistent with this being a ciliopathy.
Mendeliome v0.3211 CCDC32 Zornitza Stark Gene: ccdc32 has been classified as Green List (High Evidence).
Mendeliome v0.3211 CCDC32 Zornitza Stark Classified gene: CCDC32 as Green List (high evidence)
Mendeliome v0.3211 CCDC32 Zornitza Stark Gene: ccdc32 has been classified as Green List (High Evidence).
Mendeliome v0.3210 CAPZA2 Zornitza Stark Gene: capza2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3210 CAPZA2 Zornitza Stark Classified gene: CAPZA2 as Amber List (moderate evidence)
Mendeliome v0.3210 CAPZA2 Zornitza Stark Gene: capza2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3209 PPP3R1 Zornitza Stark Gene: ppp3r1 has been classified as Red List (Low Evidence).
Mendeliome v0.3209 PPP3R1 Zornitza Stark Classified gene: PPP3R1 as Red List (low evidence)
Mendeliome v0.3209 PPP3R1 Zornitza Stark Gene: ppp3r1 has been classified as Red List (Low Evidence).
Mendeliome v0.3208 PLEK Zornitza Stark Gene: plek has been classified as Red List (Low Evidence).
Mendeliome v0.3208 PLEK Zornitza Stark Classified gene: PLEK as Red List (low evidence)
Mendeliome v0.3208 PLEK Zornitza Stark Gene: plek has been classified as Red List (Low Evidence).
Mendeliome v0.3207 CNRIP1 Zornitza Stark Gene: cnrip1 has been classified as Red List (Low Evidence).
Mendeliome v0.3207 CNRIP1 Zornitza Stark Classified gene: CNRIP1 as Red List (low evidence)
Mendeliome v0.3207 CNRIP1 Zornitza Stark Gene: cnrip1 has been classified as Red List (Low Evidence).
Mendeliome v0.3206 RAD21 Zornitza Stark Gene: rad21 has been classified as Green List (High Evidence).
Mendeliome v0.3202 PPP3R1 Eleanor Williams gene: PPP3R1 was added
gene: PPP3R1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP3R1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP3R1 were set to 32337552; 19159392
Phenotypes for gene: PPP3R1 were set to Deafness, autosomal dominant 58 MIM#615654
Review for gene: PPP3R1 was set to RED
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Mendeliome v0.3202 PLEK Eleanor Williams gene: PLEK was added
gene: PLEK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLEK were set to 32337552; 19159392
Phenotypes for gene: PLEK were set to Deafness, autosomal dominant 58 MIM#615654
Review for gene: PLEK was set to RED
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Mendeliome v0.3202 CNRIP1 Eleanor Williams gene: CNRIP1 was added
gene: CNRIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNRIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNRIP1 were set to 32337552; 19159392
Phenotypes for gene: CNRIP1 were set to Deafness, autosomal dominant 58 MIM#615654
Review for gene: CNRIP1 was set to RED
Added comment: PMID: 32337552 - Lezirovitz et al 2020- ~200 Kb genomic duplication in 2p14 was found that segregates with postlingual progressive sensorineural autosomal dominant hearing loss in a large Brazilian family with 20 affected individuals (the reported DFNA58 family from PMID: 19159392). The duplication covers PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), as well as four uncharacterized long non-coding RNA genes and part of a novel protein-coding gene. Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea and CNRIP1 mRNA was overexpressed in affected family members.
Sources: Literature
Mendeliome v0.3202 SKIV2L Zornitza Stark Gene: skiv2l has been classified as Green List (High Evidence).
Mendeliome v0.3199 NLRP5 Zornitza Stark Gene: nlrp5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3199 NLRP5 Zornitza Stark Classified gene: NLRP5 as Amber List (moderate evidence)
Mendeliome v0.3199 NLRP5 Zornitza Stark Gene: nlrp5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3197 EMILIN1 Zornitza Stark Gene: emilin1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3197 EMILIN1 Zornitza Stark Classified gene: EMILIN1 as Amber List (moderate evidence)
Mendeliome v0.3197 EMILIN1 Zornitza Stark Gene: emilin1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3196 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Literature
Mendeliome v0.3195 HNRNPH1 Zornitza Stark gene: HNRNPH1 was added
gene: HNRNPH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPH1 were set to 32335897; 29938792
Phenotypes for gene: HNRNPH1 were set to HNRNPH1‐related syndromic intellectual disability
Review for gene: HNRNPH1 was set to GREEN
Added comment: 1st patient reported in 2018 with intellectual disability and dysmorphic features and HNRNPH1 heterozygous missense variant. 2020 paper reports additional 7 cases with ID, short stature, microcephaly, distinctive dysmorphic facial features, and congenital anomalies (cranial, brain, genitourinary, palate, ophthalmologic). They all had HNRNPH1 heterozygous pathogenic variants (missense, frameshift, in‐frame deletion, entire gene duplication) and were identified using clinical networks and GeneMatcher. No comments in paper if all de novo.
Sources: Literature
Mendeliome v0.3194 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to Microcephaly; intellectual disability
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies.
Sources: Literature
Mendeliome v0.3193 NME5 Zornitza Stark Gene: nme5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3193 NME5 Zornitza Stark Classified gene: NME5 as Amber List (moderate evidence)
Mendeliome v0.3193 NME5 Zornitza Stark Gene: nme5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3192 NME5 Zornitza Stark gene: NME5 was added
gene: NME5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NME5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NME5 were set to 32185794
Phenotypes for gene: NME5 were set to Primary ciliary dyskinesia
Review for gene: NME5 was set to AMBER
Added comment: One patient with PCD with situs solitus, with radial spokes (RS) and central pair (CP) defects. Patient had a homozygous nonsense variant in NME5, with parents as carriers. Morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy.
Sources: Literature
Mendeliome v0.3190 ADAMTS19 Zornitza Stark Classified gene: ADAMTS19 as Green List (high evidence)
Mendeliome v0.3190 ADAMTS19 Zornitza Stark Gene: adamts19 has been classified as Green List (High Evidence).
Mendeliome v0.3189 EMILIN1 Naomi Baker changed review comment from: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
Sources: Literature; to: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
Sources: Literature
Mendeliome v0.3189 EMILIN1 Naomi Baker gene: EMILIN1 was added
gene: EMILIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EMILIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMILIN1 were set to PMID: 31978608; 26462740.
Phenotypes for gene: EMILIN1 were set to peripheral neuropathy
Penetrance for gene: EMILIN1 were set to unknown
Review for gene: EMILIN1 was set to AMBER
Added comment: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
Sources: Literature
Mendeliome v0.3189 ADAMTS3 Zornitza Stark Gene: adamts3 has been classified as Green List (High Evidence).
Mendeliome v0.3189 ADAMTS3 Zornitza Stark Classified gene: ADAMTS3 as Green List (high evidence)
Mendeliome v0.3189 ADAMTS3 Zornitza Stark Gene: adamts3 has been classified as Green List (High Evidence).
Mendeliome v0.3188 ADAMTS3 Zornitza Stark gene: ADAMTS3 was added
gene: ADAMTS3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ADAMTS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS3 were set to 28985353; 30450763
Phenotypes for gene: ADAMTS3 were set to Hennekam lymphangiectasia-lymphedema syndrome 3 (618154)
Review for gene: ADAMTS3 was set to GREEN
Added comment: Two families reported, supportive functional data.
Sources: Expert list
Mendeliome v0.3186 SP6 Zornitza Stark Gene: sp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3186 SP6 Zornitza Stark Classified gene: SP6 as Amber List (moderate evidence)
Mendeliome v0.3186 SP6 Zornitza Stark Gene: sp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3185 MCM3AP Eleanor Williams changed review comment from: PMID: 32202298 - Woldegebriel et al - report a further two families, one in the Netherlands and one in Estonia, with probands with compound heterozygous variants in MCM3AP and a peripheral neuropathy with or without impaired intellectual development (MIM 618124) phenotype. The child from the Netherlands presented with severe hypotonia and intellectual disability. The two siblings from the Estonian family had severe generalized epilepsy and mild spastic diplegia. Functional studies using skin fibroblasts from these and other affected patients showed that disease variants result in depletion of GANP (encoded by MCM3AP) except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants.; to: PMID: 32202298 - Woldegebriel et al 2020 - report a further two families, one in the Netherlands and one in Estonia, with probands with compound heterozygous variants in MCM3AP and a peripheral neuropathy with or without impaired intellectual development (MIM 618124) phenotype. The child from the Netherlands presented with severe hypotonia and intellectual disability. The two siblings from the Estonian family had severe generalized epilepsy and mild spastic diplegia. Functional studies using skin fibroblasts from these and other affected patients showed that disease variants result in depletion of GANP (encoded by MCM3AP) except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants.
Mendeliome v0.3185 SP6 Eleanor Williams gene: SP6 was added
gene: SP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SP6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SP6 were set to 32167558; 18156176; 18297738; 22676574
Phenotypes for gene: SP6 were set to hypoplastic amelogenesis imperfecta
Review for gene: SP6 was set to AMBER
Added comment: PMID: 32167558 - Smith et al 2020 - report a 2 bp variant c.817_818GC>AA in SP6 in a Caucasian family with autosomal dominant hypoplastic AI which results in a missense change. Report that mice and rat knockouts also show a dental phenotype (PMID: 18156176, 18297738, 22676574 )
Sources: Literature
Mendeliome v0.3185 MYH8 Zornitza Stark Gene: myh8 has been classified as Green List (High Evidence).
Mendeliome v0.3182 CACNB1 Zornitza Stark Gene: cacnb1 has been classified as Red List (Low Evidence).
Mendeliome v0.3182 CACNB1 Zornitza Stark gene: CACNB1 was added
gene: CACNB1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CACNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNB1 were set to 27832566; 8943043; 29212769
Phenotypes for gene: CACNB1 were set to Malignant hyperthermia susceptibility
Added comment: A single heterozygous case with a positive IVCT muscle biopsy has been reported with p.Val156Ala. The European non-Finnish allele frequency in gnomAD v2.1 is 0.001146 (148/129,118 alleles), which is higher than the expected population frequency for dominantly inherited malignant hyperthermia (0.1%). Additionally, functional assays of this variant, suggest it would only significantly affect function in the homozygous state (suggesting a recessive condition).
Sources: Expert list
Mendeliome v0.3181 GATA6 Zornitza Stark Gene: gata6 has been classified as Green List (High Evidence).
Mendeliome v0.3181 GATA6 Zornitza Stark Phenotypes for gene: GATA6 were changed from to Pancreatic agenesis and congenital heart defects, 600001; Atrial septal defect 9, 614475; Atrioventricular septal defect 5, 614474; Tetralogy of Fallot, 187500; Persistent truncus arteriosus, 217095
Mendeliome v0.3177 GATA6 Elena Savva reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:20581743, 19666519; Phenotypes: Pancreatic agenesis and congenital heart defects, 600001, Atrial septal defect 9, 614475, Atrioventricular septal defect 5, 614474, Tetralogy of Fallot, 187500, Persistent truncus arteriosus, 217095; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.3177 CDH2 Zornitza Stark Phenotypes for gene: CDH2 were changed from Intellectual disability; corpus callosum abnormalities; congenital abnormalities to Intellectual disability; corpus callosum abnormalities; congenital abnormalities; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929
Mendeliome v0.3176 CDH2 Zornitza Stark edited their review of gene: CDH2: Changed phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities, Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929
Mendeliome v0.3174 TSHZ1 Zornitza Stark changed review comment from: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487).; to: Two individuals reported with LoF variants, both with a phenotype of congenital aural atresia and hyposmia (PMID: 22152683). Temporal and spatial expression of Tshz1 mRNA during development of the middle ear is consistent with the phenotype (PMID: 17586487). Tsh2 null mouse model showed a middle ear malformation, and neonatal lethality. A conditional nervous system-specific Tshz1 knock out mouse model demonstrated hyposmia (PMIDs: 24487590; 17586487). Also note original report contains four individuals with deletions of this gene, further supporting gene-disease association.
Mendeliome v0.3173 TSHZ1 Zornitza Stark Gene: tshz1 has been classified as Green List (High Evidence).
Mendeliome v0.3173 TSHZ1 Zornitza Stark Phenotypes for gene: TSHZ1 were changed from to Aural atresia, congenital, MIM# 607842; Hyposmia
Mendeliome v0.3170 TSHZ1 Zornitza Stark reviewed gene: TSHZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15834955, 22152683, 17586487, 24487590; Phenotypes: Aural atresia, congenital, MIM# 607842, Hyposmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3170 ZBTB18 Zornitza Stark Gene: zbtb18 has been classified as Green List (High Evidence).
Mendeliome v0.3166 ESR2 Bryony Thompson Classified gene: ESR2 as Amber List (moderate evidence)
Mendeliome v0.3166 ESR2 Bryony Thompson Gene: esr2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3164 MT-TP Bryony Thompson Gene: mt-tp has been classified as Red List (Low Evidence).
Mendeliome v0.3164 MT-TP Bryony Thompson Classified gene: MT-TP as Red List (low evidence)
Mendeliome v0.3164 MT-TP Bryony Thompson Added comment: Comment on list classification: This is a mitochondrial gene, which is on the Mitochondrial disease gene panel.
Mendeliome v0.3164 MT-TP Bryony Thompson Gene: mt-tp has been classified as Red List (Low Evidence).
Mendeliome v0.3163 SETD2 Zornitza Stark Gene: setd2 has been classified as Green List (High Evidence).
Mendeliome v0.3160 UBE2A Zornitza Stark Gene: ube2a has been classified as Green List (High Evidence).
Mendeliome v0.3157 AXL Bryony Thompson Gene: axl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3157 AXL Bryony Thompson Classified gene: AXL as Amber List (moderate evidence)
Mendeliome v0.3157 AXL Bryony Thompson Gene: axl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3156 AXL Bryony Thompson gene: AXL was added
gene: AXL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AXL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXL were set to 18787040; 24476074
Phenotypes for gene: AXL were set to Kallman syndrome; normosmic idiopathic hypogonadotropic hypogonadism
Review for gene: AXL was set to AMBER
Added comment: Axl null mice had delayed first oestrus and persistently abnormal oestrous cyclicality compared with wild-type controls. Only a single study reported screening human cases. In a screen of 104 probands with KS or nIHH, four heterozygous AXL mutations were identified in two KS and two nIHH unrelated subjects (two males and two females). Three of the variants appear to be too common in gnomAD v2.1 given the reported prevalence of KS reported in GeneReviews (1:30,000 in males and 1:125,000 in females): c.587-6C>T (normal splicing in RNA studies, NFE AF 0.0001472), p.Q361P (NFE 0.002560), p.L50F (AJ 0.004405). The other variant p.S202C (4 hets, 1 female in gnomAD v2.1) is rare enough in gnomAD for a dominant disorder. In vitro functional assays were conducted and p.S202C had an significant effect on function, but so did the more common variant p.Q361P.
Sources: Literature
Mendeliome v0.3155 GANAB Zornitza Stark Gene: ganab has been classified as Green List (High Evidence).
Mendeliome v0.3151 GOLGA2 Zornitza Stark Gene: golga2 has been classified as Green List (High Evidence).
Mendeliome v0.3151 GOLGA2 Zornitza Stark Classified gene: GOLGA2 as Green List (high evidence)
Mendeliome v0.3151 GOLGA2 Zornitza Stark Gene: golga2 has been classified as Green List (High Evidence).
Mendeliome v0.3150 GOLGA2 Elena Savva gene: GOLGA2 was added
gene: GOLGA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GOLGA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Phenotypes for gene: GOLGA2 were set to Nueromuscular disorder
Review for gene: GOLGA2 was set to GREEN
Added comment: PMID: 30237576 - One 11 year old patient with a homozygous PTC.
Patient had global dev delay, microcephaly, distal muscle weakness with joint contractures and elevated CK levels. Muscle biopsy showed dystrophin changes. MRI at 2 years old showed brain atrophy with thin corpus callosum and hypomyelination. No seizures or regression.

PMID: 26742501 - One infant with a homozygous PTC.
Patient had dev delay, seizures, microcephaly and muscular dystrophy. Zebrafish null model recapitulates the human phenotype with microcephaly and skeletal muscle disorganization.

