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Mendeliome v1.1045 TMEM63B Achchuthan Shanmugasundram changed review comment from: There is sufficient evidence for this gene to be included with green rating in intellectual disability and epilepsy panels.

17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame.

All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.

All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature; to: There is sufficient evidence for this gene to be included with green rating in 'Intellectual disability syndromic and non-syndromic' and 'Genetic epilepsy' panels.

17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame.

All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.

All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature
Mendeliome v1.1045 TMEM63B Achchuthan Shanmugasundram gene: TMEM63B was added
gene: TMEM63B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63B were set to 37421948
Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: TMEM63B was set to GREEN
Added comment: There is sufficient evidence for this gene to be included with green rating in intellectual disability and epilepsy panels.

17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame.

All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.

All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature
Mendeliome v1.1045 DHX9 Achchuthan Shanmugasundram gene: DHX9 was added
gene: DHX9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX9 were set to 37467750
Phenotypes for gene: DHX9 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; Charcot-Marie-Tooth disease, MONDO:0015626
Review for gene: DHX9 was set to GREEN
Added comment: PMID:37467750 - 17 unrelated individuals were identified with de novo, ultra-rare, heterozygous missense or loss-of-function DHX9 variants, of which 14 individuals were reported with a neurodevelopmental disorder (NDD) and three were reported with Charcot-Marie-Tooth disease (CMT). All 14 cases with NDD had developmental delay, of which eight were reported with intellectual disability (4 severe, 1 moderate, 3 mild). Two cases did not have ID, one had borderline ID and three cases were too young (0-5 years old). The three cases with CMT presented with adult-onset axonal neuropathy.
Sources: Literature
Mendeliome v1.1045 KLK1 Zornitza Stark Phenotypes for gene: KLK1 were changed from [Kallikrein, decreased urinary activity of] 615953 to [Kallikrein, decreased urinary activity of] 615953; Pulmonary arterial hypertension MONDO:0015924
Mendeliome v1.1042 KLK1 Zornitza Stark edited their review of gene: KLK1: Added comment: Association with PAH:

PMID: 31727138
screening of the biobank - 12 individuals with genetic variant in KLK1 relevant to PAH (not all were found to be hereditary). Assay showed that carriers of variants in KLK1 are less clinically severe compared to those who carry variants in BMPR2.

PMID: 17573418
Functional study using sensitive and specific type ELISAs to assay multiple panels of human tissue. KLK1 tissue was abundantly expressed in the pancreas and salivary gland and moderately expressed in the lungs.

Reviewed by ClinGen Pulmonary Hypertension GCEP on 30/8/2022 with LIMITED evidence supporting gene-disease validity; Changed publications: 31727138, 17573418; Changed phenotypes: [Kallikrein, decreased urinary activity of] 615953, Pulmonary arterial hypertension MONDO:0015924; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1041 WBP4 Zornitza Stark Marked gene: WBP4 as ready
Mendeliome v1.1040 WBP4 Zornitza Stark Marked gene: WBP4 as ready
Mendeliome v1.1039 KDM2A Zornitza Stark Marked gene: KDM2A as ready
Mendeliome v1.1035 INTS13 Zornitza Stark Marked gene: INTS13 as ready
Mendeliome v1.1031 TUBB4B Zornitza Stark Phenotypes for gene: TUBB4B were changed from Leber congenital amaurosis with early onset deafness, LCAEOD, OMIM #617879; MONDO:0060650 to Leber congenital amaurosis with early onset deafness, LCAEOD, OMIM #617879; MONDO:0060650; Primary ciliary dyskinesia, MONDO:0016575, TUBB4B-related
Mendeliome v1.1030 CYHR1 Zornitza Stark Marked gene: CYHR1 as ready
Mendeliome v1.1029 TSPOAP1 Zornitza Stark Phenotypes for gene: TSPOAP1 were changed from Dystonia, intellectual disability and cerebellar atrophy to Dystonia 22, MIM# 620453
Mendeliome v1.1027 NAA60 Zornitza Stark Marked gene: NAA60 as ready
Mendeliome v1.1026 POPDC2 Zornitza Stark Marked gene: POPDC2 as ready
Mendeliome v1.1025 GPATCH11 Zornitza Stark Marked gene: GPATCH11 as ready
Mendeliome v1.1024 KCNA3 Zornitza Stark Marked gene: KCNA3 as ready
Mendeliome v1.1023 FSD1L Zornitza Stark Marked gene: FSD1L as ready
Mendeliome v1.1022 DENND5B Zornitza Stark Marked gene: DENND5B as ready
Mendeliome v1.1021 DMAP1 Zornitza Stark Marked gene: DMAP1 as ready
Mendeliome v1.1020 VGLL2 Zornitza Stark Marked gene: VGLL2 as ready
Mendeliome v1.1014 PLCG1 Zornitza Stark Marked gene: PLCG1 as ready
Mendeliome v1.1011 DCAF15 Zornitza Stark Marked gene: DCAF15 as ready
Mendeliome v1.1009 WBP4 Chirag Patel gene: WBP4 was added
gene: WBP4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WBP4 were set to Neurodevelopmental disorder
Review for gene: WBP4 was set to GREEN
gene: WBP4 was marked as current diagnostic
Added comment: ESHG 2023:
11 individuals from 8 families with homozygous LOF variants in WBP4 gene (4 different variants). Presentation of severe DD and ID, hypotonia, abnormal outer ears, and varying congenital anomalies. WBP4 is spliceosome protein which binds/interacts with SNRNP200. In vivo and in vitro studies previously showed WBP4 enhances splicing and regulates alternative splicing. Patient fibroblasts showed loss of expression of WBP4. RNA sequencing analysis showed abnormal splicing patterns. Proposed spliceosomopathy.
Sources: Other
Mendeliome v1.1007 KDM2A Chirag Patel gene: KDM2A was added
gene: KDM2A was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KDM2A were set to Neurodevelopmental disorder
Review for gene: KDM2A was set to GREEN
gene: KDM2A was marked as current diagnostic
Added comment: ESHG 2023:
14 patients with de novo HTZ variants in KDM2A (5 x truncating, 9 x missense)
Presentation with DD, ID (mild), seizures, growth retardation, and dysmorphism.