Summary: 2 patients + animal model
Sources: Expert list
Mendeliome v0.3150 MUC7 Bryony Thompson Classified gene: MUC7 as Red List (low evidence)
Mendeliome v0.3150 MUC7 Bryony Thompson Gene: muc7 has been classified as Red List (Low Evidence).
Mendeliome v0.3149 HTR3D Bryony Thompson Gene: htr3d has been classified as Red List (Low Evidence).
Mendeliome v0.3149 HTR3D Bryony Thompson Classified gene: HTR3D as Red List (low evidence)
Mendeliome v0.3149 HTR3D Bryony Thompson Gene: htr3d has been classified as Red List (Low Evidence).
Mendeliome v0.3148 ALOX5AP Bryony Thompson Gene: alox5ap has been classified as Red List (Low Evidence).
Mendeliome v0.3148 ALOX5AP Bryony Thompson Classified gene: ALOX5AP as Red List (low evidence)
Mendeliome v0.3148 ALOX5AP Bryony Thompson Gene: alox5ap has been classified as Red List (Low Evidence).
Mendeliome v0.3147 PHOX2A Zornitza Stark Gene: phox2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3147 PHOX2A Zornitza Stark Phenotypes for gene: PHOX2A were changed from to Fibrosis of extraocular muscles, congenital, 2 602078
Mendeliome v0.3144 PHOX2A Zornitza Stark Classified gene: PHOX2A as Amber List (moderate evidence)
Mendeliome v0.3144 PHOX2A Zornitza Stark Gene: phox2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3143 PHOX2A Elena Savva reviewed gene: PHOX2A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 11600883, 18323871; Phenotypes: Fibrosis of extraocular muscles, congenital, 2 602078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3140 ANKRD1 Zornitza Stark Gene: ankrd1 has been classified as Red List (Low Evidence).
Mendeliome v0.3137 ANKRD1 Zornitza Stark Classified gene: ANKRD1 as Red List (low evidence)
Mendeliome v0.3137 ANKRD1 Zornitza Stark Gene: ankrd1 has been classified as Red List (Low Evidence).
Mendeliome v0.3136 CALR3 Zornitza Stark Gene: calr3 has been classified as Red List (Low Evidence).
Mendeliome v0.3133 CALR3 Zornitza Stark Classified gene: CALR3 as Red List (low evidence)
Mendeliome v0.3133 CALR3 Zornitza Stark Gene: calr3 has been classified as Red List (Low Evidence).
Mendeliome v0.3132 ALPK3 Zornitza Stark Gene: alpk3 has been classified as Green List (High Evidence).
Mendeliome v0.3129 HSF4 Zornitza Stark Gene: hsf4 has been classified as Green List (High Evidence).
Mendeliome v0.3126 FITM2 Bryony Thompson Gene: fitm2 has been classified as Green List (High Evidence).
Mendeliome v0.3126 FITM2 Bryony Thompson Classified gene: FITM2 as Green List (high evidence)
Mendeliome v0.3126 FITM2 Bryony Thompson Gene: fitm2 has been classified as Green List (High Evidence).
Mendeliome v0.3125 FITM2 Bryony Thompson gene: FITM2 was added
gene: FITM2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FITM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FITM2 were set to 28067622; 30214770; 30288795
Phenotypes for gene: FITM2 were set to Siddiqi syndrome MIM#618635; dystonia; deafness
Review for gene: FITM2 was set to GREEN
Added comment: 7 cases from 3 unrelated families (2 consanguineous) with a dystonia-deafness syndrome and a supporting Drosophila model.
Sources: Expert list
Mendeliome v0.3123 CHD1L Zornitza Stark Gene: chd1l has been classified as Red List (Low Evidence).
Mendeliome v0.3120 CHD1L Zornitza Stark Classified gene: CHD1L as Red List (low evidence)
Mendeliome v0.3120 CHD1L Zornitza Stark Gene: chd1l has been classified as Red List (Low Evidence).
Mendeliome v0.3119 NEXMIF Zornitza Stark Gene: nexmif has been classified as Green List (High Evidence).
Mendeliome v0.3116 MEF2C Zornitza Stark Gene: mef2c has been classified as Green List (High Evidence).
Mendeliome v0.3114 KDM6A Zornitza Stark Gene: kdm6a has been classified as Green List (High Evidence).
Mendeliome v0.3111 STAG3 Bryony Thompson Gene: stag3 has been classified as Green List (High Evidence).
Mendeliome v0.3111 STAG3 Bryony Thompson Classified gene: STAG3 as Green List (high evidence)
Mendeliome v0.3111 STAG3 Bryony Thompson Gene: stag3 has been classified as Green List (High Evidence).
Mendeliome v0.3109 SOHLH1 Bryony Thompson Gene: sohlh1 has been classified as Green List (High Evidence).
Mendeliome v0.3109 SOHLH1 Bryony Thompson Classified gene: SOHLH1 as Green List (high evidence)
Mendeliome v0.3109 SOHLH1 Bryony Thompson Gene: sohlh1 has been classified as Green List (High Evidence).
Mendeliome v0.3108 SOHLH1 Bryony Thompson gene: SOHLH1 was added
gene: SOHLH1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SOHLH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SOHLH1 were set to 25774885; 16690745; 31042289; 20506135; 28718531
Phenotypes for gene: SOHLH1 were set to Ovarian dysgenesis 5 MIM#617690; Spermatogenic failure 32 MIM#618115
Review for gene: SOHLH1 was set to GREEN
Added comment: Women in 3 unrelated families with ovarian dysgenesis and homozygous variants, and a supporting null mouse model.
At least 4 males with heterozygous variants and spermatogenic failure.
Sources: Expert list
Mendeliome v0.3107 HFM1 Bryony Thompson Gene: hfm1 has been classified as Green List (High Evidence).
Mendeliome v0.3107 HFM1 Bryony Thompson Classified gene: HFM1 as Green List (high evidence)
Mendeliome v0.3107 HFM1 Bryony Thompson Gene: hfm1 has been classified as Green List (High Evidence).
Mendeliome v0.3106 HFM1 Bryony Thompson gene: HFM1 was added
gene: HFM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HFM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: HFM1 were set to 23555294; 24597873; 31279343
Phenotypes for gene: HFM1 were set to Premature ovarian failure 9 MIM#615724
Review for gene: HFM1 was set to GREEN
Added comment: Three cases from 2 unrelated families with compound heterozygous variants, and a single family with a heterozygous variant have been reported with ovarian failure. There is also a supporting null mouse model.
Sources: Expert list
Mendeliome v0.3105 NEK9 Zornitza Stark Gene: nek9 has been classified as Red List (Low Evidence).
Mendeliome v0.3105 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from to Lethal congenital contracture syndrome 10, MIM# 617022; Skeletal dysplasia
Mendeliome v0.3102 NEK9 Zornitza Stark Classified gene: NEK9 as Red List (low evidence)
Mendeliome v0.3102 NEK9 Zornitza Stark Gene: nek9 has been classified as Red List (Low Evidence).
Mendeliome v0.3101 NEK9 Zornitza Stark reviewed gene: NEK9: Rating: RED; Mode of pathogenicity: None; Publications: 26908619; Phenotypes: Lethal congenital contracture syndrome 10, MIM# 617022, Skeletal dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3101 MSTN Zornitza Stark Gene: mstn has been classified as Red List (Low Evidence).
Mendeliome v0.3098 MSTN Zornitza Stark Classified gene: MSTN as Red List (low evidence)
Mendeliome v0.3098 MSTN Zornitza Stark Gene: mstn has been classified as Red List (Low Evidence).
Mendeliome v0.3097 HSPB8 Zornitza Stark Gene: hspb8 has been classified as Green List (High Evidence).
Mendeliome v0.3094 AMPD1 Zornitza Stark Gene: ampd1 has been classified as Red List (Low Evidence).
Mendeliome v0.3091 AMPD1 Zornitza Stark Classified gene: AMPD1 as Red List (low evidence)
Mendeliome v0.3091 AMPD1 Zornitza Stark Gene: ampd1 has been classified as Red List (Low Evidence).
Mendeliome v0.3089 DCAF8 Bryony Thompson Classified gene: DCAF8 as Amber List (moderate evidence)
Mendeliome v0.3089 DCAF8 Bryony Thompson Gene: dcaf8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3088 DCAF8 Bryony Thompson gene: DCAF8 was added
gene: DCAF8 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DCAF8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DCAF8 were set to 24500646
Phenotypes for gene: DCAF8 were set to Giant axonal neuropathy 2, autosomal dominant MIM#610100
Review for gene: DCAF8 was set to AMBER
Added comment: A single large family segregating a missense variant and in vitro functional assays demonstrating the variant reduces the association of DCAF8 and DDB1, which is important in Cul4-ubiquitin E3 function
Sources: Expert list
Mendeliome v0.3087 ARL6IP1 Bryony Thompson Gene: arl6ip1 has been classified as Green List (High Evidence).
Mendeliome v0.3087 ARL6IP1 Bryony Thompson Classified gene: ARL6IP1 as Green List (high evidence)
Mendeliome v0.3087 ARL6IP1 Bryony Thompson Gene: arl6ip1 has been classified as Green List (High Evidence).
Mendeliome v0.3086 ARL6IP1 Bryony Thompson gene: ARL6IP1 was added
gene: ARL6IP1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL6IP1 were set to 24482476; 31272422; 30980493; 28471035
Phenotypes for gene: ARL6IP1 were set to Spastic paraplegia 61, autosomal recessive MIM#615685
Review for gene: ARL6IP1 was set to GREEN
gene: ARL6IP1 was marked as current diagnostic
Added comment: At least 4 families reported with paediatric onset complicated spastic paraplegia and neuropathy. Supporting zebrafish model.
Sources: Expert list
Mendeliome v0.3085 PMP2 Bryony Thompson Gene: pmp2 has been classified as Green List (High Evidence).
Mendeliome v0.3085 PMP2 Bryony Thompson Classified gene: PMP2 as Green List (high evidence)
Mendeliome v0.3085 PMP2 Bryony Thompson Gene: pmp2 has been classified as Green List (High Evidence).
Mendeliome v0.3078 SI Zornitza Stark Marked gene: SI as ready
Mendeliome v0.3078 SI Zornitza Stark Gene: si has been classified as Green List (High Evidence).
Mendeliome v0.3078 SI Zornitza Stark Phenotypes for gene: SI were changed from to Sucrase-isomaltase deficiency, congenital #222900
Mendeliome v0.3077 SI Zornitza Stark Publications for gene: SI were set to
Mendeliome v0.3076 SI Zornitza Stark Mode of inheritance for gene: SI was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.3075 SV2B Seb Lunke Gene: sv2b has been classified as Red List (Low Evidence).
Mendeliome v0.3074 SI Elena Savva reviewed gene: SI: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 3149304, 31557950; Phenotypes: Sucrase-isomaltase deficiency, congenital #222900; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.3074 RYR3 Zornitza Stark Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3074 RYR3 Zornitza Stark Classified gene: RYR3 as Amber List (moderate evidence)
Mendeliome v0.3074 RYR3 Zornitza Stark Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3073 RYR3 Zornitza Stark gene: RYR3 was added
gene: RYR3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RYR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RYR3 were set to 29498452; 32451403; 31230720
Phenotypes for gene: RYR3 were set to Nemaline myopathy; fetal akinesia; arthrogryposis
Review for gene: RYR3 was set to AMBER
Added comment: One family reported with nemaline myopathy and other cases reported as part of large fetal akinesia/arthrogryposis discovery cohorts reporting multiple novel gene candidates.
Sources: Expert list
Mendeliome v0.3072 SCN3A Zornitza Stark Gene: scn3a has been classified as Green List (High Evidence).
Mendeliome v0.3068 HMGA2 Zornitza Stark Phenotypes for gene: HMGA2 were changed from Silver-Russel syndrome to Silver-Russel syndrome, MIM#618908
Mendeliome v0.3066 HMGA2 Zornitza Stark Classified gene: HMGA2 as Green List (high evidence)
Mendeliome v0.3066 HMGA2 Zornitza Stark Gene: hmga2 has been classified as Green List (High Evidence).
Mendeliome v0.3065 HMGA2 Zornitza Stark edited their review of gene: HMGA2: Added comment: At least four families reported with SNVs.; Changed rating: GREEN; Changed publications: 29655892, 25809938, 29453418, 29655892, 28796236; Changed phenotypes: Silver-Russel syndrome, MIM#618908
Mendeliome v0.3065 PLAG1 Zornitza Stark Gene: plag1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3065 PLAG1 Zornitza Stark Phenotypes for gene: PLAG1 were changed from to Silver-Russell syndrome, MIM#618907
Mendeliome v0.3062 PLAG1 Zornitza Stark Classified gene: PLAG1 as Amber List (moderate evidence)
Mendeliome v0.3062 PLAG1 Zornitza Stark Gene: plag1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3061 PLAG1 Zornitza Stark reviewed gene: PLAG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28796236, 29913240; Phenotypes: Silver-Russell syndrome, MIM#618907; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3061 NEFH Zornitza Stark Gene: nefh has been classified as Green List (High Evidence).
Mendeliome v0.3057 SLC6A1 Zornitza Stark Gene: slc6a1 has been classified as Green List (High Evidence).
Mendeliome v0.3054 GATM Zornitza Stark Gene: gatm has been classified as Green List (High Evidence).
Mendeliome v0.3051 TRIM69 Zornitza Stark Gene: trim69 has been classified as Red List (Low Evidence).
Mendeliome v0.3051 TRIM69 Zornitza Stark gene: TRIM69 was added
gene: TRIM69 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TRIM69 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TRIM69 were set to 22105173
Phenotypes for gene: TRIM69 were set to Susceptibility to herpes simplex encephalitis
Review for gene: TRIM69 was set to RED
Added comment: One individual with bi-allelic and one individual with mono-allelic variants in this gene described.
Sources: Expert list
Mendeliome v0.3050 LIMS2 Zornitza Stark Gene: lims2 has been classified as Red List (Low Evidence).
Mendeliome v0.3050 LIMS2 Zornitza Stark gene: LIMS2 was added
gene: LIMS2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: LIMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIMS2 were set to 25589244; 16317048
Phenotypes for gene: LIMS2 were set to Muscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongue MIM#616827
Review for gene: LIMS2 was set to RED
Added comment: Only one family reported and Pinch2 -/- mice were viable and fertile with no apparent phenotype.
Sources: Expert list
Mendeliome v0.3049 PSMB1 Zornitza Stark Gene: psmb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3049 PSMB1 Zornitza Stark Classified gene: PSMB1 as Amber List (moderate evidence)
Mendeliome v0.3049 PSMB1 Zornitza Stark Gene: psmb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3048 PSMB1 Zornitza Stark gene: PSMB1 was added
gene: PSMB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMB1 were set to 32129449
Phenotypes for gene: PSMB1 were set to Intellectual disability; microcephaly
Review for gene: PSMB1 was set to AMBER
Added comment: Two siblings reported with a homozygous missense variant in this gene; supportive experimental evidence including zebrafish model.
Sources: Literature
Mendeliome v0.3047 SLC12A6 Zornitza Stark Gene: slc12a6 has been classified as Green List (High Evidence).
Mendeliome v0.3047 SLC12A6 Zornitza Stark Phenotypes for gene: SLC12A6 were changed from to Andermann syndrome; Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum; Intermediate CMT
Mendeliome v0.3044 SLC12A6 Zornitza Stark reviewed gene: SLC12A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31439721; Phenotypes: Andermann syndrome, Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum, Intermediate CMT; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3044 C16orf62 Zornitza Stark changed review comment from: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).
Sources: Expert list; to: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475;31712251).
Sources: Expert list
Mendeliome v0.3044 EWSR1 Seb Lunke Gene: ewsr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3044 EWSR1 Seb Lunke Phenotypes for gene: EWSR1 were changed from to Amyotrophic lateral sclerosis
Mendeliome v0.3041 EWSR1 Seb Lunke Classified gene: EWSR1 as Amber List (moderate evidence)
Mendeliome v0.3041 EWSR1 Seb Lunke Gene: ewsr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3040 EWSR1 Seb Lunke reviewed gene: EWSR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29731676, 22454397; Phenotypes: Amyotrophic lateral sclerosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3040 TRPM7 Zornitza Stark Gene: trpm7 has been classified as Red List (Low Evidence).
Mendeliome v0.3040 TRPM7 Zornitza Stark Phenotypes for gene: TRPM7 were changed from to {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500
Mendeliome v0.3039 TRPM7 Zornitza Stark Classified gene: TRPM7 as Red List (low evidence)
Mendeliome v0.3039 TRPM7 Zornitza Stark Gene: trpm7 has been classified as Red List (Low Evidence).
Mendeliome v0.3038 TRPM7 Zornitza Stark reviewed gene: TRPM7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500; Mode of inheritance: None
Mendeliome v0.3038 C16orf62 Zornitza Stark Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3038 C16orf62 Zornitza Stark Classified gene: C16orf62 as Amber List (moderate evidence)
Mendeliome v0.3038 C16orf62 Zornitza Stark Gene: c16orf62 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3037 C16orf62 Zornitza Stark gene: C16orf62 was added
gene: C16orf62 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 25434475
Phenotypes for gene: C16orf62 were set to 3C/Ritscher-Schinzel-like syndrome
Review for gene: C16orf62 was set to AMBER
Added comment: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475).
Sources: Expert list
Mendeliome v0.3036 RHOBTB2 Zornitza Stark Gene: rhobtb2 has been classified as Green List (High Evidence).
Mendeliome v0.3032 PPP1CB Zornitza Stark Gene: ppp1cb has been classified as Green List (High Evidence).
Mendeliome v0.3029 NUP88 Zornitza Stark Gene: nup88 has been classified as Green List (High Evidence).
Mendeliome v0.3029 NUP88 Zornitza Stark Classified gene: NUP88 as Green List (high evidence)
Mendeliome v0.3029 NUP88 Zornitza Stark Gene: nup88 has been classified as Green List (High Evidence).
Mendeliome v0.3028 NUP88 Zornitza Stark gene: NUP88 was added
gene: NUP88 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUP88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP88 were set to 30543681
Phenotypes for gene: NUP88 were set to Fetal akinesia deformation sequence 4, MIM# 618393
Review for gene: NUP88 was set to GREEN
Added comment: Two unrelated families, functional data on the variants support pathogenicity as does a zebrafish model.
Sources: Literature
Mendeliome v0.3027 SMO Zornitza Stark Gene: smo has been classified as Green List (High Evidence).
Mendeliome v0.3027 SMO Zornitza Stark Phenotypes for gene: SMO were changed from to Microcephaly, congenital heart disease, polydactyly, aganglionosis; Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3024 SMO Zornitza Stark reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 32413283, 27236920; Phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Curry-Jones syndrome, somatic mosaic 601707; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3024 RBL2 Zornitza Stark Gene: rbl2 has been classified as Red List (Low Evidence).
Mendeliome v0.3024 RBL2 Zornitza Stark gene: RBL2 was added
gene: RBL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBL2 were set to 32105419; 9806916
Phenotypes for gene: RBL2 were set to Intellectual disability
Review for gene: RBL2 was set to RED
Added comment: Single family reported with pair of affected siblings. Supportive mouse model.
Sources: Literature
Mendeliome v0.3023 GRM7 Zornitza Stark Gene: grm7 has been classified as Green List (High Evidence).
Mendeliome v0.3023 GRM7 Zornitza Stark Classified gene: GRM7 as Green List (high evidence)
Mendeliome v0.3023 GRM7 Zornitza Stark Gene: grm7 has been classified as Green List (High Evidence).
Mendeliome v0.3022 GRM7 Zornitza Stark gene: GRM7 was added
gene: GRM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 32286009; 32248644
Phenotypes for gene: GRM7 were set to Epilepsy, microcephaly, developmental delay
Review for gene: GRM7 was set to GREEN
Added comment: Eleven individuals from six families reported, three different homozygous variants (two missense, one LoF). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Supportive mouse model.
Sources: Literature
Mendeliome v0.3021 PYGM Zornitza Stark Gene: pygm has been classified as Green List (High Evidence).
Mendeliome v0.3018 PERP Zornitza Stark Gene: perp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3018 PERP Zornitza Stark Classified gene: PERP as Amber List (moderate evidence)
Mendeliome v0.3018 PERP Zornitza Stark Gene: perp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3017 PERP Zornitza Stark gene: PERP was added
gene: PERP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PERP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PERP were set to 31898316
Phenotypes for gene: PERP were set to Erythrokeratoderma, no OMIM # yet
Review for gene: PERP was set to AMBER
Added comment: One extended multiplex consanguineous family with Erythrokeratoderma (striking similarity to that observed in Perp −/− mice), and a novel homozygous variant (c.466G>A; p.Gly156Arg) in PERP that fully segregated with the phenotype. Functional analysis of patient‐ and control‐derived keratinocytes revealed a deleterious effect of the identified variant on the intracellular localization of PERP. A previous report showed that PERP mutation causes a dominant form of keratoderma but a single patient in that report with a homozygous variant in PERP suggests that recessive inheritance is also possible.
Sources: Literature
Mendeliome v0.3016 ADCY6 Zornitza Stark Gene: adcy6 has been classified as Green List (High Evidence).
Mendeliome v0.3016 ADCY6 Zornitza Stark Classified gene: ADCY6 as Green List (high evidence)
Mendeliome v0.3016 ADCY6 Zornitza Stark Gene: adcy6 has been classified as Green List (High Evidence).
Mendeliome v0.3015 ADCY6 Zornitza Stark gene: ADCY6 was added
gene: ADCY6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADCY6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADCY6 were set to 24319099; 26257172; 31846058
Phenotypes for gene: ADCY6 were set to Lethal congenital contracture syndrome 8, OMIM # 616287
Review for gene: ADCY6 was set to GREEN
Added comment: Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies.
Sources: Literature
Mendeliome v0.3014 DSCR3 Zornitza Stark Gene: dscr3 has been classified as Red List (Low Evidence).
Mendeliome v0.3014 DSCR3 Zornitza Stark gene: DSCR3 was added
gene: DSCR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DSCR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DSCR3 were set to 31845315
Phenotypes for gene: DSCR3 were set to Intellectual disability, no OMIM # yet
Review for gene: DSCR3 was set to RED
Added comment: 1 family/2 cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Both shared the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The nature of the variant which is predicted to result in loss‐of‐function, expression studies revealing significant reduction in the mutant transcript, and the co‐segregation of the homozygous variant with the phenotype in two affected individuals.
Sources: Literature
Mendeliome v0.3013 LEF1 Zornitza Stark Gene: lef1 has been classified as Red List (Low Evidence).
Mendeliome v0.3013 LEF1 Zornitza Stark gene: LEF1 was added
gene: LEF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LEF1 were set to 32022899
Phenotypes for gene: LEF1 were set to Ectodermal dysplasia, no OMIM# yet
Review for gene: LEF1 was set to RED
Added comment: In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. One report of two unrelated patients with 4q25 de novo deletion encompassing LEF1 , associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. So far, no pathogenic variants or variations involving the LEF1 gene have been reported in human.
Sources: Literature
Mendeliome v0.3012 OTUD7A Zornitza Stark Gene: otud7a has been classified as Red List (Low Evidence).
Mendeliome v0.3010 OTUD7A Zornitza Stark gene: OTUD7A was added
gene: OTUD7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, no OMIM# yet
Review for gene: OTUD7A was set to RED
Added comment: One patient with severe global developmental delay, language impairment and epileptic encephalopathy. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies.
Sources: Literature
Mendeliome v0.3009 GATAD2B Zornitza Stark Gene: gatad2b has been classified as Green List (High Evidence).
Mendeliome v0.3005 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Mendeliome v0.3002 COG4 Zornitza Stark Gene: cog4 has been classified as Green List (High Evidence).
Mendeliome v0.2999 ARL13B Zornitza Stark Gene: arl13b has been classified as Green List (High Evidence).
Mendeliome v0.2996 ARL13B Zornitza Stark edited their review of gene: ARL13B: Added comment: Eight families reported in the literature. Many are homozygous missense variants in consanguineous families with no further supporting evidence, but sufficient number have functional evidence at protein level. Gene has appropriate tissue expression. Zebrafish model: curved tails and cystic kidneys. Hennin mouse model discovered in ENU mutagenesis screen: has polydactyly, ciliary defect, and much more severe neurological phenotype (neural tube defect).; Changed publications: 18674751, 25138100, 26092869, 27894351, 29255182, 17488627
Mendeliome v0.2996 DNAL1 Zornitza Stark Gene: dnal1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2996 DNAL1 Zornitza Stark Phenotypes for gene: DNAL1 were changed from to Ciliary dyskinesia, primary, 16, MIM# 614017
Mendeliome v0.2993 DNAL1 Zornitza Stark Classified gene: DNAL1 as Amber List (moderate evidence)
Mendeliome v0.2993 DNAL1 Zornitza Stark Gene: dnal1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2992 DNAL1 Zornitza Stark reviewed gene: DNAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21496787; Phenotypes: Ciliary dyskinesia, primary, 16, MIM# 614017; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2992 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2992 DNAH8 Zornitza Stark Phenotypes for gene: DNAH8 were changed from to Asthenozoospermia; primary ciliary dyskinesia
Mendeliome v0.2989 DNAH8 Zornitza Stark Classified gene: DNAH8 as Amber List (moderate evidence)
Mendeliome v0.2989 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2988 DNAH8 Zornitza Stark reviewed gene: DNAH8: Rating: AMBER; Mode of pathogenicity: None; Publications: 31178125, 24307375; Phenotypes: Asthenozoospermia, primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2988 TTC5 Zornitza Stark Gene: ttc5 has been classified as Green List (High Evidence).
Mendeliome v0.2988 TTC5 Zornitza Stark Classified gene: TTC5 as Green List (high evidence)
Mendeliome v0.2988 TTC5 Zornitza Stark Gene: ttc5 has been classified as Green List (High Evidence).
Mendeliome v0.2986 ACAD11 Zornitza Stark Gene: acad11 has been classified as Red List (Low Evidence).
Mendeliome v0.2986 ACAD11 Zornitza Stark Classified gene: ACAD11 as Red List (low evidence)
Mendeliome v0.2986 ACAD11 Zornitza Stark Gene: acad11 has been classified as Red List (Low Evidence).
Mendeliome v0.2985 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2985 DNAH6 Zornitza Stark Classified gene: DNAH6 as Amber List (moderate evidence)
Mendeliome v0.2985 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2984 DRC1 Zornitza Stark Gene: drc1 has been classified as Green List (High Evidence).
Mendeliome v0.2984 DRC1 Zornitza Stark Phenotypes for gene: DRC1 were changed from to Ciliary dyskinesia, primary, 21, MIM# 615294
Mendeliome v0.2981 DRC1 Zornitza Stark reviewed gene: DRC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31960620; Phenotypes: Ciliary dyskinesia, primary, 21, MIM# 615294; Mode of inheritance: None
Mendeliome v0.2978 HIST1H4J Zornitza Stark Gene: hist1h4j has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2978 HIST1H4J Zornitza Stark Classified gene: HIST1H4J as Amber List (moderate evidence)
Mendeliome v0.2978 HIST1H4J Zornitza Stark Gene: hist1h4j has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2977 HIST1H4J Zornitza Stark gene: HIST1H4J was added
gene: HIST1H4J was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HIST1H4J was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4J were set to 31804630
Phenotypes for gene: HIST1H4J were set to microcephaly; intellectual disability; dysmorphic features
Review for gene: HIST1H4J was set to AMBER
Added comment: Single case report but with functional evidence in zebrafish and phenotypic similarity to other HIST1H4C phenotype
Sources: Literature
Mendeliome v0.2976 MCIDAS Zornitza Stark Gene: mcidas has been classified as Green List (High Evidence).
Mendeliome v0.2976 MCIDAS Zornitza Stark Phenotypes for gene: MCIDAS were changed from to Ciliary dyskinesia, primary, 42 (MIM#618695)
Mendeliome v0.2973 MCIDAS Zornitza Stark reviewed gene: MCIDAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 25048963; Phenotypes: Ciliary dyskinesia, primary, 42 (MIM#618695); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2973 VWA3B Zornitza Stark Gene: vwa3b has been classified as Red List (Low Evidence).
Mendeliome v0.2973 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 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness; Contractures
Mendeliome v0.2972 TOR1AIP1 Zornitza Stark Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness
Mendeliome v0.2971 TOR1AIP1 Zornitza Stark Added comment: Comment when marking as ready: Highly variable phenotype. Few of the features are consistently reported across affected individuals.
Mendeliome v0.2971 TOR1AIP1 Zornitza Stark Gene: tor1aip1 has been classified as Green List (High Evidence).
Mendeliome v0.2970 EFEMP1 Zornitza Stark Gene: efemp1 has been classified as Green List (High Evidence).
Mendeliome v0.2967 ZFYVE27 Bryony Thompson Classified gene: ZFYVE27 as Red List (low evidence)
Mendeliome v0.2967 ZFYVE27 Bryony Thompson Gene: zfyve27 has been classified as Red List (Low Evidence).
Mendeliome v0.2966 USP8 Bryony Thompson Classified gene: USP8 as Green List (high evidence)
Mendeliome v0.2966 USP8 Bryony Thompson Gene: usp8 has been classified as Green List (High Evidence).
Mendeliome v0.2965 USP8 Bryony Thompson gene: USP8 was added
gene: USP8 was added to Mendeliome. Sources: Expert list
somatic tags were added to gene: USP8.
Mode of inheritance for gene: USP8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: USP8 were set to 25675982; 24482476; 25485838; 25942478
Phenotypes for gene: USP8 were set to Pituitary adenoma 4, ACTH-secreting, somatic MIM#219090; hereditary spastic paraplegia
Review for gene: USP8 was set to GREEN
Added comment: Recurrent somatic gain of function missense variants in pituitary adenomas cause Cushing's disease.
A single family reported with spastic paraplegia with a homozygous variant, and a zebrafish model with a movement disorder.
Sources: Expert list
Mendeliome v0.2964 RIMS2 Zornitza Stark Gene: rims2 has been classified as Green List (High Evidence).
Mendeliome v0.2963 RIMS2 Zornitza Stark Classified gene: RIMS2 as Green List (high evidence)
Mendeliome v0.2963 RIMS2 Zornitza Stark Gene: rims2 has been classified as Green List (High Evidence).
Mendeliome v0.2961 TRIM71 Seb Lunke Gene: trim71 has been classified as Green List (High Evidence).
Mendeliome v0.2961 TRIM71 Seb Lunke Classified gene: TRIM71 as Green List (high evidence)
Mendeliome v0.2961 TRIM71 Seb Lunke Gene: trim71 has been classified as Green List (High Evidence).
Mendeliome v0.2960 SCYL2 Zornitza Stark Gene: scyl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2960 SCYL2 Zornitza Stark Classified gene: SCYL2 as Amber List (moderate evidence)
Mendeliome v0.2960 SCYL2 Zornitza Stark Gene: scyl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2959 SCYL2 Zornitza Stark gene: SCYL2 was added
gene: SCYL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCYL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCYL2 were set to 31960134; 26203146
Phenotypes for gene: SCYL2 were set to Arthrogryposis multiplex congenita (AMC); Zain syndrome
Review for gene: SCYL2 was set to AMBER
Added comment: Two unrelated families reported with AMC, variable other features including microcephaly.
Sources: Literature
Mendeliome v0.2958 CNP Seb Lunke Gene: cnp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2958 CNP Seb Lunke Classified gene: CNP as Amber List (moderate evidence)
Mendeliome v0.2958 CNP Seb Lunke Gene: cnp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2957 VWA3B Bryony Thompson Classified gene: VWA3B as Red List (low evidence)
Mendeliome v0.2957 VWA3B Bryony Thompson Added comment: Comment on list classification: Single family and in vitro assay only
Mendeliome v0.2957 VWA3B Bryony Thompson Gene: vwa3b has been classified as Red List (Low Evidence).
Mendeliome v0.2956 RIMS2 Paul De Fazio changed review comment from: Biallelic LoF variants segregate with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature; to: Biallelic LoF variants segregate with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant. Several individuals had autism. One had night blindness.
Sources: Literature
Mendeliome v0.2956 VWA3B Bryony Thompson Classified gene: VWA3B as Amber List (moderate evidence)
Mendeliome v0.2956 VWA3B Bryony Thompson Gene: vwa3b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2955 VWA3B Bryony Thompson gene: VWA3B was added
gene: VWA3B was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: VWA3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA3B were set to 26157035
Phenotypes for gene: VWA3B were set to Spinocerebellar ataxia, autosomal recessive 22 MIM#616948
Review for gene: VWA3B was set to AMBER
Added comment: A homozygous missense variant was identified in 3 brothers from a single consanguineous Japanese family with autosomal recessive cerebellar ataxia. Transfection of the mutant VWA3B protein into several different cultured cell lines resulted in decreased cell viability.
Sources: Expert list
Mendeliome v0.2952 PLD3 Bryony Thompson Classified gene: PLD3 as Amber List (moderate evidence)
Mendeliome v0.2952 PLD3 Bryony Thompson Gene: pld3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2951 SLC12A2 Zornitza Stark Classified gene: SLC12A2 as Green List (high evidence)
Mendeliome v0.2951 SLC12A2 Zornitza Stark Gene: slc12a2 has been classified as Green List (High Evidence).
Mendeliome v0.2950 PLD3 Bryony Thompson gene: PLD3 was added
gene: PLD3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PLD3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLD3 were set to 29053796; 30312375; 30312384
Phenotypes for gene: PLD3 were set to Spinocerebellar ataxia 46 MIM#617770
Review for gene: PLD3 was set to AMBER
Added comment: A heterozygous missense was identified in 8 affected members of a single family with spinocerebellar ataxia, and supporting in vitro functional assays.
Sources: Expert list
Mendeliome v0.2949 SPATA13 Zornitza Stark Gene: spata13 has been classified as Green List (High Evidence).
Mendeliome v0.2949 SPATA13 Zornitza Stark Classified gene: SPATA13 as Green List (high evidence)
Mendeliome v0.2949 SPATA13 Zornitza Stark Gene: spata13 has been classified as Green List (High Evidence).
Mendeliome v0.2948 SOX6 Seb Lunke Gene: sox6 has been classified as Green List (High Evidence).
Mendeliome v0.2948 SOX6 Seb Lunke Classified gene: SOX6 as Green List (high evidence)
Mendeliome v0.2948 SOX6 Seb Lunke Gene: sox6 has been classified as Green List (High Evidence).
Mendeliome v0.2947 KIF3B Zornitza Stark Gene: kif3b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2946 KIF3B Zornitza Stark Classified gene: KIF3B as Amber List (moderate evidence)
Mendeliome v0.2946 KIF3B Zornitza Stark Gene: kif3b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2945 KIF3B Zornitza Stark reviewed gene: KIF3B: Rating: RED; Mode of pathogenicity: None; Publications: 32386558; Phenotypes: hepatic fibrosis, retinitis pigmentosa, postaxial polydactyly; Mode of inheritance: None
Mendeliome v0.2945 POC5 Bryony Thompson Gene: poc5 has been classified as Green List (High Evidence).
Mendeliome v0.2945 POC5 Bryony Thompson Classified gene: POC5 as Green List (high evidence)
Mendeliome v0.2945 POC5 Bryony Thompson Gene: poc5 has been classified as Green List (High Evidence).
Mendeliome v0.2944 POC5 Bryony Thompson gene: POC5 was added
gene: POC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POC5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 25642776; 29272404
Phenotypes for gene: POC5 were set to Idiopathic scoliosis; retinitis pigmentosa; short stature; microcephaly; recurrent glomerulonephritis
Review for gene: POC5 was set to GREEN
Added comment: Three heterozygous missense variants identified in three families segregating with idiopathic scoliosis, and supporting zebrafish models for each of the missense variants.
Also, one case reported with retinitis pigmentosa, short stature, microcephaly, and recurrent glomerulonephritis with a homozygous truncating variant and a supporting zebrafish model.
Sources: Literature
Mendeliome v0.2943 KIF3B Paul De Fazio gene: KIF3B was added
gene: KIF3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIF3B were set to hepatic fibrosis; retinitis pigmentosa; postaxial polydactyly
Review for gene: KIF3B was set to AMBER
Added comment: 2 families reported with missense variants, one de novo and one segregating in a six-generation pedigree. Functional studies in zebrafish showed the variants result in impaired rhodopsin trafficking.
Sources: Literature
Mendeliome v0.2943 SOX6 Paul De Fazio gene: SOX6 was added
gene: SOX6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SOX6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX6 were set to 32442410
Phenotypes for gene: SOX6 were set to ADHD; Craniosynostosis; Osteochondromas
Added comment: 6 LoF and 4 missense variants identified in individuals with a neurodevelopmental syndrome, however the number of families is unclear to me.
Sources: Literature
Mendeliome v0.2943 CNP Kristin Rigbye gene: CNP was added
gene: CNP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNP were set to 32128616; 12590258
Phenotypes for gene: CNP were set to Hypomyelinating leukodystrophy
Review for gene: CNP was set to AMBER
Added comment: Single consanguineous family described with homozygous missense in affected child (additional two affected deceased offspring unavailable for testing; healthy carrier parents and sibling).
Loss of protein by Western blot and defect in F-actin structure and organization observed in patient fibroblasts.
Deficiency of CNP in mouse has previously been shown to cause a lethal white matter neurodegenerative phenotype (PMID: 12590258), similar to the phenotype observed in this family.
Sources: Literature
Mendeliome v0.2943 RIMS2 Paul De Fazio changed review comment from: Segregates with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature; to: Biallelic LoF variants segregate with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature
Mendeliome v0.2943 RIMS2 Paul De Fazio gene: RIMS2 was added
gene: RIMS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RIMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIMS2 were set to 32470375
Review for gene: RIMS2 was set to GREEN
Added comment: Segregates with Syndromic Congenital Cone-Rod Synaptic Disease in 7 individuals across 4 families. Some functional studies related to insulin secretion but they are non-significant.
Sources: Literature
Mendeliome v0.2943 RBM7 Bryony Thompson Classified gene: RBM7 as Amber List (moderate evidence)
Mendeliome v0.2943 RBM7 Bryony Thompson Gene: rbm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2942 RBM7 Bryony Thompson gene: RBM7 was added
gene: RBM7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RBM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBM7 were set to 27193168
Phenotypes for gene: RBM7 were set to SMA-like spinal motor neuropathy; dHMN/dSMA
Review for gene: RBM7 was set to AMBER
Added comment: Single case with a homozygote variant, with functional assays in patient fibroblasts. Also, supporting zebrafish model.
Sources: Expert list
Mendeliome v0.2941 SORD Seb Lunke Gene: sord has been classified as Green List (High Evidence).
Mendeliome v0.2941 SORD Seb Lunke Classified gene: SORD as Green List (high evidence)
Mendeliome v0.2941 SORD Seb Lunke Gene: sord has been classified as Green List (High Evidence).
Mendeliome v0.2940 KCNJ8 Zornitza Stark Gene: kcnj8 has been classified as Red List (Low Evidence).
Mendeliome v0.2937 KCNJ8 Zornitza Stark Classified gene: KCNJ8 as Red List (low evidence)
Mendeliome v0.2937 KCNJ8 Zornitza Stark Gene: kcnj8 has been classified as Red List (Low Evidence).
Mendeliome v0.2936 KCNE3 Zornitza Stark Gene: kcne3 has been classified as Red List (Low Evidence).
Mendeliome v0.2933 KCNE3 Zornitza Stark Classified gene: KCNE3 as Red List (low evidence)
Mendeliome v0.2933 KCNE3 Zornitza Stark Gene: kcne3 has been classified as Red List (Low Evidence).
Mendeliome v0.2932 XIST Zornitza Stark Gene: xist has been classified as Green List (High Evidence).
Mendeliome v0.2930 SYNE2 Zornitza Stark Gene: syne2 has been classified as Red List (Low Evidence).
Mendeliome v0.2928 SYNE2 Bryony Thompson Classified gene: SYNE2 as Red List (low evidence)
Mendeliome v0.2928 SYNE2 Bryony Thompson Gene: syne2 has been classified as Red List (Low Evidence).
Mendeliome v0.2927 PRKAG3 Bryony Thompson Classified gene: PRKAG3 as Amber List (moderate evidence)
Mendeliome v0.2927 PRKAG3 Bryony Thompson Gene: prkag3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2926 ANO5 Zornitza Stark Gene: ano5 has been classified as Green List (High Evidence).
Mendeliome v0.2925 ANO5 Zornitza Stark Phenotypes for gene: ANO5 were changed from to Gnathodiaphyseal dysplasia MIM#166260; Miyoshi muscular dystrophy 3 MIM#613319; Muscular dystrophy, limb-girdle, autosomal recessive 12 MIM#611307
Mendeliome v0.2923 CPT1B Zornitza Stark Gene: cpt1b has been classified as Red List (Low Evidence).
Mendeliome v0.2921 MYF6 Bryony Thompson Classified gene: MYF6 as Red List (low evidence)
Mendeliome v0.2921 MYF6 Bryony Thompson Gene: myf6 has been classified as Red List (Low Evidence).
Mendeliome v0.2920 MTMR14 Bryony Thompson Classified gene: MTMR14 as Red List (low evidence)
Mendeliome v0.2920 MTMR14 Bryony Thompson Added comment: Comment on list classification: No evidence of Mendelian disease
Mendeliome v0.2920 MTMR14 Bryony Thompson Gene: mtmr14 has been classified as Red List (Low Evidence).
Mendeliome v0.2919 CPT1B Bryony Thompson Classified gene: CPT1B as Red List (low evidence)
Mendeliome v0.2919 CPT1B Bryony Thompson Gene: cpt1b has been classified as Red List (Low Evidence).
Mendeliome v0.2918 ANO5 Bryony Thompson reviewed gene: ANO5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32112655; Phenotypes: Gnathodiaphyseal dysplasia MIM#166260, Miyoshi muscular dystrophy 3 MIM#613319, Muscular dystrophy, limb-girdle, autosomal recessive 12 MIM#611307; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2918 DNAJB11 Zornitza Stark Gene: dnajb11 has been classified as Green List (High Evidence).
Mendeliome v0.2915 GPR143 Zornitza Stark Gene: gpr143 has been classified as Green List (High Evidence).
Mendeliome v0.2912 ELP1 Zornitza Stark Gene: elp1 has been classified as Green List (High Evidence).
Mendeliome v0.2909 SNRNP200 Zornitza Stark Gene: snrnp200 has been classified as Green List (High Evidence).
Mendeliome v0.2906 SNRNP200 Ain Roesley changed review comment from: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.4Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo; to: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.1Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo
Mendeliome v0.2906 SNRNP200 Ain Roesley changed review comment from: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.1Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo; to: PMID: 31260034; more than 20 families reported with either de novo or AD with RP or retinal dystrophy (RD)

PMID: 29320387; p.(Arg1090Gln) in a proband with RP from a consag family with unaffected het parents and sibling

PMID: 23847139; p.(Pro1045Thr) homozygous in a patient with Leber congenital amaurosis (LCA)

PMID: 31260034: p.(Arg545His) homozygous in a patient with RP with asymptomatic het parents and sister

PMID: 27735924: in a patient with RP who is cHet for p.(Pro105Thr) in SNRNP200 and a 1.4Mb deletion spanning SNRNP200. Father is a carrier of the missense and is unaffected and the deletion was de novo
Mendeliome v0.2906 ALOXE3 Zornitza Stark Gene: aloxe3 has been classified as Green List (High Evidence).
Mendeliome v0.2906 ALOXE3 Zornitza Stark Phenotypes for gene: ALOXE3 were changed from to Ichthyosis, congenital, autosomal recessive 3, MIM#606545
Mendeliome v0.2903 ARMC1 Zornitza Stark Gene: armc1 has been classified as Red List (Low Evidence).
Mendeliome v0.2903 ARMC1 Zornitza Stark Classified gene: ARMC1 as Red List (low evidence)
Mendeliome v0.2903 ARMC1 Zornitza Stark Gene: armc1 has been classified as Red List (Low Evidence).
Mendeliome v0.2902 ALOXE3 Chern Lim reviewed gene: ALOXE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116617, 31046801, 26370990; Phenotypes: Ichthyosis, congenital, autosomal recessive 3, MIM#606545; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2902 STK36 Zornitza Stark Gene: stk36 has been classified as Red List (Low Evidence).
Mendeliome v0.2902 STK36 Zornitza Stark Phenotypes for gene: STK36 were changed from to Primary ciliary dyskinesia
Mendeliome v0.2899 STK36 Zornitza Stark Classified gene: STK36 as Red List (low evidence)
Mendeliome v0.2899 STK36 Zornitza Stark Gene: stk36 has been classified as Red List (Low Evidence).
Mendeliome v0.2898 STK36 Zornitza Stark reviewed gene: STK36: Rating: RED; Mode of pathogenicity: None; Publications: 28543983; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2898 NME8 Zornitza Stark Gene: nme8 has been classified as Red List (Low Evidence).
Mendeliome v0.2898 NME8 Zornitza Stark Phenotypes for gene: NME8 were changed from to Ciliary dyskinesia, primary, 6, MIM# 610852
Mendeliome v0.2895 NME8 Zornitza Stark Classified gene: NME8 as Red List (low evidence)
Mendeliome v0.2895 NME8 Zornitza Stark Gene: nme8 has been classified as Red List (Low Evidence).
Mendeliome v0.2894 TFAP2A Zornitza Stark Gene: tfap2a has been classified as Green List (High Evidence).
Mendeliome v0.2890 NME8 Elena Savva reviewed gene: NME8: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 17360648; Phenotypes: Ciliary dyskinesia, primary, 6 610852; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2890 ARL3 Bryony Thompson Gene: arl3 has been classified as Green List (High Evidence).
Mendeliome v0.2890 ARL3 Bryony Thompson Classified gene: ARL3 as Green List (high evidence)
Mendeliome v0.2890 ARL3 Bryony Thompson Gene: arl3 has been classified as Green List (High Evidence).
Mendeliome v0.2889 ARL3 Bryony Thompson gene: ARL3 was added
gene: ARL3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARL3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ARL3 were set to 30269812; 16565502; 26964041; 30932721
Phenotypes for gene: ARL3 were set to Joubert syndrome 35 MIM#618161; Retinitis pigmentosa 83 MIM#618173
Review for gene: ARL3 was set to GREEN
Added comment: 4 patients from 2 unrelated consanguineous families with a phenotype resembling Joubert syndrome with homozygous missense mutations affecting the same residue (R149C, R149H), and supporting in vitro functional assays. All reported cases had rod-cone dystrophy. An Arl3 null mouse model has a ciliary disease phenotype affecting the kidney, biliary tract, pancreas, and retina.
Two unrelated families with retinitis pigmentosa segregating the same heterozygous missense variant (Y90C).
Sources: Expert list
Mendeliome v0.2888 RARA Zornitza Stark Gene: rara has been classified as Red List (Low Evidence).
Mendeliome v0.2888 RARA Zornitza Stark Classified gene: RARA as Red List (low evidence)
Mendeliome v0.2888 RARA Zornitza Stark Gene: rara has been classified as Red List (Low Evidence).
Mendeliome v0.2887 ERBB2 Zornitza Stark Gene: erbb2 has been classified as Red List (Low Evidence).
Mendeliome v0.2887 ERBB2 Zornitza Stark Classified gene: ERBB2 as Red List (low evidence)
Mendeliome v0.2887 ERBB2 Zornitza Stark Gene: erbb2 has been classified as Red List (Low Evidence).
Mendeliome v0.2886 ERBB2 Zornitza Stark Classified gene: ERBB2 as Red List (low evidence)
Mendeliome v0.2886 ERBB2 Zornitza Stark Gene: erbb2 has been classified as Red List (Low Evidence).
Mendeliome v0.2885 BCR Zornitza Stark Gene: bcr has been classified as Red List (Low Evidence).
Mendeliome v0.2885 BCR Zornitza Stark Phenotypes for gene: BCR were changed from to Leukemia, acute lymphocytic, Philadelphia chromosome positive, somatic 613065; Leukemia, chronic myeloid, Philadelphia chromosome positive, somatic 608232
Mendeliome v0.2884 BCR Zornitza Stark Classified gene: BCR as Red List (low evidence)
Mendeliome v0.2884 BCR Zornitza Stark Gene: bcr has been classified as Red List (Low Evidence).
Mendeliome v0.2883 BCR Zornitza Stark reviewed gene: BCR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukemia, acute lymphocytic, Philadelphia chromosome positive, somatic 613065, Leukemia, chronic myeloid, Philadelphia chromosome positive, somatic 608232; Mode of inheritance: None
Mendeliome v0.2883 CEP19 Bryony Thompson Classified gene: CEP19 as Amber List (moderate evidence)
Mendeliome v0.2883 CEP19 Bryony Thompson Gene: cep19 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2882 CEP19 Bryony Thompson gene: CEP19 was added
gene: CEP19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP19 were set to 29127258; 24268657
Phenotypes for gene: CEP19 were set to Morbid obesity and spermatogenic failure MIM#615703
Review for gene: CEP19 was set to AMBER
Added comment: A consanguineous Arab family with morbid obesity and infertility with a homozygous predicted null variant, and a mouse model that recapitulates the phenotype. Another homozygous variant has been identified in a consanguineous Bardet Beidl syndrome.
Sources: Literature
Mendeliome v0.2881 DALRD3 Zornitza Stark Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2881 DALRD3 Zornitza Stark Classified gene: DALRD3 as Amber List (moderate evidence)
Mendeliome v0.2881 DALRD3 Zornitza Stark Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2879 GDF3 Zornitza Stark Gene: gdf3 has been classified as Red List (Low Evidence).
Mendeliome v0.2877 GDF3 Zornitza Stark Classified gene: GDF3 as Red List (low evidence)
Mendeliome v0.2877 GDF3 Zornitza Stark Gene: gdf3 has been classified as Red List (Low Evidence).
Mendeliome v0.2876 KRAS Zornitza Stark Gene: kras has been classified as Green List (High Evidence).
Mendeliome v0.2872 GAA Zornitza Stark Gene: gaa has been classified as Green List (High Evidence).
Mendeliome v0.2870 HEXA Zornitza Stark Gene: hexa has been classified as Green List (High Evidence).
Mendeliome v0.2870 HEXA Zornitza Stark Phenotypes for gene: HEXA were changed from to GM2-gangliosidosis, several forms 272800; Tay-Sachs disease 272800
Mendeliome v0.2867 DHX30 Zornitza Stark Gene: dhx30 has been classified as Green List (High Evidence).
Mendeliome v0.2864 FAT1 Zornitza Stark Gene: fat1 has been classified as Green List (High Evidence).
Mendeliome v0.2864 FAT1 Zornitza Stark Phenotypes for gene: FAT1 were changed from to facial dysmorphism; colobomatous microphthalmia; ptosis; syndactyly with or without nephropathy
Mendeliome v0.2861 HEXA Elena Savva reviewed gene: HEXA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31388111; Phenotypes: [Hex A pseudodeficiency] 272800, GM2-gangliosidosis, several forms 272800, Tay-Sachs disease 272800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2861 PITPNM3 Bryony Thompson Gene: pitpnm3 has been classified as Red List (Low Evidence).
Mendeliome v0.2861 PITPNM3 Bryony Thompson Classified gene: PITPNM3 as Red List (low evidence)
Mendeliome v0.2861 PITPNM3 Bryony Thompson Gene: pitpnm3 has been classified as Red List (Low Evidence).
Mendeliome v0.2860 FAT1 Ee Ming Wong reviewed gene: FAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30862798; Phenotypes: facial dysmorphism, colobomatous microphthalmia, ptosis, syndactyly with or without nephropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2860 JARID2 Zornitza Stark Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2860 JARID2 Zornitza Stark Classified gene: JARID2 as Amber List (moderate evidence)
Mendeliome v0.2860 JARID2 Zornitza Stark Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2857 ADIPOR1 Zornitza Stark Gene: adipor1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2854 ADIPOR1 Zornitza Stark Classified gene: ADIPOR1 as Amber List (moderate evidence)
Mendeliome v0.2854 ADIPOR1 Zornitza Stark Gene: adipor1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2853 TRIP12 Zornitza Stark Gene: trip12 has been classified as Green List (High Evidence).
Mendeliome v0.2850 CX3CR1 Zornitza Stark Gene: cx3cr1 has been classified as Red List (Low Evidence).
Mendeliome v0.2850 CX3CR1 Zornitza Stark Phenotypes for gene: CX3CR1 were changed from to Coronary artery disease, resistance to}, MIM# 607339; {Macular degeneration, age-related, 12} 613784; {Rapid progression to AIDS from HIV1 infection} 609423
Mendeliome v0.2849 CX3CR1 Zornitza Stark Classified gene: CX3CR1 as Red List (low evidence)
Mendeliome v0.2849 CX3CR1 Zornitza Stark Gene: cx3cr1 has been classified as Red List (Low Evidence).
Mendeliome v0.2849 CX3CR1 Bryony Thompson Classified gene: CX3CR1 as Red List (low evidence)
Mendeliome v0.2849 CX3CR1 Bryony Thompson Gene: cx3cr1 has been classified as Red List (Low Evidence).
Mendeliome v0.2848 CX3CR1 Zornitza Stark reviewed gene: CX3CR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Coronary artery disease, resistance to}, MIM# 607339, {Macular degeneration, age-related, 12} 613784, {Rapid progression to AIDS from HIV1 infection} 609423; Mode of inheritance: None
Mendeliome v0.2848 CLCC1 Zornitza Stark Gene: clcc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2848 CLCC1 Bryony Thompson Classified gene: CLCC1 as Amber List (moderate evidence)
Mendeliome v0.2848 CLCC1 Bryony Thompson Gene: clcc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2846 B9D1 Zornitza Stark Gene: b9d1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2843 B9D1 Zornitza Stark Classified gene: B9D1 as Amber List (moderate evidence)
Mendeliome v0.2843 B9D1 Zornitza Stark Gene: b9d1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2842 B9D1 Zornitza Stark changed review comment from: Two unrelated individuals with JS and bi-allelic variants in this gene, plus one individual with a more severe Meckel phenotype described. Intellectual disability is part of the phenotype.
Sources: Expert list; to: Two unrelated individuals with JS and bi-allelic variants in this gene, plus one individual with a more severe Meckel phenotype described. This latter individual had a splice site variant and a deletion. Splice variant proven to result in exon skipping -> PTC, but the deletion spans a large region including 18 other genes. Patient also had an additional variant in CEP290 called LP. Authors perform functional studies on patient cells but given the large deletion/CEP290 variant i dont see the results are usable PMID: 25920555 - another report of digenic inheritance - not usable, patient was only heterozygous for a single B9D1 variant.
Mendeliome v0.2839 ZNF423 Zornitza Stark Classified gene: ZNF423 as Amber List (moderate evidence)
Mendeliome v0.2839 ZNF423 Zornitza Stark Gene: znf423 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2838 PACS1 Zornitza Stark Gene: pacs1 has been classified as Green List (High Evidence).
Mendeliome v0.2835 SLC15A4 Zornitza Stark Gene: slc15a4 has been classified as Red List (Low Evidence).
Mendeliome v0.2834 SLC15A4 Zornitza Stark Classified gene: SLC15A4 as Red List (low evidence)
Mendeliome v0.2834 SLC15A4 Zornitza Stark Gene: slc15a4 has been classified as Red List (Low Evidence).
Mendeliome v0.2833 STARD7 Zornitza Stark Gene: stard7 has been classified as Green List (High Evidence).
Mendeliome v0.2833 STARD7 Zornitza Stark Classified gene: STARD7 as Green List (high evidence)
Mendeliome v0.2833 STARD7 Zornitza Stark Gene: stard7 has been classified as Green List (High Evidence).
Mendeliome v0.2832 STARD7 Zornitza Stark gene: STARD7 was added
gene: STARD7 was added to Mendeliome. Sources: Expert list
STR tags were added to gene: STARD7.
Mode of inheritance for gene: STARD7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STARD7 were set to 11701600; 24114805; 31664034
Phenotypes for gene: STARD7 were set to Epilepsy, familial adult myoclonic, 2, 607876
Mode of pathogenicity for gene: STARD7 was set to Other
Review for gene: STARD7 was set to GREEN
Added comment: 158 individuals from 22 families reported with heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene.
Sources: Expert list
Mendeliome v0.2831 ERC1 Zornitza Stark Gene: erc1 has been classified as Red List (Low Evidence).
Mendeliome v0.2831 ERC1 Zornitza Stark Classified gene: ERC1 as Red List (low evidence)
Mendeliome v0.2831 ERC1 Zornitza Stark Gene: erc1 has been classified as Red List (Low Evidence).
Mendeliome v0.2830 DHCR7 Zornitza Stark Gene: dhcr7 has been classified as Green List (High Evidence).
Mendeliome v0.2827 PDXK Zornitza Stark Gene: pdxk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2826 PDXK Zornitza Stark Classified gene: PDXK as Amber List (moderate evidence)
Mendeliome v0.2826 PDXK Zornitza Stark Gene: pdxk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2825 NDP Zornitza Stark Gene: ndp has been classified as Green List (High Evidence).
Mendeliome v0.2822 TMEM107 Zornitza Stark Gene: tmem107 has been classified as Green List (High Evidence).
Mendeliome v0.2819 ALPL Zornitza Stark Gene: alpl has been classified as Green List (High Evidence).
Mendeliome v0.2819 ALPL Zornitza Stark Phenotypes for gene: ALPL were changed from to Hypophosphatasia, adult 146300 (AD, AR); Hypophosphatasia, childhood 241510 AR; Hypophosphatasia, infantile 241500 AR; Odontohypophosphatasia 146300 AD, AR
Mendeliome v0.2815 LRRC56 Zornitza Stark Gene: lrrc56 has been classified as Green List (High Evidence).
Mendeliome v0.2815 LRRC56 Zornitza Stark Classified gene: LRRC56 as Green List (high evidence)
Mendeliome v0.2815 LRRC56 Zornitza Stark Gene: lrrc56 has been classified as Green List (High Evidence).
Mendeliome v0.2814 LRRC56 Zornitza Stark reviewed gene: LRRC56: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 39, MIM# 618254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2814 ALPL Melanie Marty reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: Other; Publications: 19500388, 23688511; Phenotypes: Hypophosphatasia, adult 146300 (AD, AR), Hypophosphatasia, childhood 241510 AR, Hypophosphatasia, infantile 241500 AR, Odontohypophosphatasia 146300 AD, AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.2814 LRRC56 Elena Savva gene: LRRC56 was added
gene: LRRC56 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: LRRC56 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC56 were set to PMID: 30388400
Phenotypes for gene: LRRC56 were set to Ciliary dyskinesia, primary, 39 618254
Added comment: PMID: 30388400 - used protist null model to show abnormal ciliary beatings, replicated the phenotype when the protist was transfected with mutant allele observed in a patient.
3 unrelated families reported with either homozygous splice, missense or chet (nonsense/splice). Patients exhibited phenotypes including chronic respiratory/ear infections, situs inversus
Sources: Expert list
Mendeliome v0.2814 MOGS Zornitza Stark Gene: mogs has been classified as Green List (High Evidence).
Mendeliome v0.2811 TCF7L1 Zornitza Stark Gene: tcf7l1 has been classified as Red List (Low Evidence).
Mendeliome v0.2808 TCF7L1 Zornitza Stark Classified gene: TCF7L1 as Red List (low evidence)
Mendeliome v0.2808 TCF7L1 Zornitza Stark Gene: tcf7l1 has been classified as Red List (Low Evidence).
Mendeliome v0.2807 GFI1B Bryony Thompson Gene: gfi1b has been classified as Green List (High Evidence).
Mendeliome v0.2807 GFI1B Bryony Thompson Classified gene: GFI1B as Green List (high evidence)
Mendeliome v0.2807 GFI1B Bryony Thompson Gene: gfi1b has been classified as Green List (High Evidence).
Mendeliome v0.2805 PRKD1 Zornitza Stark Gene: prkd1 has been classified as Green List (High Evidence).
Mendeliome v0.2805 PRKD1 Zornitza Stark Phenotypes for gene: PRKD1 were changed from to Congenital heart defects and ectodermal dysplasia, 617364
Mendeliome v0.2802 NODAL Zornitza Stark Gene: nodal has been classified as Red List (Low Evidence).
Mendeliome v0.2799 NODAL Zornitza Stark Classified gene: NODAL as Red List (low evidence)
Mendeliome v0.2799 NODAL Zornitza Stark Gene: nodal has been classified as Red List (Low Evidence).
Mendeliome v0.2798 PIH1D3 Zornitza Stark Gene: pih1d3 has been classified as Green List (High Evidence).
Mendeliome v0.2798 PIH1D3 Zornitza Stark Phenotypes for gene: PIH1D3 were changed from to Ciliary dyskinesia, primary, 36, X-linked (MIM#300991)
Mendeliome v0.2795 PIH1D3 Zornitza Stark reviewed gene: PIH1D3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28041644, 24421334, 28176794; Phenotypes: Ciliary dyskinesia, primary, 36, X-linked (MIM#300991); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.2795 COL10A1 Zornitza Stark Gene: col10a1 has been classified as Green List (High Evidence).
Mendeliome v0.2795 COL10A1 Zornitza Stark Phenotypes for gene: COL10A1 were changed from to Metaphyseal chondrodysplasia, Schmid type, MIM#156500
Mendeliome v0.2792 COL10A1 Zornitza Stark reviewed gene: COL10A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15880705, 31633898; Phenotypes: Metaphyseal chondrodysplasia, Schmid type, MIM#156500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2792 CEP112 Bryony Thompson Classified gene: CEP112 as Amber List (moderate evidence)
Mendeliome v0.2792 CEP112 Bryony Thompson Gene: cep112 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2791 CEP112 Bryony Thompson gene: CEP112 was added
gene: CEP112 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP112 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP112 were set to 31654588
Phenotypes for gene: CEP112 were set to Acephalic spermatozoa; infertility
Review for gene: CEP112 was set to AMBER
Added comment: Two unrelated cases reported with acephalic spermatozoa, one case with a homozygous nonsense variant and the other case with biallelic missense variants. CEP112 expression was significantly reduced in one of the cases, suggesting loss of function as a mechanism of disease.
Sources: Literature
Mendeliome v0.2790 PRKD1 Kristin Rigbye reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2790 KPNA7 Alison Yeung Gene: kpna7 has been classified as Red List (Low Evidence).
Mendeliome v0.2790 KPNA7 Alison Yeung gene: KPNA7 was added
gene: KPNA7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KPNA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KPNA7 were set to 24045845; 32179771
Phenotypes for gene: KPNA7 were set to Epilepsy; intellectual disability
Review for gene: KPNA7 was set to RED
Added comment: Single family with two siblings
Sources: Literature
Mendeliome v0.2789 NR4A2 Zornitza Stark Gene: nr4a2 has been classified as Green List (High Evidence).
Mendeliome v0.2789 NR4A2 Zornitza Stark Classified gene: NR4A2 as Green List (high evidence)
Mendeliome v0.2789 NR4A2 Zornitza Stark Gene: nr4a2 has been classified as Green List (High Evidence).
Mendeliome v0.2787 TOMM70 Zornitza Stark Gene: tomm70 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2787 TOMM70 Zornitza Stark Classified gene: TOMM70 as Amber List (moderate evidence)
Mendeliome v0.2787 TOMM70 Zornitza Stark Gene: tomm70 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2786 TOMM70 Zornitza Stark gene: TOMM70 was added
gene: TOMM70 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TOMM70 were set to 31907385; 32356556
Phenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis, developmental delay; White matter abnormalities, developmental delay, regression, movement disorder
Review for gene: TOMM70 was set to AMBER
Added comment: TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria.
Bi-allelic disease: one individual reported with compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)]. Clinical features included severe anaemia, lactic acidosis, and developmental delay. Some functional data: in vitro cell model compensatory experiments.
Monoallelic disease: de novo mono allelic variants in the C-terminal region of TOMM70 reported in two individuals. While both individuals exhibited shared symptoms including hypotonia, hyperreflexia, ataxia, dystonia, and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset, with one experiencing episodes of regression. Some functional data.
Sources: Expert list
Mendeliome v0.2784 CUL3 Zornitza Stark Gene: cul3 has been classified as Green List (High Evidence).
Mendeliome v0.2781 EGR2 Zornitza Stark Gene: egr2 has been classified as Green List (High Evidence).
Mendeliome v0.2777 GAS2L2 Zornitza Stark Gene: gas2l2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2777 GAS2L2 Zornitza Stark Phenotypes for gene: GAS2L2 were changed from to Ciliary dyskinesia, primary, 41 (MIM # 618449)
Mendeliome v0.2774 GAS2L2 Zornitza Stark Classified gene: GAS2L2 as Amber List (moderate evidence)
Mendeliome v0.2774 GAS2L2 Zornitza Stark Gene: gas2l2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2773 GAS2L2 Zornitza Stark reviewed gene: GAS2L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30665704; Phenotypes: Ciliary dyskinesia, primary, 41 (MIM # 618449); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2773 KLB Zornitza Stark Gene: klb has been classified as Green List (High Evidence).
Mendeliome v0.2772 KLB Zornitza Stark Classified gene: KLB as Green List (high evidence)
Mendeliome v0.2772 KLB Zornitza Stark Gene: klb has been classified as Green List (High Evidence).
Mendeliome v0.2771 KLB Zornitza Stark gene: KLB was added
gene: KLB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLB were set to 28754744
Review for gene: KLB was set to GREEN
Added comment: Seven heterozygous loss‐of‐function KLB mutations in 13 individuals reported. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21.
Functional analysis showed decreased activity in response to FGF21 and FGF8.
KLB is an obligate coreceptor for FGF21 alongside FGFR1.
Sources: Literature
Mendeliome v0.2770 NDNF Zornitza Stark Gene: ndnf has been classified as Green List (High Evidence).
Mendeliome v0.2770 NDNF Zornitza Stark Classified gene: NDNF as Green List (high evidence)
Mendeliome v0.2770 NDNF Zornitza Stark Gene: ndnf has been classified as Green List (High Evidence).
Mendeliome v0.2768 UGDH Zornitza Stark Gene: ugdh has been classified as Green List (High Evidence).
Mendeliome v0.2768 UGDH Zornitza Stark Classified gene: UGDH as Green List (high evidence)
Mendeliome v0.2768 UGDH Zornitza Stark Gene: ugdh has been classified as Green List (High Evidence).
Mendeliome v0.2767 UGDH Zornitza Stark gene: UGDH was added
gene: UGDH was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Review for gene: UGDH was set to GREEN
Added comment: 36 individuals with biallelic UGDH pathogenic variants reported. The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate. Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ. Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors
Sources: Literature
Mendeliome v0.2766 TRIM33 Zornitza Stark Gene: trim33 has been classified as Red List (Low Evidence).
Mendeliome v0.2766 TRIM33 Zornitza Stark Classified gene: TRIM33 as Red List (low evidence)
Mendeliome v0.2766 TRIM33 Zornitza Stark Gene: trim33 has been classified as Red List (Low Evidence).
Mendeliome v0.2765 YIF1B Zornitza Stark Gene: yif1b has been classified as Green List (High Evidence).
Mendeliome v0.2765 YIF1B Zornitza Stark Classified gene: YIF1B as Green List (high evidence)
Mendeliome v0.2765 YIF1B Zornitza Stark Gene: yif1b has been classified as Green List (High Evidence).
Mendeliome v0.2764 YIF1B Zornitza Stark gene: YIF1B was added
gene: YIF1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098; 26077767
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Review for gene: YIF1B was set to GREEN
Added comment: 6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.
Sources: Literature
Mendeliome v0.2760 TNRC6B Zornitza Stark Classified gene: TNRC6B as Green List (high evidence)
Mendeliome v0.2760 TNRC6B Zornitza Stark Gene: tnrc6b has been classified as Green List (High Evidence).
Mendeliome v0.2759 TNRC6B Zornitza Stark edited their review of gene: TNRC6B: Added comment: 17 unrelated individuals with heterozygous TNRC6B variants reported. Features included hypotonia (10/17), DD/ID (17/17 - ID was not universal: average IQ of 12 individuals was 73 (range : 50-113) with 4 having below 70), ADHD (11/17), ASD or autistic traits (8/17 and 5/17). Some/few presented with abnormal OFC (micro- / macrocephaly in 3/17 and 2/17), abnormal vision or hearing, variable other congenital anomalies, echocardiographic, GI or renal abnormalities, etc. Epilepsy was reported in 1/17. There was no recognisable gestalt.Detected variants included 14 pLoF, 1 missense SNV and 2 intragenic deletions. Variants had occurred as de novo events in 10/13 subjects for whom testing of both parents was possible. 3/13 subjects had inherited the variant from a parent with milder phenotype. Based on the type of variants identified, the pLI score of 1 in gnomAD and the HI index of 5.61%, the authors suggest haploinsufficiency as the most likely mechanism. Individuals with de novo TNRC6B variants have also been reported in larger cohorts (e.g. DDD study - PMID: 28135719, Iossifov et al - PMID: 25363768, Lelieveld et al - PMID: 27479843, Jónsson et al - PMID: 28959963). A previous study provided details on 2 sibs harboring a translocation which disrupted both TNRC6B and TCF20 (also associated with ID)(Babbs et al - PMID: 25228304).; Changed rating: GREEN; Changed publications: 32152250, 28135719, 25363768, 27479843, 28959963, 25228304; Changed phenotypes: Global developmental delay, Intellectual disability, Autistic behavior; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2759 CDC42BPB Zornitza Stark Gene: cdc42bpb has been classified as Green List (High Evidence).
Mendeliome v0.2759 CDC42BPB Zornitza Stark Classified gene: CDC42BPB as Green List (high evidence)
Mendeliome v0.2759 CDC42BPB Zornitza Stark Gene: cdc42bpb has been classified as Green List (High Evidence).
Mendeliome v0.2757 DNAJB13 Zornitza Stark Gene: dnajb13 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2757 DNAJB13 Zornitza Stark Phenotypes for gene: DNAJB13 were changed from to Ciliary dyskinesia, primary, 34, MIM# 617091
Mendeliome v0.2754 DNAJB13 Zornitza Stark Classified gene: DNAJB13 as Amber List (moderate evidence)
Mendeliome v0.2754 DNAJB13 Zornitza Stark Gene: dnajb13 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2753 DNAJB13 Zornitza Stark reviewed gene: DNAJB13: Rating: AMBER; Mode of pathogenicity: None; Publications: 27486783; Phenotypes: Ciliary dyskinesia, primary, 34, MIM# 617091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2753 CFC1 Zornitza Stark Gene: cfc1 has been classified as Green List (High Evidence).
Mendeliome v0.2750 CFAP53 Zornitza Stark Gene: cfap53 has been classified as Green List (High Evidence).
Mendeliome v0.2750 CFAP53 Zornitza Stark Phenotypes for gene: CFAP53 were changed from to Heterotaxy, visceral, 6, autosomal recessive 614779
Mendeliome v0.2747 CFAP53 Zornitza Stark reviewed gene: CFAP53: Rating: GREEN; Mode of pathogenicity: None; Publications: 28621423, 22577226, 26531781; Phenotypes: Heterotaxy, visceral, 6, autosomal recessive 614779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2747 TTC25 Zornitza Stark Gene: ttc25 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2747 TTC25 Zornitza Stark Phenotypes for gene: TTC25 were changed from to Ciliary dyskinesia, primary, 35 (MIM#617092)
Mendeliome v0.2744 TTC25 Zornitza Stark Classified gene: TTC25 as Amber List (moderate evidence)
Mendeliome v0.2744 TTC25 Zornitza Stark Gene: ttc25 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2743 TTC25 Zornitza Stark reviewed gene: TTC25: Rating: AMBER; Mode of pathogenicity: None; Publications: 27486780; Phenotypes: Ciliary dyskinesia, primary, 35 (MIM#617092); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2743 CFAP43 Zornitza Stark Gene: cfap43 has been classified as Green List (High Evidence).
Mendeliome v0.2743 CFAP43 Zornitza Stark Classified gene: CFAP43 as Green List (high evidence)
Mendeliome v0.2743 CFAP43 Zornitza Stark Gene: cfap43 has been classified as Green List (High Evidence).
Mendeliome v0.2742 CFAP43 Elena Savva gene: CFAP43 was added
gene: CFAP43 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP43 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CFAP43 were set to PMID: 31884020; 28552195; 31004071; 29449551
Phenotypes for gene: CFAP43 were set to Hydrocephalus, normal pressure, 1 236690; Spermatogenic failure 19 617592
Added comment: aka WDR96