Functional studies:
-patient blood showed aberrant genome wide methylation profile - potential episignature
-HEK293T cells showed altered subcellular localisation of KDM2A
-Drosophila models showed variants caused neurotoxicity
Sources: Other
Mendeliome v1.1005 NSUN6 Chirag Patel changed review comment from: Sufficient evidence for upgrade; to: Drosophila KO showed locomotion defects and reduced learning ability. Sufficient evidence for upgrade
Mendeliome v1.1003 INTS13 Chirag Patel gene: INTS13 was added
gene: INTS13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INTS13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS13 were set to PMID: 36229431
Phenotypes for gene: INTS13 were set to Oral-facial-digital syndrome
Review for gene: INTS13 was set to GREEN
gene: INTS13 was marked as current diagnostic
Added comment: 2 families with 4 affected individuals with Oral-facial-digital (OFD) phenotype. Homozygosity mapping and WES found 2 homozygous variants in INTS13 gene. This is a subunit of the Integrator complex, which associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. Variants segregated with disease. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Knockdown in Xenopus embryos leads to motile cilia anomalies.
Sources: Literature
Mendeliome v1.1002 TUBB4B Chirag Patel reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1001 DCAF15 Chirag Patel gene: DCAF15 was added
gene: DCAF15 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DCAF15 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DCAF15 were set to Cornelia de Lange syndrome
Review for gene: DCAF15 was set to AMBER
Added comment: ESHG 2023:
3 unrelated cases with CdLS (1 x TOP with MCA, 1 x death @20mths, 1 x living child)
Features suggestive of CdLS - DD, microcephaly, CHD, dysmorphism, visual/hearing impairment.

WES identified recurrent de novo variant (p.Ser470Phe) in DCAF15 gene. This mediates ubiquitination and degradation of target proteins, and interacts with cohesin complex members (SMC1/SMC3).

Protein analysis from individuals showed increased accumulation of ubiquitination-modified proteins and SM3 (GOF mechanism). EpiSign analysis showed same DNA methylation pattern as other CdLS cases/genes. Zebrafish model showed reduced body length, reduced head size, reduced oligodendrocytes, heart defect, aberrant motor neurons, and abnormal response to visual/auditory stimuli.
Sources: Other
Mendeliome v1.997 PMVK Zornitza Stark changed review comment from: Association with auto inflammatory syndrome:

Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; to: Association with auto inflammatory syndrome:

Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.