PMID: 31884020 - animal models (mouse, frog) demonstrate the protein localizes in ciliary axoneme and is involved in MOTILE cilia movement. LOF CFAP43 caused mucus acucmulation in airways, impaired spermatogenesis and hydrocephalus.

PMID: 28552195 - 3x chet (bilallelic PTCs or chet PTC/missense) with abnormal sperm motility. Null mouse models were also infertile.

PMID: 31004071 - one family with a heterozygous nonsense and AD inheritance of late onset hydrocephaly (checked in Mutalyzer, variant is NMD predicted). Abnormal cilia observed from mucosa sample. Null mice also show abnormal sperm and dilation of brain ventricles.

PMID: 29449551 - reports an additional 10 patients with either homozygous PTCs or chet PTC/missense who were infertile with flagella defects

Summary: single report of AD hydrocephaly
Sources: Literature
Mendeliome v0.2742 MYLK2 Zornitza Stark Gene: mylk2 has been classified as Red List (Low Evidence).
Mendeliome v0.2739 MYLK2 Zornitza Stark Classified gene: MYLK2 as Red List (low evidence)
Mendeliome v0.2739 MYLK2 Zornitza Stark Gene: mylk2 has been classified as Red List (Low Evidence).
Mendeliome v0.2738 CDX2 Zornitza Stark Gene: cdx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2738 CDX2 Zornitza Stark Phenotypes for gene: CDX2 were changed from to Persistent cloaca
Mendeliome v0.2735 CDX2 Zornitza Stark Classified gene: CDX2 as Amber List (moderate evidence)
Mendeliome v0.2735 CDX2 Zornitza Stark Gene: cdx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2734 CDX2 Zornitza Stark reviewed gene: CDX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29177441; Phenotypes: Persistent cloaca; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2734 TAPT1 Zornitza Stark Gene: tapt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2734 TAPT1 Zornitza Stark Phenotypes for gene: TAPT1 were changed from to Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897)
Mendeliome v0.2731 TAPT1 Zornitza Stark Classified gene: TAPT1 as Amber List (moderate evidence)
Mendeliome v0.2731 TAPT1 Zornitza Stark Gene: tapt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2730 TAPT1 Zornitza Stark reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365339; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2730 CCDC28B Zornitza Stark Classified gene: CCDC28B as Amber List (moderate evidence)
Mendeliome v0.2730 CCDC28B Zornitza Stark Gene: ccdc28b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2729 CCDC28B Zornitza Stark edited their review of gene: CCDC28B: Added comment: PMID: 32139166 - Single family with Joubert syndrome. Patient was homozygous for a missense, with polydactyly, severe ID, and the molar tooth sign observed in MRI. Sibling fetus MRI showed vermis hypoplasia, and was also homozygous for the variant. Parents confirmed unaffected carriers. Knockdown of CCDC28B in human TERT retinal pigment epithelial cells reduced both the number and length of cilia 430C-T variant is postulated to be a modifier of BBS.; Changed rating: AMBER; Changed publications: 32139166; Changed phenotypes: {Bardet-Biedl syndrome 1, modifier of}, MIM#209900, Joubert syndrome
Mendeliome v0.2729 C21orf59 Zornitza Stark Gene: c21orf59 has been classified as Green List (High Evidence).
Mendeliome v0.2729 C11orf70 Zornitza Stark Gene: c11orf70 has been classified as Green List (High Evidence).
Mendeliome v0.2729 C11orf70 Zornitza Stark Phenotypes for gene: C11orf70 were changed from to Ciliary dyskinesia, primary, 38, MIM# 618063
Mendeliome v0.2726 C11orf70 Zornitza Stark reviewed gene: C11orf70: Rating: GREEN; Mode of pathogenicity: None; Publications: 29727693, 29727692; Phenotypes: Ciliary dyskinesia, primary, 38, MIM# 618063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2726 ARMC9 Zornitza Stark Gene: armc9 has been classified as Green List (High Evidence).
Mendeliome v0.2723 ARMC9 Zornitza Stark edited their review of gene: ARMC9: Added comment: ARMC9 localizes to the ciliary basal body and daughter centriole and is predicted to function in ciliogenesis PMID: 28625504 - 8 families with Joubert syndrome, all variant types detected. Functional studies show protein localizes at the basal body and upregulates during ciliogenesis. Zebrafish with frameshift mutation recapitulated the human phenotype including a curved body, coloboma, retinal dystrophy and less cilia.; Changed rating: GREEN; Changed publications: 28625504
Mendeliome v0.2723 ARMC8 Zornitza Stark Gene: armc8 has been classified as Red List (Low Evidence).
Mendeliome v0.2723 ARMC8 Zornitza Stark Classified gene: ARMC8 as Red List (low evidence)
Mendeliome v0.2723 ARMC8 Zornitza Stark Gene: armc8 has been classified as Red List (Low Evidence).
Mendeliome v0.2722 ARMC4 Zornitza Stark Gene: armc4 has been classified as Green List (High Evidence).
Mendeliome v0.2722 ARMC4 Zornitza Stark Phenotypes for gene: ARMC4 were changed from to Ciliary dyskinesia, primary, 23, MIM# 615451
Mendeliome v0.2719 ARMC4 Zornitza Stark reviewed gene: ARMC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31765523, 23849778; Phenotypes: Ciliary dyskinesia, primary, 23, MIM# 615451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2719 ACVR2B Zornitza Stark Gene: acvr2b has been classified as Red List (Low Evidence).
Mendeliome v0.2716 ACVR2B Zornitza Stark Classified gene: ACVR2B as Red List (low evidence)
Mendeliome v0.2716 ACVR2B Zornitza Stark Gene: acvr2b has been classified as Red List (Low Evidence).
Mendeliome v0.2715 NID1 Zornitza Stark Gene: nid1 has been classified as Green List (High Evidence).
Mendeliome v0.2712 DARS Zornitza Stark Gene: dars has been classified as Green List (High Evidence).
Mendeliome v0.2709 CCDC65 Zornitza Stark Gene: ccdc65 has been classified as Green List (High Evidence).
Mendeliome v0.2709 CCDC65 Zornitza Stark Phenotypes for gene: CCDC65 were changed from to Ciliary dyskinesia, primary, 27, MIM# 615504
Mendeliome v0.2706 CCDC65 Zornitza Stark reviewed gene: CCDC65: Rating: GREEN; Mode of pathogenicity: None; Publications: 23991085, 24094744; Phenotypes: Ciliary dyskinesia, primary, 27, MIM# 615504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2706 C21orf59 Zornitza Stark Gene: c21orf59 has been classified as Green List (High Evidence).
Mendeliome v0.2706 C21orf59 Zornitza Stark Phenotypes for gene: C21orf59 were changed from to Ciliary dyskinesia, primary, 26, MIM# 615500
Mendeliome v0.2703 C21orf59 Zornitza Stark reviewed gene: C21orf59: Rating: GREEN; Mode of pathogenicity: None; Publications: 24094744; Phenotypes: Ciliary dyskinesia, primary, 26, MIM# 615500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2703 WISP3 Zornitza Stark Gene: wisp3 has been classified as Green List (High Evidence).
Mendeliome v0.2703 WISP3 Zornitza Stark Phenotypes for gene: WISP3 were changed from to Arthropathy, progressive pseudorheumatoid, of childhood, MIM# 208230; Spondyloepiphyseal dysplasia tarda with progressive arthropathy, MIM# 208230
Mendeliome v0.2700 WISP3 Zornitza Stark reviewed gene: WISP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10471507; Phenotypes: Arthropathy, progressive pseudorheumatoid, of childhood, MIM# 208230, Spondyloepiphyseal dysplasia tarda with progressive arthropathy, MIM# 208230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2700 ATP5E Zornitza Stark Gene: atp5e has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2697 ATP5E Zornitza Stark Classified gene: ATP5E as Amber List (moderate evidence)
Mendeliome v0.2697 ATP5E Zornitza Stark Gene: atp5e has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2696 ATP5D Zornitza Stark Gene: atp5d has been classified as Green List (High Evidence).
Mendeliome v0.2693 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2690 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Amber List (moderate evidence)
Mendeliome v0.2690 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2689 GLDC Zornitza Stark Gene: gldc has been classified as Green List (High Evidence).
Mendeliome v0.2686 CD4 Zornitza Stark reviewed gene: CD4: Rating: AMBER; Mode of pathogenicity: None; Publications: 31781092; Phenotypes: Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2685 TNK2 Zornitza Stark Gene: tnk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2682 TNK2 Zornitza Stark Classified gene: TNK2 as Amber List (moderate evidence)
Mendeliome v0.2682 TNK2 Zornitza Stark Gene: tnk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2681 MAN2B2 Zornitza Stark Gene: man2b2 has been classified as Red List (Low Evidence).
Mendeliome v0.2681 MAN2B2 Zornitza Stark gene: MAN2B2 was added
gene: MAN2B2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B2 were set to 31775018
Phenotypes for gene: MAN2B2 were set to Congenital disorder of glycosylation; immunodeficiency
Review for gene: MAN2B2 was set to RED
Added comment: Single individual reported.
Sources: Literature
Mendeliome v0.2680 RIPK1 Zornitza Stark Gene: ripk1 has been classified as Green List (High Evidence).
Mendeliome v0.2677 PIK3CG Zornitza Stark Gene: pik3cg has been classified as Green List (High Evidence).
Mendeliome v0.2677 PIK3CG Zornitza Stark Classified gene: PIK3CG as Green List (high evidence)
Mendeliome v0.2677 PIK3CG Zornitza Stark Gene: pik3cg has been classified as Green List (High Evidence).
Mendeliome v0.2675 RC3H1 Zornitza Stark Gene: rc3h1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2675 RC3H1 Zornitza Stark Classified gene: RC3H1 as Amber List (moderate evidence)
Mendeliome v0.2675 RC3H1 Zornitza Stark Gene: rc3h1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2675 RC3H1 Zornitza Stark Classified gene: RC3H1 as Amber List (moderate evidence)
Mendeliome v0.2675 RC3H1 Zornitza Stark Gene: rc3h1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2674 RC3H1 Zornitza Stark changed review comment from: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data.
Sources: Literature; to: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data including mouse model.
Sources: Literature
Mendeliome v0.2674 RC3H1 Zornitza Stark gene: RC3H1 was added
gene: RC3H1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RC3H1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RC3H1 were set to 31636267
Phenotypes for gene: RC3H1 were set to Relapsing HLH
Review for gene: RC3H1 was set to RED
Added comment: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data.
Sources: Literature
Mendeliome v0.2673 IFNG Zornitza Stark Gene: ifng has been classified as Red List (Low Evidence).
Mendeliome v0.2670 IFNG Zornitza Stark Classified gene: IFNG as Red List (low evidence)
Mendeliome v0.2670 IFNG Zornitza Stark Gene: ifng has been classified as Red List (Low Evidence).
Mendeliome v0.2669 ITPKB Zornitza Stark gene: ITPKB was added
gene: ITPKB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITPKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITPKB were set to 31987846
Phenotypes for gene: ITPKB were set to Severe combined immunodeficiency, absent T cells, present B cells and NK cells
Review for gene: ITPKB was set to RED
Added comment: Single individual with homozygous bi-allelic LoF variant reported.
Sources: Literature
Mendeliome v0.2668 PSMB10 Zornitza Stark Gene: psmb10 has been classified as Red List (Low Evidence).
Mendeliome v0.2668 PSMB10 Zornitza Stark gene: PSMB10 was added
gene: PSMB10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMB10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMB10 were set to 31783057
Phenotypes for gene: PSMB10 were set to Autoinflammatory syndrome
Review for gene: PSMB10 was set to RED
Added comment: PSMB10 is part of the immunoproteasome, and other components cause auto inflammatory disorders. Single individual with homozygous missense variant reported.
Sources: Literature
Mendeliome v0.2667 ABHD12 Zornitza Stark Gene: abhd12 has been classified as Green List (High Evidence).
Mendeliome v0.2665 ABCC6 Zornitza Stark Gene: abcc6 has been classified as Green List (High Evidence).
Mendeliome v0.2665 AAAS Zornitza Stark Gene: aaas has been classified as Green List (High Evidence).
Mendeliome v0.2665 AAAS Zornitza Stark Phenotypes for gene: AAAS were changed from to Achalasia-addisonianism-alacrimia syndrome, MIM#231550
Mendeliome v0.2663 NOS2 Zornitza Stark Gene: nos2 has been classified as Red List (Low Evidence).
Mendeliome v0.2663 NOS2 Zornitza Stark Phenotypes for gene: NOS2 were changed from to {Malaria, resistance to} 611162; Disseminated CMV disease
Mendeliome v0.2661 NOS2 Zornitza Stark Classified gene: NOS2 as Red List (low evidence)
Mendeliome v0.2661 NOS2 Zornitza Stark Gene: nos2 has been classified as Red List (Low Evidence).
Mendeliome v0.2660 NOS2 Zornitza Stark reviewed gene: NOS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 12433515, 31995689; Phenotypes: {Malaria, resistance to} 611162, Disseminated CMV disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2660 SNORA31 Zornitza Stark Gene: snora31 has been classified as Green List (High Evidence).
Mendeliome v0.2660 SNORA31 Zornitza Stark Classified gene: SNORA31 as Green List (high evidence)
Mendeliome v0.2660 SNORA31 Zornitza Stark Gene: snora31 has been classified as Green List (High Evidence).
Mendeliome v0.2659 SNORA31 Zornitza Stark gene: SNORA31 was added
gene: SNORA31 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SNORA31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNORA31 were set to 31806906
Phenotypes for gene: SNORA31 were set to Susceptibility to HSV1 encephalitis
Review for gene: SNORA31 was set to GREEN
Added comment: Five unrelated individuals reported with rare missense variants in this gene, functional data to support susceptibility to herpes simplex encephalitis.
Sources: Expert list
Mendeliome v0.2658 TCOF1 Zornitza Stark Gene: tcof1 has been classified as Green List (High Evidence).
Mendeliome v0.2655 EMX2 Zornitza Stark Gene: emx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2652 EMX2 Zornitza Stark Classified gene: EMX2 as Amber List (moderate evidence)
Mendeliome v0.2652 EMX2 Zornitza Stark Gene: emx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2651 ATAD3A Zornitza Stark Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, MIM# 617183 to Harel-Yoon syndrome, MIM# 617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (PHRINL SYNDROME) 618810
Mendeliome v0.2649 ATAD3A Zornitza Stark edited their review of gene: ATAD3A: Added comment: Mode of pathogenicity includes:
i) bi-allelic missense and nonsense variants and bi-allelic deletions that create an ATAD3B/ATAD3A fusion gene under the lowly expressed ATAD3B promoter
ii) monoallelic dominant-negative missense variants (either de novo or inherited) and de novo monoallelic duplications creating a dominant negative ATAD3A/ATAD3C fusion gene; Changed publications: 27640307, 32004445, 28549128; Changed phenotypes: Harel-Yoon syndrome, MIM# 617183, Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (PHRINL SYNDROME) 618810
Mendeliome v0.2649 CTSA Zornitza Stark Gene: ctsa has been classified as Green List (High Evidence).
Mendeliome v0.2649 CTSA Zornitza Stark Phenotypes for gene: CTSA were changed from to Galactosialidosis, MIM# 256540; Cathepsin A-related arteriopathy with strokes and leukoencephalopathy
Mendeliome v0.2646 MN1 Zornitza Stark Phenotypes for gene: MN1 were changed from Intellectual disability; dysmophic features; rhombencephalosynapsis to CEBALID syndrome, MIM#618774; Intellectual disability; dysmophic features; rhombencephalosynapsis
Mendeliome v0.2645 MN1 Zornitza Stark edited their review of gene: MN1: Changed phenotypes: CEBALID syndrome, MIM#618774, Intellectual disability, dysmophic features, rhombencephalosynapsis
Mendeliome v0.2645 PI4KA Zornitza Stark Gene: pi4ka has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2645 PI4KA Zornitza Stark Phenotypes for gene: PI4KA were changed from to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531
Mendeliome v0.2642 PI4KA Zornitza Stark Classified gene: PI4KA as Amber List (moderate evidence)
Mendeliome v0.2642 PI4KA Zornitza Stark Gene: pi4ka has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2641 PI4KA Zornitza Stark reviewed gene: PI4KA: Rating: AMBER; Mode of pathogenicity: None; Publications: 25855803; Phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2641 CDK5 Zornitza Stark changed review comment from: Single consanguineous family with multiple affected individuals reported.; to: Single consanguineous family with multiple affected individuals reported.
Mendeliome v0.2641 CDK5 Zornitza Stark Gene: cdk5 has been classified as Red List (Low Evidence).
Mendeliome v0.2641 CDK5 Zornitza Stark Phenotypes for gene: CDK5 were changed from to Lissencephaly 7 with cerebellar hypoplasia, MIM# 616342
Mendeliome v0.2638 CDK5 Zornitza Stark Classified gene: CDK5 as Red List (low evidence)
Mendeliome v0.2638 CDK5 Zornitza Stark Gene: cdk5 has been classified as Red List (Low Evidence).
Mendeliome v0.2637 CDK5 Zornitza Stark reviewed gene: CDK5: Rating: RED; Mode of pathogenicity: None; Publications: 25560765; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, MIM# 616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2637 VPS51 Zornitza Stark Gene: vps51 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2637 VPS51 Zornitza Stark Classified gene: VPS51 as Amber List (moderate evidence)
Mendeliome v0.2637 VPS51 Zornitza Stark Gene: vps51 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2636 VPS51 Zornitza Stark gene: VPS51 was added
gene: VPS51 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606
Review for gene: VPS51 was set to AMBER
Added comment: Two families reported with bi-allelic variants in this gene and global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable.
Sources: Expert list
Mendeliome v0.2635 CTSA Zornitza Stark changed review comment from: Bi-allelic variants cause galactosialidosis, and mono-allelic variants cause CARASAL.; to: Bi-allelic variants associated with galactosialidosis, and mono-allelic variants associated with CARASAL.
Mendeliome v0.2635 CTSA Zornitza Stark reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31177426; Phenotypes: Galactosialidosis, MIM# 256540, Cathepsin A-related arteriopathy with strokes and leukoencephalopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2635 CDK19 Zornitza Stark Gene: cdk19 has been classified as Green List (High Evidence).
Mendeliome v0.2635 CDK19 Zornitza Stark Classified gene: CDK19 as Green List (high evidence)
Mendeliome v0.2635 CDK19 Zornitza Stark Gene: cdk19 has been classified as Green List (High Evidence).
Mendeliome v0.2633 MNS1 Zornitza Stark Gene: mns1 has been classified as Green List (High Evidence).
Mendeliome v0.2633 MNS1 Zornitza Stark Classified gene: MNS1 as Green List (high evidence)
Mendeliome v0.2633 MNS1 Zornitza Stark Gene: mns1 has been classified as Green List (High Evidence).
Mendeliome v0.2631 DHX37 Zornitza Stark Gene: dhx37 has been classified as Green List (High Evidence).
Mendeliome v0.2631 DHX37 Zornitza Stark Classified gene: DHX37 as Green List (high evidence)
Mendeliome v0.2631 DHX37 Zornitza Stark Gene: dhx37 has been classified as Green List (High Evidence).
Mendeliome v0.2630 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX37 were set to 31337883; 31745530
Phenotypes for gene: DHX37 were set to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS)
Review for gene: DHX37 was set to GREEN
Added comment: Seventeen individuals with 46,XY gonadal dysgenesis reported in two studies.
Sources: Literature
Mendeliome v0.2629 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache
Mendeliome v0.2628 ALPK1 Zornitza Stark Classified gene: ALPK1 as Green List (high evidence)
Mendeliome v0.2628 ALPK1 Zornitza Stark Gene: alpk1 has been classified as Green List (High Evidence).
Mendeliome v0.2627 RAMP2 Zornitza Stark Gene: ramp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2627 RAMP2 Zornitza Stark Classified gene: RAMP2 as Amber List (moderate evidence)
Mendeliome v0.2627 RAMP2 Zornitza Stark Gene: ramp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2626 RAMP2 Zornitza Stark gene: RAMP2 was added
gene: RAMP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAMP2 were set to 31000793
Phenotypes for gene: RAMP2 were set to Primary open angle glaucoma
Review for gene: RAMP2 was set to AMBER
Added comment: Six variants identified in 16 of 4763 POAG patients from large cohorts; none identified in 10,953 control individuals. Some functional data.
Sources: Literature
Mendeliome v0.2625 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Added comment: Six unrelated families reported with same recurrent missense variant c.710C>T, (p.Thr237Met) and ROSAH syndrome phenotype. Pancytopaenia and recurrent infections present in some.; Changed rating: GREEN; Changed publications: 31053777, 30967659, 31939038; Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, ROSAH syndrome, retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache
Mendeliome v0.2625 MEPE Zornitza Stark Classified gene: MEPE as Amber List (moderate evidence)
Mendeliome v0.2625 MEPE Zornitza Stark Gene: mepe has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2624 MEPE Zornitza Stark gene: MEPE was added
gene: MEPE was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MEPE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MEPE were set to 30287925
Phenotypes for gene: MEPE were set to hereditary congenital facial paresis; otosclerosis
Review for gene: MEPE was set to AMBER
Added comment: Single four-generation family reported with variant in this gene segregating nonprogressive HCFP and mixed hearing loss (HL). Damaging variants (truncating/frameshift) found to be enriched in otosclerosis cohort (p = 0.0006–0.0060).
Sources: Literature
Mendeliome v0.2623 PAICS Zornitza Stark Gene: paics has been classified as Red List (Low Evidence).
Mendeliome v0.2623 PAICS Zornitza Stark gene: PAICS was added
gene: PAICS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PAICS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAICS were set to 31600779
Phenotypes for gene: PAICS were set to Polyhydramnios; multiple congenital abnormalities
Review for gene: PAICS was set to RED
Added comment: Two sibs from single family reported with homozygous missense variant. Functional data to demonstrate effect on protein function.
Sources: Literature
Mendeliome v0.2622 GALM Zornitza Stark Gene: galm has been classified as Green List (High Evidence).
Mendeliome v0.2622 GALM Zornitza Stark Classified gene: GALM as Green List (high evidence)
Mendeliome v0.2622 GALM Zornitza Stark Gene: galm has been classified as Green List (High Evidence).
Mendeliome v0.2621 POLR3GL Zornitza Stark Gene: polr3gl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2621 POLR3GL Zornitza Stark Classified gene: POLR3GL as Amber List (moderate evidence)
Mendeliome v0.2621 POLR3GL Zornitza Stark Gene: polr3gl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2620 GALM Hazel Phillimore gene: GALM was added
gene: GALM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALM were set to PMID: 30451973; 30910422
Phenotypes for gene: GALM were set to galactosaemia; type IV galactosaemia
Review for gene: GALM was set to GREEN
Added comment: Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). This is therefore type IV galactosaemia.
In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. Loss-of-function mechanism. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973)
In vitro expression assay and an enzyme activity assay of 67 GALM variants, taken from ExAc database (missense, nonsense, frameshift and splice). 30 variants concluded to be pathogenic due to no protein expression or faint expression. 5 variants with mildly lower levels were determined as likely pathogenic. All concluded to be loss-of-function mechanism. Incidence of galactosaemia by GALM deficiency is comparable to that of other galactosaemias. Carrier frequency and incidence was estimated for different populations. (Iwasawa, S. et al. (2019); PMID: 30910422)
Sources: Literature
Mendeliome v0.2620 POLR3GL Paul De Fazio gene: POLR3GL was added
gene: POLR3GL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR3GL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3GL were set to 31089205; 31695177
Phenotypes for gene: POLR3GL were set to endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy
Review for gene: POLR3GL was set to AMBER
gene: POLR3GL was marked as current diagnostic
Added comment: Biallelic canonical splice variants were identified in monozygotic twins and another individual with similar phenotypes from 2 unrelated families. Variants were inherited from carrier parents. RNA studies confirmed exon skipping occurs in all affected individuals.

A separate study identified a homozygous nonsense variant in an individual with features of Neonatal progeroid syndrome/Wiedemann–Rautenstrauch syndrome. Quantitative PCR showed reduction in mRNA suggestive of NMD.
Sources: Literature
Mendeliome v0.2620 TSPEAR Zornitza Stark Gene: tspear has been classified as Green List (High Evidence).
Mendeliome v0.2620 TSPEAR Zornitza Stark Phenotypes for gene: TSPEAR were changed from to Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180
Mendeliome v0.2617 PDGFRB Zornitza Stark Gene: pdgfrb has been classified as Green List (High Evidence).
Mendeliome v0.2613 TBL1Y Zornitza Stark Added comment: Comment when marking as ready: Single family, some functional data.
Mendeliome v0.2613 TBL1Y Zornitza Stark Gene: tbl1y has been classified as Red List (Low Evidence).
Mendeliome v0.2613 TBL1Y Zornitza Stark Classified gene: TBL1Y as Red List (low evidence)
Mendeliome v0.2613 TBL1Y Zornitza Stark Gene: tbl1y has been classified as Red List (Low Evidence).
Mendeliome v0.2612 DGCR8 Zornitza Stark Gene: dgcr8 has been classified as Red List (Low Evidence).
Mendeliome v0.2612 DGCR8 Zornitza Stark Classified gene: DGCR8 as Red List (low evidence)
Mendeliome v0.2612 DGCR8 Zornitza Stark Gene: dgcr8 has been classified as Red List (Low Evidence).
Mendeliome v0.2611 TSPEAR Chern Lim changed review comment from: Still a rare disease gene for ectodermal dysplasia but has been reported in at least 3 unrelated families. Functional study supported LoF. (PMIDs: 27736875, 30046887); to: Still a rare disease gene for ectodermal dysplasia but has been reported in at least 3 unrelated families in 2 papers. Functional study supported LoF. (PMIDs: 27736875, 30046887)
Mendeliome v0.2611 TSPEAR Chern Lim reviewed gene: TSPEAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 27736875, 30046887; Phenotypes: Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2611 PDGFRB Ee Ming Wong changed review comment from: - > 3 unrelated families
- Functional studies on patient fibroblasts, HeLa and HEK293 cells harbouring mutant constructs demonstrate constitutive tyrosine kinase activation (gain of function) compared with WT constructs; to: - > 3 unrelated individuals diagnosed with Penttinen syndrome
- Functional studies on patient fibroblasts, HeLa and HEK293 cells harbouring mutant constructs demonstrate constitutive tyrosine kinase activation (gain of function) compared with WT constructs
Mendeliome v0.2611 TBL1Y Paul De Fazio changed review comment from: 9 affected males in a single 5-generation pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature; to: Y-linked inheritance pattern. Complete segregation of a missense variant demonstrated in 9 affected males in a 5-generation pedigree. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature
Mendeliome v0.2611 TBL1Y Paul De Fazio changed review comment from: 9 affected males in a single pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature; to: 9 affected males in a single 5-generation pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature
Mendeliome v0.2611 TBL1Y Paul De Fazio gene: TBL1Y was added
gene: TBL1Y was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBL1Y was set to Other
Publications for gene: TBL1Y were set to 30341416
Phenotypes for gene: TBL1Y were set to Hearing loss
Review for gene: TBL1Y was set to RED
gene: TBL1Y was marked as current diagnostic
Added comment: 9 affected males in a single pedigree described with Y-linked inheritance pattern. Functional studies show the missense variant causes reduced protein stability. The gene has restricted expression in the cochlea and prostate.
Sources: Literature
Mendeliome v0.2611 FOXF2 Zornitza Stark Added comment: Comment when marking as ready: Single family: variant has functional data to demonstrate effect on protein, plus mouse model supports gene-disease association.
Mendeliome v0.2611 FOXF2 Zornitza Stark Gene: foxf2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2611 FOXF2 Zornitza Stark Classified gene: FOXF2 as Amber List (moderate evidence)
Mendeliome v0.2611 FOXF2 Zornitza Stark Gene: foxf2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2610 DGCR8 Chern Lim gene: DGCR8 was added
gene: DGCR8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DGCR8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DGCR8 were set to 31805011
Phenotypes for gene: DGCR8 were set to Early-onset multinodular goiter and schwannomatosis
Review for gene: DGCR8 was set to RED
Added comment: A germline missense variant segregates in one family with autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter (MNG) with schwannomatosis. The missense is also a recurrent somatic missense variant in Wilms tumour. (PMID:31805011)
Sources: Literature
Mendeliome v0.2610 TDRD7 Zornitza Stark Phenotypes for gene: TDRD7 were changed from to Cataract 36 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis
Mendeliome v0.2607 TDRD7 Ee Ming Wong reviewed gene: TDRD7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28837160, 21436445; Phenotypes: cataract, glaucoma, nonobstructive azoospermia, arrested spermatogenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2607 FOXF2 Hazel Phillimore changed review comment from: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639).
This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403).
Sources: Literature; to: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639).
This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403).
Previous names for FOXF2 include FKHL6 and FREAC2.
Sources: Literature
Mendeliome v0.2607 FOXF2 Hazel Phillimore gene: FOXF2 was added
gene: FOXF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOXF2 were set to PMID: 30561639; 22022403
Phenotypes for gene: FOXF2 were set to profound sensorineural hearing loss (SNHL); cochlea malformations; incomplete partition type I anomaly of the cochlea
Review for gene: FOXF2 was set to AMBER
Added comment: Homozygous missense, NM_001452.1: c.325A>T (p.I109F), in a 10 year old girl (consanguineous, parents were first cousins) with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is absent in the gnomAD v2.1.1. In vitro studies indicated instability, shorter half-life of the protein compared to wildtype. Embryonic knockout mouse showed shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Homozygous knockout mice do not survive. (Bademci, G. et al. (2019); PMID: 30561639).
This gene has also been reported in association with other anomalies including cleft lip, cleft palate, brain anomalies, intestine anomalies, and eye anomalies. Eye anomalies include anterior segment dysgenesis, as shown in mice with variant, W174R, affecting the Fox domain. Homozygote mice do not survive. (McKeone, R. et al. (2011); PMID: 22022403).
Sources: Literature
Mendeliome v0.2607 COL13A1 Zornitza Stark Gene: col13a1 has been classified as Green List (High Evidence).
Mendeliome v0.2604 KIAA1161 Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317 to Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome
Mendeliome v0.2602 KIAA1161 Hazel Phillimore reviewed gene: KIAA1161: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29910000, 31009047; Phenotypes: Basal ganglia calcification, idiopathic, 7, autosomal recessive (OMIM #618317), primary familial brain calcifications (PFBC), ataxia, dysarthria, cerebellar atrophy, akinetic-hypertonic syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2602 CACNB4 Zornitza Stark edited their review of gene: CACNB4: Added comment: PMID 32176688: A homozygous missense variant (Leu126Pro) reported in two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. Some functional data.; Changed publications: 10762541, 9628818, 27003325, 32176688; Changed phenotypes: Episodic ataxia, type 5, MIM#613855, Intellectual disability, Epilepsy, Movement disorder
Mendeliome v0.2602 WDR83OS Zornitza Stark Gene: wdr83os has been classified as Red List (Low Evidence).
Mendeliome v0.2601 WDR83OS Zornitza Stark Classified gene: WDR83OS as Red List (low evidence)
Mendeliome v0.2601 WDR83OS Zornitza Stark Gene: wdr83os has been classified as Red List (Low Evidence).
Mendeliome v0.2600 LSR Zornitza Stark Gene: lsr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2599 LSR Zornitza Stark Classified gene: LSR as Amber List (moderate evidence)
Mendeliome v0.2599 LSR Zornitza Stark Gene: lsr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2598 WDR83OS Ee Ming Wong gene: WDR83OS was added
gene: WDR83OS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to PMID: 30250217
Phenotypes for gene: WDR83OS were set to Cholestasis
Review for gene: WDR83OS was set to RED
Added comment: - 1 consanguineous family with 3 affected individuals found to carry a homozygous splice site variant in WDR83OS
- The variant results in an aberrant truncated RNA transcript as demonstrated by RT-PCR
Sources: Literature
Mendeliome v0.2598 LSR Zornitza Stark reviewed gene: LSR: Rating: AMBER; Mode of pathogenicity: None; Publications: 32303357, 30250217; Phenotypes: Cholestasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2598 LSR Zornitza Stark Classified gene: LSR as Green List (high evidence)
Mendeliome v0.2598 LSR Zornitza Stark Gene: lsr has been classified as Green List (High Evidence).
Mendeliome v0.2597 LSR Zornitza Stark reviewed gene: LSR: Rating: GREEN; Mode of pathogenicity: None; Publications: 32303357; Phenotypes: Cholestasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2597 LSR Zornitza Stark Classified gene: LSR as Amber List (moderate evidence)
Mendeliome v0.2597 LSR Zornitza Stark Gene: lsr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2595 LSR Ee Ming Wong reviewed gene: LSR: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32303357, 30250217; Phenotypes: Intrahepatic cholestasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2595 USP53 Zornitza Stark Gene: usp53 has been classified as Green List (High Evidence).
Mendeliome v0.2595 USP53 Zornitza Stark Phenotypes for gene: USP53 were changed from Deafness to Cholestasis; deafness
Mendeliome v0.2594 USP53 Zornitza Stark Classified gene: USP53 as Green List (high evidence)
Mendeliome v0.2594 USP53 Zornitza Stark Gene: usp53 has been classified as Green List (High Evidence).
Mendeliome v0.2593 USP53 Zornitza Stark reviewed gene: USP53: Rating: GREEN; Mode of pathogenicity: None; Publications: 32124521; Phenotypes: Cholestasis, deafness; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2593 USP53 Zornitza Stark Classified gene: USP53 as Red List (low evidence)
Mendeliome v0.2593 USP53 Zornitza Stark Gene: usp53 has been classified as Red List (Low Evidence).
Mendeliome v0.2592 LSR Ee Ming Wong gene: LSR was added
gene: LSR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LSR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSR were set to PMID: 30250217
Phenotypes for gene: LSR were set to transient neonatal cholestasis; intellectual disability; short stature
Review for gene: LSR was set to RED
Added comment: 1 individual from 1 consanguineous family carrying a homozygous missense variant in LSR
Sources: Literature
Mendeliome v0.2592 PPM1F Zornitza Stark Gene: ppm1f has been classified as Red List (Low Evidence).
Mendeliome v0.2592 PPM1F Zornitza Stark Classified gene: PPM1F as Red List (low evidence)
Mendeliome v0.2592 PPM1F Zornitza Stark Gene: ppm1f has been classified as Red List (Low Evidence).
Mendeliome v0.2591 PPM1F Ee Ming Wong gene: PPM1F was added
gene: PPM1F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPM1F was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPM1F were set to PMID: 30250217
Phenotypes for gene: PPM1F were set to sclerosing cholangitis; short stature; hypothyroidism; abnormal tongue pigmentation
Review for gene: PPM1F was set to RED
Added comment: 1 consanguineous family found to carry a homozygous missense variant in PPM1F
Sources: Literature
Mendeliome v0.2591 SPEF2 Zornitza Stark Phenotypes for gene: SPEF2 were changed from Spermatogenic failure 43, MIM#618751 to Spermatogenic failure 43, MIM#618751; Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype
Mendeliome v0.2589 SPEF2 Zornitza Stark reviewed gene: SPEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942643; Phenotypes: Spermatogenic failure 43, MIM#618751, Primary ciliary dyskinesia-like phenotype; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2589 KLC2 Zornitza Stark Gene: klc2 has been classified as Green List (High Evidence).
Mendeliome v0.2589 KLC2 Zornitza Stark Classified gene: KLC2 as Green List (high evidence)
Mendeliome v0.2589 KLC2 Zornitza Stark Gene: klc2 has been classified as Green List (High Evidence).
Mendeliome v0.2588 KLC2 Zornitza Stark gene: KLC2 was added
gene: KLC2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLC2 were set to 26385635
Phenotypes for gene: KLC2 were set to Spastic paraplegia, optic atrophy, and neuropathy MIM#609541
Review for gene: KLC2 was set to GREEN
Added comment: In 73 Brazilian patients and 2 sibs of Egyptian descent with SPOAN, a homozygous 216-bp deletion in the noncoding upstream region of the KLC2 gene was identified. Only reported cause of condition is the upstream large deletion, which is not detected by whole-exome sequencing.
Sources: Expert Review
Mendeliome v0.2587 KIF12 Zornitza Stark Phenotypes for gene: KIF12 were changed from Prenatal cholestasis; High Gamma-Glutamyltransferase (GGT) to Cholestasis; High Gamma-Glutamyltransferase (GGT)
Mendeliome v0.2586 KIF12 Zornitza Stark Gene: kif12 has been classified as Green List (High Evidence).
Mendeliome v0.2585 KIF12 Zornitza Stark Classified gene: KIF12 as Green List (high evidence)
Mendeliome v0.2585 KIF12 Zornitza Stark Gene: kif12 has been classified as Green List (High Evidence).
Mendeliome v0.2584 KIF12 Zornitza Stark reviewed gene: KIF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 30250217, 30976738; Phenotypes: Cholestasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2584 ALPK1 Zornitza Stark Gene: alpk1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2584 ALPK1 Zornitza Stark Classified gene: ALPK1 as Amber List (moderate evidence)
Mendeliome v0.2584 ALPK1 Zornitza Stark Gene: alpk1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2582 LRRC32 Zornitza Stark Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2582 LRRC32 Zornitza Stark Classified gene: LRRC32 as Amber List (moderate evidence)
Mendeliome v0.2582 LRRC32 Zornitza Stark Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2580 KIF12 Ee Ming Wong gene: KIF12 was added
gene: KIF12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF12 were set to PMID: 30250217; 30976738
Phenotypes for gene: KIF12 were set to Prenatal cholestasis; High Gamma-Glutamyltransferase (GGT)
Review for gene: KIF12 was set to AMBER
gene: KIF12 was marked as current diagnostic
Added comment: > 3 unrelated families,but they are all consanguineous families
Sources: Literature
Mendeliome v0.2579 CSGALNACT1 Zornitza Stark reviewed gene: CSGALNACT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31705726, 31325655; Phenotypes: Congenital disorder of glycosylation, skeletal dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2577 RHOA Zornitza Stark Phenotypes for gene: RHOA were changed from normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia to normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia; dental anomalies; body asymmetry; limb length discrepancy
Mendeliome v0.2575 IQCE Zornitza Stark Gene: iqce has been classified as Green List (High Evidence).
Mendeliome v0.2575 IQCE Zornitza Stark Classified gene: IQCE as Green List (high evidence)
Mendeliome v0.2575 IQCE Zornitza Stark Gene: iqce has been classified as Green List (High Evidence).
Mendeliome v0.2574 IQCE Zornitza Stark gene: IQCE was added
gene: IQCE was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IQCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQCE were set to 31549751; 28488682
Phenotypes for gene: IQCE were set to Postaxial polydactyly
Review for gene: IQCE was set to GREEN
Added comment: Four families reported with bi-allelic variants in this gene. The c.895_904del (p.Val301Serfs*8) was found in three of the families without sharing a common haplotype, suggesting a recurrent mechanism. RNA expression analysis on patients’ fibroblasts showed that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrated a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects.
Sources: Literature
Mendeliome v0.2573 NKX2-3 Zornitza Stark Gene: nkx2-3 has been classified as Red List (Low Evidence).
Mendeliome v0.2573 NKX2-3 Zornitza Stark gene: NKX2-3 was added
gene: NKX2-3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NKX2-3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NKX2-3 were set to 31498527
Phenotypes for gene: NKX2-3 were set to Intestinal varicosities
Review for gene: NKX2-3 was set to RED
Added comment: Single multiplex family where truncating variant in this gene segregated with intestinal varicosities with a LOD score of 3.3. NKX2‐3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice.
Sources: Literature
Mendeliome v0.2572 RPSA Zornitza Stark Gene: rpsa has been classified as Green List (High Evidence).
Mendeliome v0.2569 TBX6 Zornitza Stark Phenotypes for gene: TBX6 were changed from to Skeletal dysplasia; spondylocostal dysostosis; congenital scoliosis
Mendeliome v0.2567 CRAT Zornitza Stark Gene: crat has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2567 CRAT Zornitza Stark Classified gene: CRAT as Amber List (moderate evidence)
Mendeliome v0.2567 CRAT Zornitza Stark Gene: crat has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2565 CWF19L1 Zornitza Stark Gene: cwf19l1 has been classified as Green List (High Evidence).
Mendeliome v0.2565 CWF19L1 Zornitza Stark Phenotypes for gene: CWF19L1 were changed from to Spinocerebellar ataxia, autosomal recessive 17, MIM#616127; intellectual disability, developmental delay
Mendeliome v0.2562 CWF19L1 Zornitza Stark reviewed gene: CWF19L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25361784, 15981765, 26197978, 27016154, 30167849; Phenotypes: Spinocerebellar ataxia, autosomal recessive 17, MIM#616127, intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2562 B4GAT1 Zornitza Stark Classified gene: B4GAT1 as Green List (high evidence)
Mendeliome v0.2562 B4GAT1 Zornitza Stark Gene: b4gat1 has been classified as Green List (High Evidence).
Mendeliome v0.2561 B4GAT1 Zornitza Stark Gene: b4gat1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2558 B4GAT1 Zornitza Stark Classified gene: B4GAT1 as Amber List (moderate evidence)
Mendeliome v0.2558 B4GAT1 Zornitza Stark Gene: b4gat1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2557 RSRC1 Zornitza Stark Classified gene: RSRC1 as Green List (high evidence)
Mendeliome v0.2557 RSRC1 Zornitza Stark Gene: rsrc1 has been classified as Green List (High Evidence).
Mendeliome v0.2556 THG1L Zornitza Stark edited their review of gene: THG1L: Changed rating: GREEN; Changed phenotypes: Spinocerebellar ataxia, autosomal recessive 28, MIM# 618800
Mendeliome v0.2556 THG1L Zornitza Stark Gene: thg1l has been classified as Green List (High Evidence).
Mendeliome v0.2556 THG1L Zornitza Stark Classified gene: THG1L as Green List (high evidence)
Mendeliome v0.2556 THG1L Zornitza Stark Gene: thg1l has been classified as Green List (High Evidence).
Mendeliome v0.2555 THG1L Zornitza Stark Classified gene: THG1L as Amber List (moderate evidence)
Mendeliome v0.2555 THG1L Zornitza Stark Gene: thg1l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2554 THG1L Zornitza Stark gene: THG1L was added
gene: THG1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THG1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THG1L were set to 27307223; 31168944; 30214071
Phenotypes for gene: THG1L were set to Spinocerebellar ataxia, autosomal recessive 28, MIM# 618800
Review for gene: THG1L was set to AMBER
Added comment: Five individuals from two Ashkenazi Jewish families with same homozygous missense variant, and another family ascertained through a large microcephaly cohort, also with SCA.
Sources: Literature
Mendeliome v0.2553 TRPV1 Zornitza Stark Gene: trpv1 has been classified as Red List (Low Evidence).
Mendeliome v0.2552 ZP2 Zornitza Stark Gene: zp2 has been classified as Green List (High Evidence).
Mendeliome v0.2552 ZP2 Zornitza Stark Classified gene: ZP2 as Green List (high evidence)
Mendeliome v0.2552 ZP2 Zornitza Stark Gene: zp2 has been classified as Green List (High Evidence).
Mendeliome v0.2550 RSRC1 Zornitza Stark edited their review of gene: RSRC1: Added comment: 17 additional individuals reported.; Changed rating: GREEN; Changed publications: 28640246, 29522154, 32227164; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 70, MIM# 618402
Mendeliome v0.2550 GAD1 Zornitza Stark Classified gene: GAD1 as Green List (high evidence)
Mendeliome v0.2550 GAD1 Zornitza Stark Gene: gad1 has been classified as Green List (High Evidence).
Mendeliome v0.2549 GAD1 Zornitza Stark changed review comment from: Single family reported with bi-allelic variants. Association studies linking with neuropsychiatric issues.; to: Single family reported with bi-allelic variants and CP phenotype. Association studies linking with neuropsychiatric issues.
Mendeliome v0.2549 GAD1 Zornitza Stark edited their review of gene: GAD1: Added comment: 2020: 11 individuals from 6 consanguineous families reported with bi-allelic LOF variant and a developmental/epileptic encephalopathy. Seizure onset occurred in the first 2 months of life in all. All 10 individuals, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight individuals had joint contractures and/or pes equinovarus. Seven presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four individuals died before 4 years of age.; Changed rating: GREEN; Changed publications: 15571623, 32282878; Changed phenotypes: Cerebral palsy, spastic quadriplegic, 1, MIM#603513, Developmental and epileptic encephalopathy
Mendeliome v0.2549 GALNT2 Zornitza Stark Classified gene: GALNT2 as Green List (high evidence)
Mendeliome v0.2549 GALNT2 Zornitza Stark Gene: galnt2 has been classified as Green List (High Evidence).
Mendeliome v0.2548 GALNT2 Zornitza Stark gene: GALNT2 was added
gene: GALNT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation
Review for gene: GALNT2 was set to GREEN
Added comment: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities.
Sources: Literature
Mendeliome v0.2547 C7orf43 Zornitza Stark Gene: c7orf43 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2547 C7orf43 Zornitza Stark Classified gene: C7orf43 as Amber List (moderate evidence)
Mendeliome v0.2547 C7orf43 Zornitza Stark Gene: c7orf43 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2546 C7orf43 Zornitza Stark gene: C7orf43 was added
gene: C7orf43 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C7orf43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C7orf43 were set to 30715179
Phenotypes for gene: C7orf43 were set to Microcephaly 25, primary, autosomal recessive, MIM# 618351
Review for gene: C7orf43 was set to AMBER
Added comment: Single family reported: three affected siblings with homozygous truncating variant. Supportive zebrafish model.
Sources: Literature
Mendeliome v0.2543 GRIN2A Zornitza Stark Gene: grin2a has been classified as Green List (High Evidence).
Mendeliome v0.2539 TSEN34 Zornitza Stark Gene: tsen34 has been classified as Red List (Low Evidence).
Mendeliome v0.2539 TSEN34 Zornitza Stark Phenotypes for gene: TSEN34 were changed from to Pontocerebellar hypoplasia type 2C, MIM# 612390
Mendeliome v0.2536 TSEN34 Zornitza Stark Classified gene: TSEN34 as Red List (low evidence)
Mendeliome v0.2536 TSEN34 Zornitza Stark Gene: tsen34 has been classified as Red List (Low Evidence).
Mendeliome v0.2535 TSEN34 Zornitza Stark reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 18711368; Phenotypes: Pontocerebellar hypoplasia type 2C, MIM# 612390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2535 TSEN54 Zornitza Stark Gene: tsen54 has been classified as Green List (High Evidence).
Mendeliome v0.2535 TSEN54 Zornitza Stark Phenotypes for gene: TSEN54 were changed from to Pontocerebellar hypoplasia type 2A 277470; Pontocerebellar hypoplasia type 4 225753; Ataxia
Mendeliome v0.2532 TSEN54 Zornitza Stark reviewed gene: TSEN54: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia type 2A 277470, Pontocerebellar hypoplasia type 4 225753, Ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2530 TMPRSS9 Zornitza Stark Gene: tmprss9 has been classified as Red List (Low Evidence).
Mendeliome v0.2530 SLC6A6 Zornitza Stark Gene: slc6a6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2526 NDE1 Zornitza Stark Gene: nde1 has been classified as Green List (High Evidence).
Mendeliome v0.2523 CDC45 Zornitza Stark Gene: cdc45 has been classified as Green List (High Evidence).
Mendeliome v0.2519 CPSF1 Zornitza Stark Gene: cpsf1 has been classified as Green List (High Evidence).
Mendeliome v0.2519 CPSF1 Zornitza Stark Classified gene: CPSF1 as Green List (high evidence)
Mendeliome v0.2519 CPSF1 Zornitza Stark Gene: cpsf1 has been classified as Green List (High Evidence).
Mendeliome v0.2518 CHD4 Zornitza Stark Gene: chd4 has been classified as Green List (High Evidence).
Mendeliome v0.2518 CHD4 Zornitza Stark Phenotypes for gene: CHD4 were changed from to Sifrim-Hitz-Weiss syndrome, MIM 617159
Mendeliome v0.2512 CFAP69 Zornitza Stark Gene: cfap69 has been classified as Green List (High Evidence).
Mendeliome v0.2509 ABCA4 Zornitza Stark Gene: abca4 has been classified as Green List (High Evidence).
Mendeliome v0.2506 TLK2 Zornitza Stark Gene: tlk2 has been classified as Green List (High Evidence).
Mendeliome v0.2503 DYRK1A Zornitza Stark Gene: dyrk1a has been classified as Green List (High Evidence).
Mendeliome v0.2500 WARS Zornitza Stark Gene: wars has been classified as Green List (High Evidence).
Mendeliome v0.2500 WARS Zornitza Stark Classified gene: WARS as Green List (high evidence)
Mendeliome v0.2500 WARS Zornitza Stark Gene: wars has been classified as Green List (High Evidence).
Mendeliome v0.2498 POLR1B Zornitza Stark Gene: polr1b has been classified as Green List (High Evidence).
Mendeliome v0.2498 POLR1B Zornitza Stark Phenotypes for gene: POLR1B were changed from bilateral malar and mandibular hypoplasia; microtia; coloboma; downslanting palpebral fissures; conductive deafness; cleft palate; heart malformations to Treacher-Collins syndrome
Mendeliome v0.2497 POLR1B Zornitza Stark Classified gene: POLR1B as Green List (high evidence)
Mendeliome v0.2497 POLR1B Zornitza Stark Gene: polr1b has been classified as Green List (High Evidence).
Mendeliome v0.2496 POLR1B Zornitza Stark changed review comment from: Five unrelated families and a zebrafish model.; to: Five unrelated families and a zebrafish model. Note four of the families had missense variants affecting same residue, p.Arg1003
Mendeliome v0.2496 POLR1B Zornitza Stark changed review comment from: Six unrelated families and a zebrafish model.; to: Five unrelated families and a zebrafish model.
Mendeliome v0.2496 SLC35D1 Zornitza Stark Gene: slc35d1 has been classified as Green List (High Evidence).
Mendeliome v0.2496 SLC35D1 Zornitza Stark Phenotypes for gene: SLC35D1 were changed from to Schneckenbecken dysplasia, MIM 269250
Mendeliome v0.2493 C1orf194 Zornitza Stark Gene: c1orf194 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2492 C1orf194 Zornitza Stark Classified gene: C1orf194 as Amber List (moderate evidence)
Mendeliome v0.2492 C1orf194 Zornitza Stark Gene: c1orf194 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2491 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Mendeliome v0.2491 REC114 Zornitza Stark Classified gene: REC114 as Green List (high evidence)
Mendeliome v0.2491 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Mendeliome v0.2490 UBA2 Zornitza Stark Gene: uba2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2490 UBA2 Zornitza Stark Classified gene: UBA2 as Amber List (moderate evidence)
Mendeliome v0.2490 UBA2 Zornitza Stark Gene: uba2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2489 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
Mendeliome v0.2485 ORAI1 Zornitza Stark Gene: orai1 has been classified as Green List (High Evidence).
Mendeliome v0.2481 RTTN Zornitza Stark Gene: rttn has been classified as Green List (High Evidence).
Mendeliome v0.2478 UBAP1 Zornitza Stark Gene: ubap1 has been classified as Green List (High Evidence).
Mendeliome v0.2475 SLC6A6 Zornitza Stark Classified gene: SLC6A6 as Amber List (moderate evidence)
Mendeliome v0.2475 SLC6A6 Zornitza Stark Gene: slc6a6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2473 TMPRSS9 Zornitza Stark Classified gene: TMPRSS9 as Red List (low evidence)
Mendeliome v0.2473 TMPRSS9 Zornitza Stark Gene: tmprss9 has been classified as Red List (Low Evidence).
Mendeliome v0.2472 MCAT Zornitza Stark Gene: mcat has been classified as Red List (Low Evidence).
Mendeliome v0.2472 MCAT Zornitza Stark Classified gene: MCAT as Red List (low evidence)
Mendeliome v0.2472 MCAT Zornitza Stark Gene: mcat has been classified as Red List (Low Evidence).
Mendeliome v0.2471 ABCC1 Zornitza Stark Gene: abcc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2471 ABCC1 Zornitza Stark Classified gene: ABCC1 as Amber List (moderate evidence)
Mendeliome v0.2471 ABCC1 Zornitza Stark Gene: abcc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2469 GABRA1 Zornitza Stark Gene: gabra1 has been classified as Green List (High Evidence).
Mendeliome v0.2466 SIGMAR1 Zornitza Stark Marked gene: SIGMAR1 as ready
Mendeliome v0.2466 SIGMAR1 Zornitza Stark Gene: sigmar1 has been classified as Green List (High Evidence).
Mendeliome v0.2466 SIGMAR1 Zornitza Stark Phenotypes for gene: SIGMAR1 were changed from to Amyotrophic lateral sclerosis 16, juvenile 614373; ?Spinal muscular atrophy, distal, autosomal recessive, 2 605726; distal hereditary motor neuropathy of Jerash type (HMNJ)
Mendeliome v0.2465 SIGMAR1 Zornitza Stark Publications for gene: SIGMAR1 were set to
Mendeliome v0.2464 SIGMAR1 Zornitza Stark Mode of inheritance for gene: SIGMAR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2463 ATOH7 Zornitza Stark Gene: atoh7 has been classified as Green List (High Evidence).
Mendeliome v0.2463 ATOH7 Zornitza Stark Phenotypes for gene: ATOH7 were changed from to Persistent hyperplastic primary vitreous, autosomal recessive, MIM# 221900; microphthalmia; cataract; glaucoma; congenital retinal nonattachment
Mendeliome v0.2460 GNAI2 Zornitza Stark Classified gene: GNAI2 as Amber List (moderate evidence)
Mendeliome v0.2460 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2459 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Red List (Low Evidence).
Mendeliome v0.2459 GNAI2 Zornitza Stark Classified gene: GNAI2 as Red List (low evidence)
Mendeliome v0.2459 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Red List (Low Evidence).
Mendeliome v0.2458 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy to Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Hypertrophic cardiomyopathy
Mendeliome v0.2455 FEM1B Zornitza Stark Gene: fem1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2454 FEM1B Zornitza Stark Classified gene: FEM1B as Amber List (moderate evidence)
Mendeliome v0.2454 FEM1B Zornitza Stark Gene: fem1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2453 WIPI2 Zornitza Stark Classified gene: WIPI2 as Red List (low evidence)
Mendeliome v0.2453 WIPI2 Zornitza Stark Gene: wipi2 has been classified as Red List (Low Evidence).
Mendeliome v0.2452 SEC31A Zornitza Stark Gene: sec31a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2451 SEC31A Zornitza Stark Classified gene: SEC31A as Amber List (moderate evidence)
Mendeliome v0.2451 SEC31A Zornitza Stark Gene: sec31a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2450 SLC44A1 Zornitza Stark Gene: slc44a1 has been classified as Green List (High Evidence).
Mendeliome v0.2450 SLC44A1 Zornitza Stark Classified gene: SLC44A1 as Green List (high evidence)
Mendeliome v0.2450 SLC44A1 Zornitza Stark Gene: slc44a1 has been classified as Green List (High Evidence).
Mendeliome v0.2449 SMCHD1 Zornitza Stark Added comment: Comment when marking as ready: Note association with FSHD2 is postulated to have digenic inheritance, caused by the combination of a heterozygous mutation in the SMCHD1 gene (614982) on chromosome 18p and presence of a haplotype on chromosome 4 that is permissive for DUX4 (606009) expression.
Mendeliome v0.2449 SMCHD1 Zornitza Stark Gene: smchd1 has been classified as Green List (High Evidence).
Mendeliome v0.2446 CDKL5 Zornitza Stark Gene: cdkl5 has been classified as Green List (High Evidence).
Mendeliome v0.2443 AEBP1 Zornitza Stark Gene: aebp1 has been classified as Green List (High Evidence).
Mendeliome v0.2443 AEBP1 Zornitza Stark Phenotypes for gene: AEBP1 were changed from to Ehlers-Danlos syndrome, classic-like, 2, MIM# 618000
Mendeliome v0.2440 AEBP1 Zornitza Stark reviewed gene: AEBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29606302, 30668708, 30548383, 30759870; Phenotypes: Ehlers-Danlos syndrome, classic-like, 2, MIM# 618000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2440 SLC6A6 Chern Lim gene: SLC6A6 was added
gene: SLC6A6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC6A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034
Phenotypes for gene: SLC6A6 were set to Early retinal degeneration; cardiomyopathy
Review for gene: SLC6A6 was set to AMBER
Added comment: Different homozygous missense variants in 2 unrelated consanguineous families with early retinal degeneration, some functional studies. Patients in one of the families also had cardiomyopathy. (PMIDs: 31345061, 31903486)