Amber for bi-allelic disease association.
Mendeliome v1.997 PMVK Zornitza Stark edited their review of gene: PMVK: Added comment: Association with auto inflammatory syndrome:

Five-year-old girl with recurring hyperinflammatory episodes initially presenting at 9mo with fever, arthritis, aphthous stomatitis and maculopapular rash with homozygous variant in PMVK p.Val131Ala (NM_006556.4: c.392T>C) with clinical overlap with MVK deficiency. Supportive functional data. Second patient, 6yo boy with compound heterozygous c.329G >A (p. Arg110Gln) and c.316G >A (p. Val106Met) mutations in trans configuration with similar phenotype.; Changed publications: 26202976, 37364720, 36410683; Changed phenotypes: Porokeratosis 1, multiple types, MIM# 175800, Autoinflammatory syndrome, MONDO:0019751, PMVK-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.997 RIPK3 Zornitza Stark Marked gene: RIPK3 as ready
Mendeliome v1.996 RIPK3 Zornitza Stark gene: RIPK3 was added
gene: RIPK3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RIPK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPK3 were set to 37083451
Phenotypes for gene: RIPK3 were set to Hereditary susceptibility to infections, MONDO:0015979, RIPK3-related; Recurrent HSV encephalitis
Review for gene: RIPK3 was set to AMBER
Added comment: Single female patient with independent episodes of HSE at 6 and 17 months of age and with autoimmune encephalitis 1 month after the second episode of HSE with two heterozygous mutations of RIPK3 predicted to be loss of function (pLOF): p. Arg422* (c.1264 C > T, MAF 0.001568, CADD 35) and p. Pro493fs9* (c.1475 C > CC, MAF 0.002611, CADD 24.2). Extensive supportive functional data including RIPK3 knockout human pluripotent stem cell–derived cortical neurons.
Sources: Expert Review
Mendeliome v1.995 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from Intestinal dysmotility syndrome, MIM# 620045; Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features to Intestinal dysmotility syndrome, MIM# 620045; Moyamoya disease, MONDO:0016820, ANO1 related
Mendeliome v1.992 ANO1 Zornitza Stark edited their review of gene: ANO1: Added comment: PMID 37253099: screening analysis of Moyamoya disease (MMD) cohort revealed 8 individuals with variants in the ANO1 gene. Two families had the same rare variant p.Met658Val. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harboring these gain-of-function ANO1 variants had classic features of MMD, but also had aneurysm, stenosis, and/or occlusion in the posterior circulation. Amber rating due to somewhat conflicting segregation and functional data presented.; Changed publications: 37253099; Changed phenotypes: Intestinal dysmotility syndrome, MIM# 620045, Moyamoya disease, MONDO:0016820, ANO1 related
Mendeliome v1.991 CYHR1 Chirag Patel gene: CYHR1 was added
gene: CYHR1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CYHR1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CYHR1 were set to Neurodevelopmental disorder and microcephaly
Review for gene: CYHR1 was set to AMBER
Added comment: ESHG 2023:
5 individuals from 3 families with biallelic LOF variants in CYHR1 (aka ZTRAF1). Presentation with microcephaly, hypotonia, DD, and ID. Expression studies showed mislocalisation of CYHR1. Mutant fibroblasts showed increased lysosomal markers and upregulated lysosomal proteins, leading to impaired autophagy. Zebrafish KO however did not show a phenotype.
Sources: Other
Mendeliome v1.989 NAA60 Chirag Patel reviewed gene: NAA60: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary familial brain calcification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.989 NAA60 Chirag Patel gene: NAA60 was added
gene: NAA60 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NAA60 were set to Basal ganglia calcification
Review for gene: NAA60 was set to GREEN
gene: NAA60 was marked as current diagnostic
Added comment: ESHG 2023:
10 individuals from 7 families with biallelic variants in NAA60 (missense and framshift).
All with primary brain calcification - 4/10 childhood onset (DD, ID), 6/10 adult onset (cerebellar and pyramidal dysfunction, dystonia, parkinsonism, cognitive impairment, psychiatric manifestations).

NAA60 catalyses N-terminal acetylation of transmembrane proteins and localises to Golgi apparatus. In vitro assay of variants showed reduced capacity of Nt acetylation. Fibroblast studies showed significantly reduced levels of phosphate importer (SLC20A2). Loss of function variants in SLC20A2 (~50% of PFBC cases) lead to increased extracellular phosphate (which is thought to lead to calcium deposits in brain).
Sources: Other
Mendeliome v1.987 POPDC2 Chirag Patel gene: POPDC2 was added
gene: POPDC2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POPDC2 were set to Sinus node dysfunction
Review for gene: POPDC2 was set to GREEN
gene: POPDC2 was marked as current diagnostic
Added comment: ESHG 2023:
3 families with 7 affected with sinus node dysfunction (bradycardia) and AV block (2/7 HCM).