One dilated cardiomyopathy patient with a homozygous deletion at a splice site (PMID: 29886034).
Sources: Literature
Mendeliome v0.2440 TMPRSS9 Chern Lim gene: TMPRSS9 was added
gene: TMPRSS9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMPRSS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS9 were set to 31943016
Phenotypes for gene: TMPRSS9 were set to autism spectrum disorder
Review for gene: TMPRSS9 was set to RED
Added comment: Association with Mendelian disease not established.

Is a candidate gene for autism spectrum disorder: single patient, compound heterozygous nonsense variants. Functional studies showed Tmprss9 gene is expressed in mouse brain, knockout mice had decreased social interest and social recognition. (PMID: 31943016)
Sources: Literature
Mendeliome v0.2440 MCAT Chern Lim gene: MCAT was added
gene: MCAT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCAT were set to 31915829
Phenotypes for gene: MCAT were set to progressive autosomal recessive optic neuropathy
Review for gene: MCAT was set to RED
Added comment: One family reported - a consanguineous family, two homozygous missense variants in both affected siblings. Functional studies showed both missense together have synergic impact on MCAT protein misfolding; p.(L81R) had more impact on MCAT protein expression reduction than did the p.(R212W); some study in conditional knockout mice. (PMID:31915829)
Sources: Literature
Mendeliome v0.2440 ATOH7 Paul De Fazio changed review comment from: Segregates with disease in 3 consanguineous families from Pakistan/Turkey and one non-consanguineous family of Swiss origin. Functional effect was demonstrated in the latter family. The mouse homolog is required for retinal ganglion cell and optic nerve formation.; to: Segregates with disease in 3 consanguineous families from Pakistan/Turkey with global eye abnormalities, and one non-consanguineous family of Swiss origin with optic nerve hypoplasia. Functional effect was demonstrated in the latter family. The mouse homolog is required for retinal ganglion cell and optic nerve formation (in mice).
Mendeliome v0.2440 GFAP Paul De Fazio changed review comment from: Many (>20) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2440 GFAP Paul De Fazio changed review comment from: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>20) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2440 PKDCC Paul De Fazio changed review comment from: 2 ("apparently") unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice.
Sources: Literature; to: 2 apparently unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice.
Sources: Literature
Mendeliome v0.2440 ORAI1 Natalie Tan changed review comment from: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy); to: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a slowly progressive myopathy (tubular aggregate myopathy/TAM)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy)
Mendeliome v0.2440 UBA2 Elena Savva gene: UBA2 was added
gene: UBA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBA2 were set to PMID: 31332306; 31587267
Phenotypes for gene: UBA2 were set to Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly
Penetrance for gene: UBA2 were set to unknown
Review for gene: UBA2 was set to AMBER
Added comment: No OMIM phenotype

PMID: 31332306 - a single patient with a de novo PTC and split hand/foot malformation (SHFM). Additional two multigenic CNVs including this gene in patients with SHFM and ectrodactyly. Authors mention an additional de novo missense but the patient didnt have SHFM, argue low penetrance

PMID: 31587267 - a mother and son with aplasia cutis congenita (ACC), with a heterozygous PTC. Son also has ectrodactyly. Authors note an additional de novo missense in a patient with ACC.
Sources: Literature
Mendeliome v0.2440 ORAI1 Natalie Tan changed review comment from: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy); to: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence):
- Dominant ORAI1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias)
- Recessive ORAI1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy)
Mendeliome v0.2440 ORAI1 Natalie Tan reviewed gene: ORAI1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31448844; Phenotypes: Progressive myopathy, contractures; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2440 GSX2 Zornitza Stark Added comment: Comment when marking as ready: Intellectual disability, spastic tetraparesis, dystonia
Mendeliome v0.2440 GSX2 Zornitza Stark Gene: gsx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2440 GSX2 Zornitza Stark Gene: gsx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2440 GSX2 Zornitza Stark Classified gene: GSX2 as Amber List (moderate evidence)
Mendeliome v0.2440 GSX2 Zornitza Stark Gene: gsx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2439 SLC35D1 Teresa Zhao reviewed gene: SLC35D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31423530, 19508970; Phenotypes: Schneckenbecken dysplasia, MIM 269250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2439 POLR1B Paul De Fazio gene: POLR1B was added
gene: POLR1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR1B were set to 31649276
Phenotypes for gene: POLR1B were set to bilateral malar and mandibular hypoplasia; microtia; coloboma; downslanting palpebral fissures; conductive deafness; cleft palate; heart malformations
Review for gene: POLR1B was set to AMBER
gene: POLR1B was marked as current diagnostic
Added comment: 6 individuals with Treacher-Collins syndrome described: 3 with de novo variants, one inherited from a mosaic father, and two inherited from affected mothers. Knockdown in zebrafish mimics the phenotype.
Sources: Literature
Mendeliome v0.2439 CREB3L1 Zornitza Stark Gene: creb3l1 has been classified as Green List (High Evidence).
Mendeliome v0.2439 CREB3L1 Zornitza Stark Phenotypes for gene: CREB3L1 were changed from to Osteogenesis imperfecta, type XVI, MIM#616229
Mendeliome v0.2436 WARS Naomi Baker gene: WARS was added
gene: WARS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WARS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WARS were set to PMID: 28369220; 31321409; 31069783.
Phenotypes for gene: WARS were set to Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); distal wasting; distal weakness; length-dependent motor axonal degeneration
Review for gene: WARS was set to GREEN
Added comment: 14 patients from five families were reported to have WARS-related neuropathy across three publications. Expression studies of mutant demonstrated decreased protein when compared to wild-type.
Sources: Literature
Mendeliome v0.2436 ACKR3 Zornitza Stark Gene: ackr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2436 ACKR3 Zornitza Stark Phenotypes for gene: ACKR3 were changed from Oculomotor synkinesis to Oculomotor synkinesis; Ptosis
Mendeliome v0.2435 ACKR3 Zornitza Stark Classified gene: ACKR3 as Amber List (moderate evidence)
Mendeliome v0.2435 ACKR3 Zornitza Stark Gene: ackr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2434 CYLD Zornitza Stark Gene: cyld has been classified as Green List (High Evidence).
Mendeliome v0.2434 CYLD Zornitza Stark Phenotypes for gene: CYLD were changed from to Brooke-Spiegler syndrome, 605041; Cylindromatosis, familial, 132700; Trichoepithelioma, multiple familial, 1, 601606; Frontotemporal dementia and amyotrophic lateral sclerosis
Mendeliome v0.2431 PCDH19 Zornitza Stark Gene: pcdh19 has been classified as Green List (High Evidence).
Mendeliome v0.2428 GFAP Zornitza Stark Gene: gfap has been classified as Green List (High Evidence).
Mendeliome v0.2425 COPA Zornitza Stark Gene: copa has been classified as Green List (High Evidence).
Mendeliome v0.2421 PLOD3 Alison Yeung Gene: plod3 has been classified as Green List (High Evidence).
Mendeliome v0.2421 FOXG1 Zornitza Stark Gene: foxg1 has been classified as Green List (High Evidence).
Mendeliome v0.2418 TBX6 Alison Yeung Added comment: Comment when marking as ready: Biallelic variants associated with spondylocostal dysostosis in >3 unrelated individuals
Mouse model recapitulates phenotype
Mendeliome v0.2418 TBX6 Alison Yeung Gene: tbx6 has been classified as Green List (High Evidence).
Mendeliome v0.2418 SAMD12 Zornitza Stark Gene: samd12 has been classified as Green List (High Evidence).
Mendeliome v0.2417 SAMD12 Zornitza Stark Classified gene: SAMD12 as Green List (high evidence)
Mendeliome v0.2417 SAMD12 Zornitza Stark Gene: samd12 has been classified as Green List (High Evidence).
Mendeliome v0.2416 UBE3A Alison Yeung Gene: ube3a has been classified as Green List (High Evidence).
Mendeliome v0.2416 ADAMTS19 Alison Yeung Gene: adamts19 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2416 ADAMTS19 Alison Yeung Classified gene: ADAMTS19 as Amber List (moderate evidence)
Mendeliome v0.2416 ADAMTS19 Alison Yeung Added comment: Comment on list classification: Two different homozygous variants in two consanguineous families. Animal model demonstrates cardiac phenotype
Await further reported families
Mendeliome v0.2416 ADAMTS19 Alison Yeung Gene: adamts19 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2415 YARS Zornitza Stark Gene: yars has been classified as Green List (High Evidence).
Mendeliome v0.2412 CFAP65 Zornitza Stark Gene: cfap65 has been classified as Green List (High Evidence).
Mendeliome v0.2412 CFAP65 Zornitza Stark Classified gene: CFAP65 as Green List (high evidence)
Mendeliome v0.2412 CFAP65 Zornitza Stark Gene: cfap65 has been classified as Green List (High Evidence).
Mendeliome v0.2411 CAP2 Alison Yeung Gene: cap2 has been classified as Red List (Low Evidence).
Mendeliome v0.2411 CAP2 Alison Yeung Classified gene: CAP2 as Red List (low evidence)
Mendeliome v0.2411 CAP2 Alison Yeung Added comment: Comment on list classification: Currently only one consanguineous family reported.
Knockout mouse model shows cardiomyopathy but not other clinical features reported in this family
Mendeliome v0.2411 CAP2 Alison Yeung Gene: cap2 has been classified as Red List (Low Evidence).
Mendeliome v0.2410 IGF1R Zornitza Stark Gene: igf1r has been classified as Green List (High Evidence).
Mendeliome v0.2410 IGF1R Zornitza Stark Phenotypes for gene: IGF1R were changed from to Insulin-like growth factor I, resistance to, MIM# 270450
Mendeliome v0.2407 SHANK3 Zornitza Stark Gene: shank3 has been classified as Green List (High Evidence).
Mendeliome v0.2406 CHD4 Teresa Zhao reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:31388190; Phenotypes: Sifrim-Hitz-Weiss syndrome, MIM 617159; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.2404 SCN1A Zornitza Stark Gene: scn1a has been classified as Green List (High Evidence).
Mendeliome v0.2401 CPSF1 Kristin Rigbye changed review comment from: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (30689892).
Sources: Literature; to: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (PMID: 30689892).
Sources: Literature
Mendeliome v0.2401 CPSF1 Kristin Rigbye gene: CPSF1 was added
gene: CPSF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CPSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CPSF1 were set to 30689892
Phenotypes for gene: CPSF1 were set to Myopia 27, 618827; high myopia; early-onset high myopiaHigh myopia
Review for gene: CPSF1 was set to GREEN
Added comment: 6 unrelated probands reported (3 nonsense, 1 frameshift, 1 splice, 1 missense) with variants all assumed to result in a loss of function. Variants were shown to be inherited from affected parents in 2 families. Gene-disease association was supported by knockdown of cpsf1 in zebrafish which caused abnormal ocular morphogenesis (30689892).
Sources: Literature
Mendeliome v0.2401 STXBP1 Zornitza Stark Gene: stxbp1 has been classified as Green List (High Evidence).
Mendeliome v0.2398 NAA10 Zornitza Stark Gene: naa10 has been classified as Green List (High Evidence).
Mendeliome v0.2395 WDR45 Zornitza Stark Gene: wdr45 has been classified as Green List (High Evidence).
Mendeliome v0.2395 SIGMAR1 Michelle Torres changed review comment from: PMID: 31511340:
- N167I (1 het in gnomAD): in 7 consanguinous families from region of Jordan with a specific type of distal hereditary motor neuropathy of Jerash type (HMNJ). Experiments show loss of function effect.
- Lists recent publications with other variants (missense and truncating) in patients with distal hereditary motor neuropathy (dHMN) with mild pyramidal signs and jALS (juvenile ALS); to: PMID: 31511340:
- N167I (1 het in gnomAD): in 7 consanguinous families from region of Jordan with a specific type of distal hereditary motor neuropathy of Jerash type (HMNJ). Experiments show loss of function effect.
- Lists recent publications with other variants (missense and truncating) in patients with distal hereditary motor neuropathy (dHMN) with mild pyramidal signs and jALS (juvenile ALS)
Mendeliome v0.2392 SIGMAR1 Michelle Torres reviewed gene: SIGMAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31511340; Phenotypes: ?Amyotrophic lateral sclerosis 16, juvenile 614373, ?Spinal muscular atrophy, distal, autosomal recessive, 2 605726, distal hereditary motor neuropathy of Jerash type (HMNJ); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2392 GNAI2 Elena Savva gene: GNAI2 was added
gene: GNAI2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNAI2 were set to PMID: 31036916
Phenotypes for gene: GNAI2 were set to Pituitary adenoma, ACTH-secreting, somatic; Ventricular tachycardia, idiopathic 192605; Syndromic developmental disorder
Review for gene: GNAI2 was set to AMBER
Added comment: Papers associating this gene to tachycardia are very old (pre 2000, OMIM).

PMID: 31036916 - a single de novo patient with syndromic developmental disorder

Summary: AMBER - one report, may be a coincidental de novo finding
Sources: Literature
Mendeliome v0.2389 ASCC1 Zornitza Stark Gene: ascc1 has been classified as Green List (High Evidence).
Mendeliome v0.2386 FEM1B Elena Savva gene: FEM1B was added
gene: FEM1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FEM1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FEM1B were set to PMID: 31036916
Phenotypes for gene: FEM1B were set to Syndromic global developmental delay
Review for gene: FEM1B was set to AMBER
Added comment: No OMIM phenotype

PMID: 31036916 - a single de novo patient reported in a neurodevelopmental disorder cohort. Authors note another de novo case with the exact same variant (p.Arg126Gln) from the DDD study, and a 3rd patient from GeneMatcher with the same de novo missense again. Decipher shows this variant to be in a highly constrained region of the protein.

Have selected AMBER for now - not sure if GeneMatcher findings can be used as a 3rd case
Sources: Literature
Mendeliome v0.2386 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
Mendeliome v0.2384 RXFP2 Alison Yeung Classified gene: RXFP2 as Red List (low evidence)
Mendeliome v0.2384 RXFP2 Alison Yeung Added comment: Comment on list classification: Only single reported family with animal model reported. Both reviews to date are based on same publication. No new publications/reported cases since this one.
Mendeliome v0.2384 RXFP2 Alison Yeung Gene: rxfp2 has been classified as Red List (Low Evidence).
Mendeliome v0.2383 GFAP Paul De Fazio changed review comment from: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2383 GFAP Paul De Fazio changed review comment from: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.; to: Many (>10) de novo individuals described with Alexander disease. Three forms of disease are described with decreasing severity: infant-onset, juveline-onset, and adult-onset. Later-onset cases are more phenotypically heterogeneous.
Mendeliome v0.2382 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Red List (Low Evidence).
Mendeliome v0.2379 RXFP2 Zornitza Stark Classified gene: RXFP2 as Red List (low evidence)
Mendeliome v0.2379 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Red List (Low Evidence).
Mendeliome v0.2378 SEC31A Hazel Phillimore gene: SEC31A was added
gene: SEC31A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to PMID: 30464055
Phenotypes for gene: SEC31A were set to congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive
Review for gene: SEC31A was set to AMBER
Added comment: Frameshift. c.2776_2777, TA duplication, causing predicted p.A927fs*61 truncation and predicted NMD in 2 affected siblings in consanguineous Bedouin family with severe congenital neurological syndrome with spastic paraplegia, multiple contractures, profound developmental delay and convulsions. Failure to thrive. Lethal by age 4 years. Also had hearing defect, bilateral congenital cataract, horizontal nystagmus, with flat retina and optic atrophy. Supporting functional assays from knockout drosophila.
Sources: Literature
Mendeliome v0.2378 SLC44A1 Sebastian Lunke gene: SLC44A1 was added
gene: SLC44A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC44A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC44A1 were set to 31855247
Phenotypes for gene: SLC44A1 were set to progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria
Review for gene: SLC44A1 was set to GREEN
Added comment: Four affected individuals from three families with homozygous frameshift variants. Functional evidence points to impaired choline transporter function yet unchanged membrane phosphatidylcholine content. Choline treatments may be beneficial.
Sources: Literature
Mendeliome v0.2377 TBX6 Dean Phelan reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30307510, 31015262; Phenotypes: congenital vertebral malformations, congenital scoliosis, spondylocostal dysostosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2377 GSX2 Elena Savva gene: GSX2 was added
gene: GSX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GSX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSX2 were set to PMID: 31412107
Phenotypes for gene: GSX2 were set to Diencephalic-mesencephalic junction dysplasia syndrome 2 618646
Review for gene: GSX2 was set to GREEN
Added comment: PMID: 31412107 - 2 unrelated patients with homozygous mutations (nonsense, missense). Functional analysis of the missense in transfected HeLa cells demonstrated protein mislocalization and protein expression. Downstream gene expression was also reduced by both mutations.

Summary: GREEN - 2 patients and functional evidence
Sources: Literature
Mendeliome v0.2377 SPEF2 Zornitza Stark Gene: spef2 has been classified as Green List (High Evidence).
Mendeliome v0.2377 SPEF2 Zornitza Stark Classified gene: SPEF2 as Green List (high evidence)
Mendeliome v0.2377 SPEF2 Zornitza Stark Gene: spef2 has been classified as Green List (High Evidence).
Mendeliome v0.2376 CREB3L1 Kristin Rigbye reviewed gene: CREB3L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24079343, 28817112, 29936144, 30657919; Phenotypes: Osteogenesis imperfecta, type XVI, 616229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2376 PKDCC Alison Yeung Gene: pkdcc has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2376 PKDCC Alison Yeung Classified gene: PKDCC as Amber List (moderate evidence)
Mendeliome v0.2376 PKDCC Alison Yeung Added comment: Comment on list classification: Two unrelated consanguineous families reported with different homozygous variants
Pre-existing mouse model has similar phenotype
Needs more functional evidence or further reported families
Mendeliome v0.2376 PKDCC Alison Yeung Gene: pkdcc has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2375 DHH Zornitza Stark Phenotypes for gene: DHH were changed from to 46XY partial gonadal dysgenesis, with minifascicular neuropathy, MIM# 607080
Mendeliome v0.2372 ACKR3 Elena Savva gene: ACKR3 was added
gene: ACKR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACKR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACKR3 were set to PMID: 3121183
Phenotypes for gene: ACKR3 were set to Oculomotor synkinesis
Review for gene: ACKR3 was set to AMBER
Added comment: No phenotype currently listed in OMIM

PMID: 3121183 - 1 family (3 siblings and a cousin) with congenital ptosis and oculomotor synkinesis. Mouse model reciprocated the phenotype. Functional assay using transfected HEK293 cells show protein mislocalization and lower binding affinity

Emerging gene-disease association
Sources: Literature
Mendeliome v0.2372 MYCN Zornitza Stark Gene: mycn has been classified as Green List (High Evidence).
Mendeliome v0.2372 CYLD Kristin Rigbye reviewed gene: CYLD: Rating: GREEN; Mode of pathogenicity: None; Publications: 10835629, 16307661, 12950348, 19807742; Phenotypes: Brooke-Spiegler syndrome, 605041, Cylindromatosis, familial, 132700, Trichoepithelioma, multiple familial, 1, 601606, Frontotemporal dementia and amyotrophic lateral sclerosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2371 CNNM4 Zornitza Stark Gene: cnnm4 has been classified as Green List (High Evidence).
Mendeliome v0.2371 CNNM4 Zornitza Stark Phenotypes for gene: CNNM4 were changed from to Jalili syndrome 217080; amelogenesis imperfecta, cone-rod dystrophy
Mendeliome v0.2368 ATM Zornitza Stark Gene: atm has been classified as Green List (High Evidence).
Mendeliome v0.2365 SAMD12 Melanie Marty gene: SAMD12 was added
gene: SAMD12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SAMD12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD12 were set to 30194086; 29507423
Phenotypes for gene: SAMD12 were set to Epilepsy, familial adult myoclonic, 1 601068
Review for gene: SAMD12 was set to GREEN
Added comment: Repeat expansions of intronic TTTCA and TTTTA motifs within SAMD12 have been identified in over 50 Japanese and Chinese families. Most families with affected individuals were heterozygous however 4 patients from 3 families had homozygous repeat expansions, which was associated with a more severe phenotype. Western blot analysis showed decreased levels of the protein in patient brains.
Sources: Literature
Mendeliome v0.2365 FUS Elena Savva gene: FUS was added
gene: FUS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FUS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FUS were set to PMID: 32281455; 20668259; 20385912
Phenotypes for gene: FUS were set to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia 608030; Essential tremor, hereditary, 4 614782
Mode of pathogenicity for gene: FUS was set to Other
Review for gene: FUS was set to GREEN
Added comment: PMID: 32281455 - Reports a case of Pediatric Amyotrophic Lateral Sclerosis. Reviews and shows multiple other reports of ALS casued by FUS

PMID: 20668259 - additional reports of ALS

PMID: 20385912 - postulated that disruption of this region may disrupt subcellular distribution of FUS, in turn affecting transcription and RNA processing and conferring a toxic gain of function.
Sources: Literature
Mendeliome v0.2365 TBX6 Sarah Pantaleo reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 8954725, 20503311, 23335591, 25564734, 31015262; Phenotypes: Skeletal dysplasia, spondylocostal dysostosis, congenital scoliosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2365 C9orf72 Elena Savva gene: C9orf72 was added
gene: C9orf72 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C9orf72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: C9orf72 were set to PMID: 30120348; 23284068
Phenotypes for gene: C9orf72 were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550
Review for gene: C9orf72 was set to AMBER
Added comment: Possibly RED

Caused by expansion of GGGGCC repeats, dont know if these qualify for mendeliome
Sources: Literature
Mendeliome v0.2365 ELOVL1 Hazel Phillimore reviewed gene: ELOVL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30487246, 29496980; Phenotypes: ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness, optic atrophy, nystagmus; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2365 TNFRSF21 Alison Yeung Gene: tnfrsf21 has been classified as Red List (Low Evidence).
Mendeliome v0.2365 TNFRSF21 Alison Yeung Classified gene: TNFRSF21 as Red List (low evidence)
Mendeliome v0.2365 TNFRSF21 Alison Yeung Added comment: Comment on list classification: Report of single family
Limited functional evidence: tissue expression studies
Mendeliome v0.2365 TNFRSF21 Alison Yeung Gene: tnfrsf21 has been classified as Red List (Low Evidence).
Mendeliome v0.2364 USP45 Alison Yeung Gene: usp45 has been classified as Green List (High Evidence).
Mendeliome v0.2364 USP45 Alison Yeung Classified gene: USP45 as Green List (high evidence)
Mendeliome v0.2364 USP45 Alison Yeung Added comment: Comment on list classification: Two unrelated families
Functional studies in animal model recapitulate retinal phenotype
Mendeliome v0.2364 USP45 Alison Yeung Gene: usp45 has been classified as Green List (High Evidence).
Mendeliome v0.2363 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Mendeliome v0.2363 SYCP2 Zornitza Stark Classified gene: SYCP2 as Green List (high evidence)
Mendeliome v0.2363 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Mendeliome v0.2362 IGF1R Michelle Torres reviewed gene: IGF1R: Rating: GREEN; Mode of pathogenicity: None; Publications: 31586944; Phenotypes: Insulin-like growth factor I, resistance to 270450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2361 ASCC1 Sarah Pantaleo reviewed gene: ASCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30327447, 12077347, 26924529, 31880396, 26503956; Phenotypes: Arthrogryposis, congenital bone fractures, spinal muscular atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2361 PKDCC Paul De Fazio gene: PKDCC was added
gene: PKDCC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKDCC were set to PMID:30478137; 19097194
Phenotypes for gene: PKDCC were set to Dysmorphism; shortening of extremities
Review for gene: PKDCC was set to AMBER
gene: PKDCC was marked as current diagnostic
Added comment: 2 ("apparently") unrelated individuals with homozygous LoF (1x nonsense, 1x canonical splice) variants reported. Their phenotype is similar to knockout mice.
Sources: Literature
Mendeliome v0.2361 DHH Naomi Baker reviewed gene: DHH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31018998, 29471294, 11017805; Phenotypes: gonadal dysgenesis, minifascicular neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2361 USP45 Kristin Rigbye gene: USP45 was added
gene: USP45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP45 were set to 30573563
Phenotypes for gene: USP45 were set to Leber congenital amaurosis; retinal dystrophy
Review for gene: USP45 was set to GREEN
Added comment: 2 unrelated Chinese families reported with rare homozygous variants (one missense, one nonsense) and Leber congenital amaurosis. Animal knockout functional studies supported gene-disease association.

PMID: 30573563 "By analysing WES data based on allele frequencies of in-house controls, population allele frequencies and in silico prediction tools, two rare homozygous mutations in USP45 were identified in two unrelated families. Immunohistochemistry of USP45 in the human and zebrafish retinal sections revealed enriched expression in the inner segments of photoreceptors. The knockdown of usp45 transcript in zebrafish led to abnormal retinal development with effects on photoreceptors, which could be successfully rescued by wild-type usp45 mRNA. Moreover, targeted knockout of Usp45 in mice caused abnormal electroretinography responses, similar to that seen in patients with LCA."
Sources: Literature
Mendeliome v0.2361 CNNM4 Ain Roesley reviewed gene: CNNM4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30705057; Phenotypes: Jalili syndrome (amelogenesis imperfecta, cone-rod dystrophy); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2361 ATM Kristin Rigbye reviewed gene: ATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 30819809; Phenotypes: Ataxia-telangiectasia MIM#208900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2361 BAZ2B Zornitza Stark Gene: baz2b has been classified as Green List (High Evidence).
Mendeliome v0.2361 BAZ2B Zornitza Stark Classified gene: BAZ2B as Green List (high evidence)
Mendeliome v0.2361 BAZ2B Zornitza Stark Gene: baz2b has been classified as Green List (High Evidence).
Mendeliome v0.2360 BAZ2B Zornitza Stark gene: BAZ2B was added
gene: BAZ2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BAZ2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAZ2B were set to 31999386; 28135719; 25363768
Phenotypes for gene: BAZ2B were set to Intellectual disability; autism
Review for gene: BAZ2B was set to GREEN
Added comment: Postulated as a candidate gene for ID/ASD by large-scale studies. Case series reports two individuals with small CNVs and and six with SNVs, mostly LoF type variants. Although the gene is generally intolerant of LoF, some LoF variants present in gnomad ?incomplete penetrance. Additional reported features were inconsistent
Sources: Literature
Mendeliome v0.2359 TPI1 Zornitza Stark Gene: tpi1 has been classified as Green List (High Evidence).
Mendeliome v0.2359 TPI1 Zornitza Stark Classified gene: TPI1 as Green List (high evidence)
Mendeliome v0.2359 TPI1 Zornitza Stark Gene: tpi1 has been classified as Green List (High Evidence).
Mendeliome v0.2357 EMG1 Zornitza Stark Gene: emg1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2357 EMG1 Zornitza Stark Classified gene: EMG1 as Amber List (moderate evidence)
Mendeliome v0.2357 EMG1 Zornitza Stark Gene: emg1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2355 EIF2AK4 Zornitza Stark Gene: eif2ak4 has been classified as Green List (High Evidence).
Mendeliome v0.2355 EIF2AK4 Zornitza Stark Classified gene: EIF2AK4 as Green List (high evidence)
Mendeliome v0.2355 EIF2AK4 Zornitza Stark Gene: eif2ak4 has been classified as Green List (High Evidence).
Mendeliome v0.2354 EIF2AK4 Zornitza Stark gene: EIF2AK4 was added
gene: EIF2AK4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: EIF2AK4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: EIF2AK4 were set to Pulmonary venoocclusive disease 2, MIM#234810
Review for gene: EIF2AK4 was set to GREEN
Added comment: Sources: Expert list
Mendeliome v0.2353 AGBL5 Zornitza Stark Gene: agbl5 has been classified as Green List (High Evidence).
Mendeliome v0.2353 AGBL5 Zornitza Stark Classified gene: AGBL5 as Green List (high evidence)
Mendeliome v0.2353 AGBL5 Zornitza Stark Gene: agbl5 has been classified as Green List (High Evidence).
Mendeliome v0.2351 CPT1C Bryony Thompson Gene: cpt1c has been classified as Green List (High Evidence).
Mendeliome v0.2351 CPT1C Bryony Thompson Classified gene: CPT1C as Green List (high evidence)
Mendeliome v0.2351 CPT1C Bryony Thompson Gene: cpt1c has been classified as Green List (High Evidence).
Mendeliome v0.2349 ATP2B4 Bryony Thompson Gene: atp2b4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2349 ATP2B4 Bryony Thompson Classified gene: ATP2B4 as Amber List (moderate evidence)
Mendeliome v0.2349 ATP2B4 Bryony Thompson Gene: atp2b4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2345 SEC63 Zornitza Stark Gene: sec63 has been classified as Green List (High Evidence).
Mendeliome v0.2342 CYP1B1 Zornitza Stark Gene: cyp1b1 has been classified as Green List (High Evidence).
Mendeliome v0.2342 CYP1B1 Zornitza Stark Phenotypes for gene: CYP1B1 were changed from to Anterior segment dysgenesis 6, multiple subtypes, 617315; Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, 231300
Mendeliome v0.2339 DAG1 Zornitza Stark Gene: dag1 has been classified as Green List (High Evidence).
Mendeliome v0.2336 DPYD Zornitza Stark Gene: dpyd has been classified as Green List (High Evidence).
Mendeliome v0.2333 MFSD8 Zornitza Stark Gene: mfsd8 has been classified as Green List (High Evidence).
Mendeliome v0.2333 MFSD8 Zornitza Stark Phenotypes for gene: MFSD8 were changed from to Ceroid lipofuscinosis, neuronal, 7 610951; Macular dystrophy with central cone involvement 616170
Mendeliome v0.2330 NF1 Zornitza Stark Gene: nf1 has been classified as Green List (High Evidence).
Mendeliome v0.2330 NF1 Zornitza Stark Phenotypes for gene: NF1 were changed from to Leukemia, juvenile myelomonocytic 607785; Neurofibromatosis, familial spinal 162210; Neurofibromatosis, type 1 162200; Neurofibromatosis-Noonan syndrome 601321; Watson syndrome 193520
Mendeliome v0.2328 TECTA Zornitza Stark Added comment: Comment when marking as ready: Both recessive and dominant deafness associations assessed as DEFINITIVE by ClinGen.
Mendeliome v0.2328 TECTA Zornitza Stark Gene: tecta has been classified as Green List (High Evidence).
Mendeliome v0.2328 TECTA Zornitza Stark Phenotypes for gene: TECTA were changed from to Deafness, autosomal recessive 21 603629; Deafness, autosomal dominant 8/12 601543
Mendeliome v0.2323 TRAPPC9 Zornitza Stark Gene: trappc9 has been classified as Green List (High Evidence).
Mendeliome v0.2323 TRAPPC9 Zornitza Stark Phenotypes for gene: TRAPPC9 were changed from to Mental retardation, autosomal recessive 13, MIM# 613192
Mendeliome v0.2320 TRAPPC9 Zornitza Stark reviewed gene: TRAPPC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 22549410, 20004765, 20004763; Phenotypes: Mental retardation, autosomal recessive 13, MIM# 613192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2320 SOS1 Zornitza Stark Added comment: Comment when marking as ready: The association with Noonan syndrome is well established; the association with gingival fibromatosis is questionable.
Mendeliome v0.2320 SOS1 Zornitza Stark Gene: sos1 has been classified as Green List (High Evidence).
Mendeliome v0.2320 SOS1 Zornitza Stark Phenotypes for gene: SOS1 were changed from to ?Fibromatosis, gingival, 1, 135300; Noonan syndrome 4, 610733
Mendeliome v0.2316 F11 Zornitza Stark Gene: f11 has been classified as Green List (High Evidence).
Mendeliome v0.2316 F11 Zornitza Stark Phenotypes for gene: F11 were changed from to Factor XI deficiency, autosomal dominant 612416; Factor XI deficiency, autosomal recessive, MIM#612416
Mendeliome v0.2313 MED13L Zornitza Stark Gene: med13l has been classified as Green List (High Evidence).
Mendeliome v0.2313 MED13L Zornitza Stark Phenotypes for gene: MED13L were changed from to Mental retardation and distinctive facial features with or without cardiac defects 616789; Transposition of the great arteries, dextro-looped 1 608808
Mendeliome v0.2310 PROKR2 Zornitza Stark Gene: prokr2 has been classified as Green List (High Evidence).
Mendeliome v0.2310 CCT5 Bryony Thompson Classified gene: CCT5 as Amber List (moderate evidence)
Mendeliome v0.2310 CCT5 Bryony Thompson Gene: cct5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2305 MED13L Elena Savva reviewed gene: MED13L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 29511999; Phenotypes: Mental retardation and distinctive facial features with or without cardiac defects 616789, Transposition of the great arteries, dextro-looped 1 608808; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.2305 F11 Elena Savva reviewed gene: F11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:18446632, 15026311; Phenotypes: Factor XI deficiency, autosomal dominant 612416, Factor XI deficiency, autosomal recessive; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2305 SOS1 Elena Savva reviewed gene: SOS1: 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: PMID: 25062969, 17143285, 17143282; Phenotypes: ?Fibromatosis, gingival, 1, 135300, Noonan syndrome 4, 610733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.2305 XRCC1 Bryony Thompson Gene: xrcc1 has been classified as Green List (High Evidence).
Mendeliome v0.2305 XRCC1 Bryony Thompson Classified gene: XRCC1 as Green List (high evidence)
Mendeliome v0.2305 XRCC1 Bryony Thompson Gene: xrcc1 has been classified as Green List (High Evidence).
Mendeliome v0.2304 XRCC1 Bryony Thompson gene: XRCC1 was added
gene: XRCC1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: XRCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XRCC1 were set to 28002403; 29472272
Phenotypes for gene: XRCC1 were set to Spinocerebellar ataxia, autosomal recessive 26 MIM#617633
Review for gene: XRCC1 was set to GREEN
Added comment: Three South Asian cases (one with early adult onset and the other two with onset in childhood) reported with slowly progressive cerebellar ataxia accompanied by sensorimotor neuropathy. All with the recurrent splice variant (c.1293G>C, 2 homozygotes and a compound heterozygote). Mice with conditional deletion of the Xrcc1 gene in the brain showed cerebellar ataxia.
Sources: Expert list
Mendeliome v0.2303 TRAPPC9 Elena Savva reviewed gene: TRAPPC9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive 13, 613192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2303 TECTA Elena Savva reviewed gene: TECTA: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:22718023, 17136632, 31554319, 21520338; Phenotypes: Deafness, autosomal recessive 21 603629, Deafness, autosomal dominant 8/12 601543; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.2303 NF1 Elena Savva reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukemia, juvenile myelomonocytic 607785, Neurofibromatosis, familial spinal 162210, Neurofibromatosis, type 1 162200, Neurofibromatosis-Noonan syndrome 601321, Watson syndrome 193520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.2303 TRPC3 Bryony Thompson Gene: trpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2303 TRPC3 Bryony Thompson Classified gene: TRPC3 as Amber List (moderate evidence)
Mendeliome v0.2303 TRPC3 Bryony Thompson Gene: trpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2301 MFSD8 Elena Savva reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:31006324; Phenotypes: Ceroid lipofuscinosis, neuronal, 7 610951, Macular dystrophy with central cone involvement 616170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2301 CYP1B1 Elena Savva reviewed gene: CYP1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:21730847, 27243976; Phenotypes: Anterior segment dysgenesis 6, multiple subtypes, 617315, Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, 231300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2301 SLC9A1 Zornitza Stark Gene: slc9a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2301 SLC9A1 Zornitza Stark Classified gene: SLC9A1 as Amber List (moderate evidence)
Mendeliome v0.2301 SLC9A1 Zornitza Stark Gene: slc9a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2299 MTCL1 Bryony Thompson Gene: mtcl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2299 MTCL1 Bryony Thompson Classified gene: MTCL1 as Amber List (moderate evidence)
Mendeliome v0.2299 MTCL1 Bryony Thompson Gene: mtcl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2298 MTCL1 Bryony Thompson gene: MTCL1 was added
gene: MTCL1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MTCL1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MTCL1 were set to 30548255; 28283581
Phenotypes for gene: MTCL1 were set to slowly progressive cerebellar ataxia; mild intellectual disability; seizures; episodic pain; spinocerebellar ataxia
Review for gene: MTCL1 was set to AMBER
Added comment: Single case with a homozygous loss of function variant in a Polish study of early-onset cerebellar ataxia, and a single family with a single heterozygous missense (p.Val1435Met) identified in two family members with adult-onset spinocerebellar ataxia. Mtcl1 gene disruption in mice results in abnormal motor coordination with Purkinje cell degeneration
Sources: Expert list
Mendeliome v0.2297 ATG5 Bryony Thompson Classified gene: ATG5 as Amber List (moderate evidence)
Mendeliome v0.2297 ATG5 Bryony Thompson Gene: atg5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2296 ATG5 Bryony Thompson gene: ATG5 was added
gene: ATG5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG5 were set to 16625204; 26812546
Phenotypes for gene: ATG5 were set to Spinocerebellar ataxia, autosomal recessive 25 MIM#617584
Review for gene: ATG5 was set to AMBER
Added comment: A homozgyous variant was identified in a single family with two affected siblings. Mice deficient for Atg5 specifically in neural cells and Atg5 null Drosophila develop progressive deficits in motor function.
Sources: Expert list
Mendeliome v0.2295 IL18BP Zornitza Stark gene: IL18BP was added
gene: IL18BP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: IL18BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL18BP were set to 31213488
Phenotypes for gene: IL18BP were set to {?Hepatitis, fulminant viral, susceptibility to} 618549
Review for gene: IL18BP was set to RED
Added comment: Single individual reported with homozygous 40bp deletion in this gene and fulminant Hep A hepatitis.
Sources: Expert list
Mendeliome v0.2291 IRF4 Zornitza Stark Classified gene: IRF4 as Red List (low evidence)
Mendeliome v0.2291 IRF4 Zornitza Stark Gene: irf4 has been classified as Red List (Low Evidence).
Mendeliome v0.2290 ACOX2 Zornitza Stark Added comment: Comment when marking as ready: The ACOX2 gene encodes a peroxisomal branched-chain acyl-CoA oxidase involved in bile acid synthesis.
Mendeliome v0.2290 ACOX2 Zornitza Stark Gene: acox2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2290 ACOX2 Zornitza Stark Classified gene: ACOX2 as Amber List (moderate evidence)
Mendeliome v0.2290 ACOX2 Zornitza Stark Gene: acox2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2289 ACOX2 Zornitza Stark gene: ACOX2 was added
gene: ACOX2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ACOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACOX2 were set to 27647924; 27884763
Phenotypes for gene: ACOX2 were set to Bile acid synthesis defect, congenital, 6, 617308
Review for gene: ACOX2 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert Review
Mendeliome v0.2288 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Mendeliome v0.2288 LARS Zornitza Stark Classified gene: LARS as Green List (high evidence)
Mendeliome v0.2288 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Mendeliome v0.2287 LARS Zornitza Stark gene: LARS was added
gene: LARS was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 28774368; 30349989; 22607940
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Review for gene: LARS was set to GREEN
gene: LARS was marked as current diagnostic
Added comment: Six unrelated families reported in the literature, reviewed in PMID: 30349989.
Sources: NHS GMS
Mendeliome v0.2286 KCNJ11 Zornitza Stark Gene: kcnj11 has been classified as Green List (High Evidence).
Mendeliome v0.2286 KCNJ11 Zornitza Stark Phenotypes for gene: KCNJ11 were changed from to {Diabetes mellitus, type 2, susceptibility to} 125853; Diabetes mellitus, transient neonatal, 3 610582; Diabetes, permanent neonatal, with or without neurologic features 606176; Hyperinsulinemic hypoglycemia, familial, 2 601820; Maturity-onset diabetes of the young, type 13 616329 AD
Mendeliome v0.2282 SIPA1L3 Bryony Thompson Marked gene: SIPA1L3 as ready
Mendeliome v0.2282 SIPA1L3 Bryony Thompson Gene: sipa1l3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2282 SIPA1L3 Bryony Thompson Classified gene: SIPA1L3 as Amber List (moderate evidence)
Mendeliome v0.2282 SIPA1L3 Bryony Thompson Gene: sipa1l3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2281 SIPA1L3 Bryony Thompson gene: SIPA1L3 was added
gene: SIPA1L3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SIPA1L3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SIPA1L3 were set to 28951961; 27993984; 25804400
Phenotypes for gene: SIPA1L3 were set to Cataract 45 MIM#616851
Review for gene: SIPA1L3 was set to AMBER
Added comment: A consanguineous German family segregating a homozygous nonsense mutation in two sisters with congenital cataracts (PMID: 25804400). Null Zebrafish, Xenopus and mouse models recapitulate the human cataract phenotype. A case with congenital cataracts as a feature of their condition harboured a de novo balanced chromosomal translocation, 46,XY,t(2;19)(q37.3;q13.1), where breakpoint mapping and sequencing showed a physical disruption of the 5′UTR of SIPA1L3 (PMID: 26231217). In a case with bilateral congenital cataracts a heterozygous missense (D148Y) was identified and in vitro functional assays of the variant resulted in abnormal actin morphology (PMID: 26231217).
Sources: Expert list
Mendeliome v0.2280 KCNJ11 Elena Savva edited their review of gene: KCNJ11: Added comment: Congenital hyperinsulinism (HI) variants are generally reported in heterozygous patients where they also carry a somatic 2nd hit, or have isodisomy of the paternal allele (focal HI), or in bilallelic patients (diffuse HI). This condition can be dominant (but rarely), where patients with these missense are diazoxide-responsive. Patients with recessively inherited variants are diazoxide-unresponsive (OMIM, PMID:11395395, PMID: 23275527, PMID: 23345197).

Genotype-phenotype correlation:
Permanent neonatal diabetes – GOF (OMIM)
Permanent neonatal diabetes + other features – GOF (OMIM)
Congenital hyperinsulinism – LOF (PMID:18250167).

PTCs - LOF
Missense - Loss and gain of function
LOF – cause reduce channel expression, channel activity and increase current decay (PMID:18250167)
GOF - impair ATP-based sensitivity, more open state channel (OMIM)

Mutations generally occur on the paternal allele (PMID: 23345197).; Changed publications: PMID:18250167, 11395395, 23275527, 23345197
Mendeliome v0.2280 KCNJ11 Elena Savva reviewed gene: KCNJ11: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: {Diabetes mellitus, type 2, susceptibility to} 125853, Diabetes mellitus, transient neonatal, 3 610582, Diabetes, permanent neonatal, with or without neurologic features 606176, Hyperinsulinemic hypoglycemia, familial, 2 601820, Maturity-onset diabetes of the young, type 13 616329 AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.2280 SLC18A2 Zornitza Stark Gene: slc18a2 has been classified as Green List (High Evidence).
Mendeliome v0.2280 SLC18A2 Zornitza Stark Classified gene: SLC18A2 as Green List (high evidence)
Mendeliome v0.2280 SLC18A2 Zornitza Stark Gene: slc18a2 has been classified as Green List (High Evidence).
Mendeliome v0.2278 RNU4ATAC Zornitza Stark Gene: rnu4atac has been classified as Green List (High Evidence).
Mendeliome v0.2275 IFT172 Zornitza Stark Gene: ift172 has been classified as Green List (High Evidence).
Mendeliome v0.2275 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from to Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome
Mendeliome v0.2272 KMT2E Zornitza Stark Gene: kmt2e has been classified as Green List (High Evidence).
Mendeliome v0.2269 MACF1 Zornitza Stark Gene: macf1 has been classified as Green List (High Evidence).
Mendeliome v0.2269 MAP1B Zornitza Stark Gene: map1b has been classified as Green List (High Evidence).
Mendeliome v0.2266 MAP3K20 Zornitza Stark Gene: map3k20 has been classified as Green List (High Evidence).
Mendeliome v0.2266 MAP3K7 Zornitza Stark Gene: map3k7 has been classified as Green List (High Evidence).
Mendeliome v0.2266 MAP3K7 Zornitza Stark Phenotypes for gene: MAP3K7 were changed from to Cardiospondylocarpofacial syndrome 157800 AD; Frontometaphyseal dysplasia 2 617137 AD
Mendeliome v0.2262 MARS2 Zornitza Stark Gene: mars2 has been classified as Green List (High Evidence).
Mendeliome v0.2262 MARS2 Zornitza Stark Phenotypes for gene: MARS2 were changed from to Combined oxidative phosphorylation deficiency 25, OMIM #616430; Spastic ataxia 3, autosomal recessive, OMIM #611390
Mendeliome v0.2259 MARS2 Zornitza Stark changed review comment from: 1 family with 2 sibs with combined oxidative phosphorylation deficiency-25 (with ID) with compound heterozygous mutations in the MARS2 gene. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV.; to: 1 family with 2 sibs with combined oxidative phosphorylation deficiency-25 (with ID) with compound heterozygous mutations in the MARS2 gene. Patient fibroblasts showed decreased activities of mitochondrial complexes I and IV, consistent with a mitochondrial translation defect. Immunoblot analysis showed reduced MARS2 protein levels as well as reduced levels of selected subunits of complexes I and IV. Spastic ataxia association: note complex chromosomal rearrangements rather than SNVs reported in group of 54 French Canadians.
Mendeliome v0.2259 MECOM Zornitza Stark Gene: mecom has been classified as Green List (High Evidence).
Mendeliome v0.2259 MECOM Zornitza Stark Phenotypes for gene: MECOM were changed from to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2, MIM#616738
Mendeliome v0.2256 MED17 Zornitza Stark Gene: med17 has been classified as Green List (High Evidence).
Mendeliome v0.2256 MED17 Zornitza Stark Phenotypes for gene: MED17 were changed from to Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM#613668
Mendeliome v0.2253 MTHFS Zornitza Stark Gene: mthfs has been classified as Green List (High Evidence).
Mendeliome v0.2253 NEBL Zornitza Stark Gene: nebl has been classified as Green List (High Evidence).
Mendeliome v0.2250 NPHP3 Zornitza Stark Gene: nphp3 has been classified as Green List (High Evidence).
Mendeliome v0.2250 NPHP3 Zornitza Stark Phenotypes for gene: NPHP3 were changed from to Meckel syndrome 7, MIM# 267010; Nephronophthisis 3, MIM# 604387; Renal-hepatic-pancreatic dysplasia 1, MIM# 208540
Mendeliome v0.2248 NPHP3 Zornitza Stark reviewed gene: NPHP3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Meckel syndrome 7, MIM# 267010, Nephronophthisis 3, MIM# 604387, Renal-hepatic-pancreatic dysplasia 1, MIM# 208540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2248 NR2E1 Zornitza Stark Gene: nr2e1 has been classified as Red List (Low Evidence).
Mendeliome v0.2248 NR2E1 Zornitza Stark Classified gene: NR2E1 as Red List (low evidence)
Mendeliome v0.2248 NR2E1 Zornitza Stark Gene: nr2e1 has been classified as Red List (Low Evidence).
Mendeliome v0.2247 NRROS Zornitza Stark Gene: nrros has been classified as Green List (High Evidence).
Mendeliome v0.2247 NUP214 Zornitza Stark Gene: nup214 has been classified as Green List (High Evidence).
Mendeliome v0.2247 NUP214 Zornitza Stark Phenotypes for gene: NUP214 were changed from epileptic encephalopathy; developmental regression; microcephaly to Encephalopathy, acute, infection-induced, susceptibility to, 9, MIM# 618426; epileptic encephalopathy; developmental regression; microcephaly
Mendeliome v0.2246 NXN Zornitza Stark Gene: nxn has been classified as Green List (High Evidence).
Mendeliome v0.2246 PAX1 Zornitza Stark Gene: pax1 has been classified as Green List (High Evidence).
Mendeliome v0.2242 PDE8B Zornitza Stark Gene: pde8b has been classified as Green List (High Evidence).
Mendeliome v0.2239 ANLN Zornitza Stark Gene: anln has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2239 ANLN Zornitza Stark Phenotypes for gene: ANLN were changed from to Focal segmental glomerulosclerosis 8, OMIM #616032
Mendeliome v0.2237 PIGG Zornitza Stark Gene: pigg has been classified as Green List (High Evidence).
Mendeliome v0.2237 PIGG Zornitza Stark Phenotypes for gene: PIGG were changed from to Mental retardation, autosomal recessive 53, MIM#616917
Mendeliome v0.2234 PIGU Zornitza Stark Gene: pigu has been classified as Green List (High Evidence).
Mendeliome v0.2234 PIGU Zornitza Stark Phenotypes for gene: PIGU were changed from to Glycosylphosphatidylinositol biosynthesis defect 21; OMIM #618590
Mendeliome v0.2231 PUS3 Zornitza Stark Gene: pus3 has been classified as Green List (High Evidence).
Mendeliome v0.2231 PUS3 Zornitza Stark Phenotypes for gene: PUS3 were changed from to Mental retardation, autosomal recessive 55, MIM# 617051
Mendeliome v0.2228 RUBCN Zornitza Stark Gene: rubcn has been classified as Green List (High Evidence).
Mendeliome v0.2228 RUBCN Zornitza Stark Phenotypes for gene: RUBCN were changed from to Spinocerebellar ataxia, autosomal recessive 15, MIM#615705
Mendeliome v0.2225 SHANK2 Zornitza Stark Gene: shank2 has been classified as Green List (High Evidence).
Mendeliome v0.2222 SLC26A4 Zornitza Stark Gene: slc26a4 has been classified as Green List (High Evidence).
Mendeliome v0.2222 SLC26A4 Zornitza Stark Phenotypes for gene: SLC26A4 were changed from to Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 600791; Pendred syndrome 274600
Mendeliome v0.2219 SMPD4 Zornitza Stark Gene: smpd4 has been classified as Green List (High Evidence).
Mendeliome v0.2219 SMPD4 Zornitza Stark Phenotypes for gene: SMPD4 were changed from to Severe neurodevelopmental delay, microcephaly, arthrogryposis
Mendeliome v0.2216 SOX11 Zornitza Stark Gene: sox11 has been classified as Green List (High Evidence).
Mendeliome v0.2216 SOX11 Zornitza Stark Phenotypes for gene: SOX11 were changed from to Coffin-Siris syndrome 9, MIM# 615866; Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.2213 SOX11 Zornitza Stark changed review comment from: Heterozygous variant in a patient with Coffin-Siris like syndrome and small kidney; but also rare variants identified in a non-syndromic CAKUT cohort with some functional data.
Sources: Expert list; to: Coffin-Siris syndrome: two individuals with de novo mono-allelic missense variants in this gene, mouse model.
CAKUT: Heterozygous variant in a patient with Coffin-Siris like syndrome and small kidney; but also rare variants identified in a non-syndromic CAKUT cohort with some functional data.
Sources: Expert list
Mendeliome v0.2213 SOX11 Zornitza Stark edited their review of gene: SOX11: Changed rating: GREEN; Changed phenotypes: Coffin-Siris syndrome 9, MIM# 615866, Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.2213 ADAM22 Zornitza Stark Gene: adam22 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2213 ADAM22 Zornitza Stark Classified gene: ADAM22 as Amber List (moderate evidence)
Mendeliome v0.2213 ADAM22 Zornitza Stark Gene: adam22 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2212 NDUFA12 Zornitza Stark Gene: ndufa12 has been classified as Red List (Low Evidence).
Mendeliome v0.2212 HOXB6 Zornitza Stark Classified gene: HOXB6 as Amber List (moderate evidence)
Mendeliome v0.2212 HOXB6 Zornitza Stark Gene: hoxb6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2211 QRSL1 Zornitza Stark Gene: qrsl1 has been classified as Green List (High Evidence).
Mendeliome v0.2208 PPCS Zornitza Stark Gene: ppcs has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2205 PPCS Zornitza Stark Classified gene: PPCS as Amber List (moderate evidence)
Mendeliome v0.2205 PPCS Zornitza Stark Gene: ppcs has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2204 PET117 Zornitza Stark Gene: pet117 has been classified as Red List (Low Evidence).
Mendeliome v0.2204 PET117 Zornitza Stark gene: PET117 was added
gene: PET117 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PET117 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PET117 were set to 28386624
Phenotypes for gene: PET117 were set to Developmental delay; Regression; Complex IV deficiency
Review for gene: PET117 was set to RED
Added comment: Two siblings reported, some functional data. PET117 postulated to be a Complex IV assembly factor.
Sources: Expert list
Mendeliome v0.2201 NUP188 Zornitza Stark Classified gene: NUP188 as Green List (high evidence)
Mendeliome v0.2201 NUP188 Zornitza Stark Gene: nup188 has been classified as Green List (High Evidence).
Mendeliome v0.2200 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2198 TBCD Zornitza Stark Gene: tbcd has been classified as Green List (High Evidence).
Mendeliome v0.2198 TBCD Zornitza Stark Phenotypes for gene: TBCD were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, MIM#617193
Mendeliome v0.2194 TMTC2 Zornitza Stark Classified gene: TMTC2 as Amber List (moderate evidence)
Mendeliome v0.2194 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2193 UMOD Zornitza Stark Gene: umod has been classified as Green List (High Evidence).
Mendeliome v0.2193 TOR1AIP1 Zornitza Stark Gene: tor1aip1 has been classified as Green List (High Evidence).
Mendeliome v0.2193 UPK3A Zornitza Stark Gene: upk3a has been classified as Red List (Low Evidence).
Mendeliome v0.2190 UPK3A Zornitza Stark Classified gene: UPK3A as Red List (low evidence)
Mendeliome v0.2190 UPK3A Zornitza Stark Gene: upk3a has been classified as Red List (Low Evidence).
Mendeliome v0.2189 VARS Zornitza Stark Gene: vars has been classified as Green List (High Evidence).
Mendeliome v0.2188 WNT10A Zornitza Stark Gene: wnt10a has been classified as Green List (High Evidence).
Mendeliome v0.2188 WNT10A Zornitza Stark Phenotypes for gene: WNT10A were changed from to Odontoonychodermal dysplasia; Schopf-Schulz-Passarge syndrome; Tooth agenesis, selective, 4
Mendeliome v0.2185 ZNF592 Zornitza Stark Gene: znf592 has been classified as Red List (Low Evidence).
Mendeliome v0.2185 ZNF592 Zornitza Stark Phenotypes for gene: ZNF592 were changed from to SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 5
Mendeliome v0.2182 ZNF592 Zornitza Stark Classified gene: ZNF592 as Red List (low evidence)
Mendeliome v0.2182 ZNF592 Zornitza Stark Gene: znf592 has been classified as Red List (Low Evidence).
Mendeliome v0.2181 CLIC5 Zornitza Stark Gene: clic5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2181 GNB2 Zornitza Stark Gene: gnb2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2181 MIR96 Zornitza Stark Gene: mir96 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2181 MYL1 Zornitza Stark Gene: myl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2181 APOL1 Zornitza Stark Gene: apol1 has been classified as Red List (Low Evidence).
Mendeliome v0.2181 ARHGEF6 Zornitza Stark Gene: arhgef6 has been classified as Red List (Low Evidence).
Mendeliome v0.2181 CEP85L Zornitza Stark Gene: cep85l has been classified as Green List (High Evidence).
Mendeliome v0.2181 CEP85L Zornitza Stark Classified gene: CEP85L as Green List (high evidence)
Mendeliome v0.2181 CEP85L Zornitza Stark Gene: cep85l has been classified as Green List (High Evidence).
Mendeliome v0.2180 MIEF2 Zornitza Stark Gene: mief2 has been classified as Red List (Low Evidence).
Mendeliome v0.2180 POLE2 Zornitza Stark Gene: pole2 has been classified as Red List (Low Evidence).
Mendeliome v0.2180 PTCD1 Zornitza Stark Gene: ptcd1 has been classified as Red List (Low Evidence).
Mendeliome v0.2180 TFAM Zornitza Stark Gene: tfam has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2180 TFAM Zornitza Stark Classified gene: TFAM as Amber List (moderate evidence)
Mendeliome v0.2180 TFAM Zornitza Stark Gene: tfam has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2179 NME3 Zornitza Stark Gene: nme3 has been classified as Red List (Low Evidence).
Mendeliome v0.2179 NME3 Zornitza Stark gene: NME3 was added
gene: NME3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NME3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NME3 were set to 30587587
Phenotypes for gene: NME3 were set to Hypotonia; Neurodegeneration; Abnormal mitochondrial dynamics
Review for gene: NME3 was set to RED
Added comment: Single individual reported. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics
Sources: Expert list
Mendeliome v0.2178 MRPS28 Zornitza Stark Gene: mrps28 has been classified as Red List (Low Evidence).
Mendeliome v0.2178 MRPS28 Zornitza Stark gene: MRPS28 was added
gene: MRPS28 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MRPS28 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS28 were set to 30566640
Phenotypes for gene: MRPS28 were set to Intrauterine growth retardation; developmental delay; dysmorphism
Review for gene: MRPS28 was set to RED
Added comment: Single individual reported.
Sources: Expert list
Mendeliome v0.2177 MRPS25 Zornitza Stark Gene: mrps25 has been classified as Red List (Low Evidence).
Mendeliome v0.2177 MRPS25 Zornitza Stark gene: MRPS25 was added
gene: MRPS25 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MRPS25 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS25 were set to 31039582
Phenotypes for gene: MRPS25 were set to Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum
Review for gene: MRPS25 was set to RED
Added comment: Single individual reported.
Sources: Expert list
Mendeliome v0.2176 MRPS23 Zornitza Stark Phenotypes for gene: MRPS23 were changed from Hepatic disease; Combined respiratory chain complex deficiencies to Hepatic disease; Combined respiratory chain complex deficienciesHepatic disease; Combined respiratory chain complex deficiencies; Cardiomyopathy; Tubulopathy; Lactic acidosis; Structural brain abnormalities
Mendeliome v0.2174 MRPS23 Zornitza Stark Classified gene: MRPS23 as Green List (high evidence)
Mendeliome v0.2174 MRPS23 Zornitza Stark Gene: mrps23 has been classified as Green List (High Evidence).
Mendeliome v0.2173 MRPS23 Zornitza Stark edited their review of gene: MRPS23: Added comment: Four families reported.; Changed rating: GREEN; Changed publications: 26741492, 17873122, 25663021, 28752220; Changed phenotypes: Hepatic disease, Combined respiratory chain complex deficiencies, Cardiomyopathy, Tubulopathy, Lactic acidosis, Structural brain abnormalities
Mendeliome v0.2173 MIEF2 Zornitza Stark gene: MIEF2 was added
gene: MIEF2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MIEF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIEF2 were set to 29361167
Phenotypes for gene: MIEF2 were set to Progressive muscle weakness; Exercise intolerance; Ragged red and COX negative fibres; Complex I and IV deficiency
Review for gene: MIEF2 was set to RED
Added comment: Single individual reported.
Sources: Expert list
Mendeliome v0.2172 ERAL1 Zornitza Stark Gene: eral1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2172 ERAL1 Zornitza Stark Classified gene: ERAL1 as Amber List (moderate evidence)
Mendeliome v0.2172 ERAL1 Zornitza Stark Gene: eral1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2170 COX5A Zornitza Stark Gene: cox5a has been classified as Red List (Low Evidence).
Mendeliome v0.2170 COX5A Zornitza Stark gene: COX5A was added
gene: COX5A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COX5A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX5A were set to 2824752
Phenotypes for gene: COX5A were set to pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency
Review for gene: COX5A was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.2169 TRAF3IP2 Zornitza Stark Gene: traf3ip2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2169 TRAF3IP2 Zornitza Stark Phenotypes for gene: TRAF3IP2 were changed from to Candidiasis, familial, 8, MIM# 615527
Mendeliome v0.2166 TRAF3IP2 Zornitza Stark Classified gene: TRAF3IP2 as Amber List (moderate evidence)
Mendeliome v0.2166 TRAF3IP2 Zornitza Stark Gene: traf3ip2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2165 TRAF3IP2 Zornitza Stark reviewed gene: TRAF3IP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24120361, 31292894, 20660351; Phenotypes: Candidiasis, familial, 8, MIM# 615527; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2165 TRAF3 Zornitza Stark Gene: traf3 has been classified as Red List (Low Evidence).
Mendeliome v0.2162 TRAF3 Zornitza Stark Classified gene: TRAF3 as Red List (low evidence)
Mendeliome v0.2162 TRAF3 Zornitza Stark Gene: traf3 has been classified as Red List (Low Evidence).
Mendeliome v0.2161 TNFSF12 Zornitza Stark Gene: tnfsf12 has been classified as Red List (Low Evidence).
Mendeliome v0.2158 TNFSF12 Zornitza Stark Classified gene: TNFSF12 as Red List (low evidence)
Mendeliome v0.2158 TNFSF12 Zornitza Stark Gene: tnfsf12 has been classified as Red List (Low Evidence).
Mendeliome v0.2157 TNFRSF4 Zornitza Stark Gene: tnfrsf4 has been classified as Red List (Low Evidence).
Mendeliome v0.2154 TNFRSF4 Zornitza Stark Classified gene: TNFRSF4 as Red List (low evidence)
Mendeliome v0.2154 TNFRSF4 Zornitza Stark Gene: tnfrsf4 has been classified as Red List (Low Evidence).
Mendeliome v0.2153 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2150 TNFRSF13C Zornitza Stark Classified gene: TNFRSF13C as Amber List (moderate evidence)
Mendeliome v0.2150 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2149 TNFRSF13B Zornitza Stark Gene: tnfrsf13b has been classified as Green List (High Evidence).
Mendeliome v0.2146 THBD Zornitza Stark Gene: thbd has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2143 THBD Zornitza Stark Classified gene: THBD as Amber List (moderate evidence)
Mendeliome v0.2143 THBD Zornitza Stark Gene: thbd has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2142 TAPBP Zornitza Stark Gene: tapbp has been classified as Red List (Low Evidence).
Mendeliome v0.2140 NXN Zornitza Stark Phenotypes for gene: NXN were changed from to Robinow syndrome, autosomal recessive 2 618529
Mendeliome v0.2137 NXN Zornitza Stark reviewed gene: NXN: Rating: GREEN; Mode of pathogenicity: None; Publications: 29276006; Phenotypes: Robinow syndrome, autosomal recessive 2 618529; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2136 TAPBP Zornitza Stark Classified gene: TAPBP as Red List (low evidence)
Mendeliome v0.2136 TAPBP Zornitza Stark Gene: tapbp has been classified as Red List (Low Evidence).
Mendeliome v0.2136 TAPBP Zornitza Stark Classified gene: TAPBP as Red List (low evidence)
Mendeliome v0.2136 TAPBP Zornitza Stark Gene: tapbp has been classified as Red List (Low Evidence).
Mendeliome v0.2135 SEMA3E Zornitza Stark Gene: sema3e has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2133 SEMA3E Zornitza Stark Classified gene: SEMA3E as Amber List (moderate evidence)
Mendeliome v0.2133 SEMA3E Zornitza Stark Gene: sema3e has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2132 RNF31 Zornitza Stark Gene: rnf31 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2129 RNF31 Zornitza Stark Classified gene: RNF31 as Amber List (moderate evidence)
Mendeliome v0.2129 RNF31 Zornitza Stark Gene: rnf31 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2128 RHOH Zornitza Stark Gene: rhoh has been classified as Red List (Low Evidence).
Mendeliome v0.2128 RHOH Zornitza Stark Phenotypes for gene: RHOH were changed from to {?Epidermodysplasia verruciformis, susceptibility to, 4}, MIM# 618307
Mendeliome v0.2125 RHOH Zornitza Stark Classified gene: RHOH as Red List (low evidence)
Mendeliome v0.2125 RHOH Zornitza Stark Gene: rhoh has been classified as Red List (Low Evidence).
Mendeliome v0.2124 RHOH Zornitza Stark reviewed gene: RHOH: Rating: RED; Mode of pathogenicity: None; Publications: 22850876, 27574848; Phenotypes: {?Epidermodysplasia verruciformis, susceptibility to, 4}, MIM# 618307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.2124 PSMB9 Zornitza Stark Gene: psmb9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2121 PSMB9 Zornitza Stark Classified gene: PSMB9 as Amber List (moderate evidence)
Mendeliome v0.2121 PSMB9 Zornitza Stark Gene: psmb9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2120 PSMB4 Zornitza Stark Gene: psmb4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2117 PSMB4 Zornitza Stark Classified gene: PSMB4 as Amber List (moderate evidence)
Mendeliome v0.2117 PSMB4 Zornitza Stark Gene: psmb4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2116 PSMA3 Zornitza Stark Gene: psma3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2113 PSMA3 Zornitza Stark Classified gene: PSMA3 as Amber List (moderate evidence)
Mendeliome v0.2113 PSMA3 Zornitza Stark Gene: psma3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2112 NFKBID Zornitza Stark Gene: nfkbid has been classified as Red List (Low Evidence).
Mendeliome v0.2111 NFKBID Zornitza Stark Classified gene: NFKBID as Red List (low evidence)
Mendeliome v0.2111 NFKBID Zornitza Stark Gene: nfkbid has been classified as Red List (Low Evidence).
Mendeliome v0.2110 NFAT5 Zornitza Stark Gene: nfat5 has been classified as Red List (Low Evidence).
Mendeliome v0.2107 NFAT5 Zornitza Stark Classified gene: NFAT5 as Red List (low evidence)
Mendeliome v0.2107 NFAT5 Zornitza Stark Gene: nfat5 has been classified as Red List (Low Evidence).
Mendeliome v0.2106 MS4A1 Zornitza Stark Gene: ms4a1 has been classified as Red List (Low Evidence).
Mendeliome v0.2103 MS4A1 Zornitza Stark Classified gene: MS4A1 as Red List (low evidence)
Mendeliome v0.2103 MS4A1 Zornitza Stark Gene: ms4a1 has been classified as Red List (Low Evidence).
Mendeliome v0.2103 MS4A1 Zornitza Stark Classified gene: MS4A1 as Red List (low evidence)
Mendeliome v0.2103 MS4A1 Zornitza Stark Gene: ms4a1 has been classified as Red List (Low Evidence).
Mendeliome v0.2102 MASP2 Zornitza Stark Gene: masp2 has been classified as Red List (Low Evidence).
Mendeliome v0.2100 MASP2 Zornitza Stark Classified gene: MASP2 as Red List (low evidence)
Mendeliome v0.2100 MASP2 Zornitza Stark Gene: masp2 has been classified as Red List (Low Evidence).
Mendeliome v0.2099 ITGAM Zornitza Stark Gene: itgam has been classified as Red List (Low Evidence).
Mendeliome v0.2099 ITGAM Zornitza Stark Classified gene: ITGAM as Red List (low evidence)
Mendeliome v0.2099 ITGAM Zornitza Stark Gene: itgam has been classified as Red List (Low Evidence).
Mendeliome v0.2098 IRF7 Zornitza Stark Gene: irf7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2095 IRF7 Zornitza Stark Classified gene: IRF7 as Amber List (moderate evidence)
Mendeliome v0.2095 IRF7 Zornitza Stark Gene: irf7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2094 IL21 Zornitza Stark Gene: il21 has been classified as Red List (Low Evidence).
Mendeliome v0.2091 IL21 Zornitza Stark Classified gene: IL21 as Red List (low evidence)
Mendeliome v0.2091 IL21 Zornitza Stark Gene: il21 has been classified as Red List (Low Evidence).
Mendeliome v0.2090 IL17F Zornitza Stark Gene: il17f has been classified as Red List (Low Evidence).
Mendeliome v0.2090 IL17F Zornitza Stark Phenotypes for gene: IL17F were changed from to Candidiasis, familial, 6, autosomal dominant, MIM# 613956
Mendeliome v0.2087 IL17F Zornitza Stark Classified gene: IL17F as Red List (low evidence)
Mendeliome v0.2087 IL17F Zornitza Stark Gene: il17f has been classified as Red List (Low Evidence).
Mendeliome v0.2086 IL17F Zornitza Stark reviewed gene: IL17F: Rating: RED; Mode of pathogenicity: None; Publications: 21350122; Phenotypes: Candidiasis, familial, 6, autosomal dominant, MIM# 613956; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.2086 FPR1 Zornitza Stark Gene: fpr1 has been classified as Red List (Low Evidence).
Mendeliome v0.2084 FPR1 Zornitza Stark Classified gene: FPR1 as Red List (low evidence)
Mendeliome v0.2084 FPR1 Zornitza Stark Gene: fpr1 has been classified as Red List (Low Evidence).
Mendeliome v0.2083 FCN3 Zornitza Stark Gene: fcn3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2080 FCN3 Zornitza Stark Classified gene: FCN3 as Amber List (moderate evidence)
Mendeliome v0.2080 FCN3 Zornitza Stark Gene: fcn3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2079 FCGR3A Zornitza Stark Gene: fcgr3a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2076 FCGR3A Zornitza Stark Classified gene: FCGR3A as Amber List (moderate evidence)
Mendeliome v0.2076 FCGR3A Zornitza Stark Gene: fcgr3a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.2075 CR2 Zornitza Stark Gene: cr2 has been classified as Amber List (Moderate Evidence).