3 x HMZ variants found in POPDC2 (2 x missense, 1 x indel). Variants predicted to diminish cAMP binding of POPDC2, and shown to disrupt regulation of TREK1 channels (lowering of outward K+ current).

POPDC2 is highly expressed in cardiac myocytes, sinoatrial node, and atrioventricular node. Knockdown in zebrafish leads to AV block, and knockout in mice leads to sinus node dysfunction. Sources: Other
Sources: Other
Mendeliome v1.985 GPATCH11 Chirag Patel gene: GPATCH11 was added
gene: GPATCH11 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: GPATCH11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPATCH11 were set to Leber congenital amaurosis and developmental delay
Review for gene: GPATCH11 was set to GREEN
gene: GPATCH11 was marked as current diagnostic
Added comment: ESHG 2023:
3 families with 8 individuals with leber congenital amaurosis, developmental delay, language disorder, and behavioural issues.
GPATCH11 localises to nucleus and basal body of primary cilium (similar to other LCA genes).
Biallelic variants found in GPATCH11 - 1 splice variant common to all 3 families (1 other variant in 3rd family). Splice variant leads to loss of exon 4 (mRNA studies).
Mouse models showed i) abnormal rod/cone responses on ERG; ii) decreased outer nuclear layer in retina, and iii) abnormal associate/episodic memory
Sources: Other
Mendeliome v1.982 KCNA3 Chirag Patel gene: KCNA3 was added
gene: KCNA3 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KCNA3 were set to Neurodevelopmental disorder
Review for gene: KCNA3 was set to GREEN
gene: KCNA3 was marked as current diagnostic
Added comment: ESHG 2023:
10 individuals with de novo missense variants in KCNA3 (K+ channel)
Variable electrophysiology studies of effect of variants (5 x LOF, 4 x GOF, 1 no change)
Presentation: abnormal speech development (8/8), ID (6/8), epilepsy (5/8), and ASD (7/8)
Sources: Other
Mendeliome v1.980 FSD1L Chirag Patel gene: FSD1L was added
gene: FSD1L was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FSD1L was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FSD1L were set to Neurodevelopmental disorder
Review for gene: FSD1L was set to GREEN
gene: FSD1L was marked as current diagnostic
Added comment: ESHG 2023:
8 families with biallelic missense/nonsense variants
Presentation only described 1 family/2 affecteds with DD, ID, spastic paraparesis, epilepsy, corpus callosum hypoplasia, and optic nerve hypoplasia

Functional assays:
-reduced expression of FSD1L in mature neurons (RNA studies)
-very low % mature neurons (neuronal differentiation)
-reduced neuronal migration
Sources: Other
Mendeliome v1.978 DENND5B Chirag Patel gene: DENND5B was added
gene: DENND5B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DENND5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DENND5B were set to Neurodevelopmental disorder with white matter anomalies
Review for gene: DENND5B was set to GREEN
gene: DENND5B was marked as current diagnostic
Added comment: ESHG 2023:
7 patients/7 families with de novo DENND5B variants (6 missense, 1 splice)
DD/ID (mod/profound)(7/7), white matter anomalies (6/7) hypotonia, epilepsy (3/7)

DENND5B acts as:
-GEF for activation of RAB proteins which are involved in membrane trafficking and neurotransmitter release
-regulator of lipid absorption and homeostasis

Functional studies showed loss of expression of DENND5B in fibroblasts, abnormal vesicle trafficking, and impaired lipid uptake and intracellular distribution
Sources: Other
Mendeliome v1.976 DMAP1 Chirag Patel gene: DMAP1 was added
gene: DMAP1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DMAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DMAP1 were set to Neurodevelopmental disorder
Review for gene: DMAP1 was set to GREEN
gene: DMAP1 was marked as current diagnostic
Added comment: ESHG 2023:
9 patients/8 families with bilallelic variants in DMAP1 (3 missense, 7 LOF)
All with DD, speech delay, hypotonia, and ID
Some with epilepsy (4/6), FTT (4/5), and brain malformations (3/5)
Drosophila showed abnormal behaviour pattern and bang sensitivity
Specific methylation episignature also seen
Sources: Other
Mendeliome v1.974 VGLL2 Chirag Patel gene: VGLL2 was added
gene: VGLL2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: VGLL2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VGLL2 were set to Syngnathia
Review for gene: VGLL2 was set to GREEN
gene: VGLL2 was marked as current diagnostic
Added comment: ESHG 2023:
4 families/7 affected individuals with isolated unilateral/bilateral syngnathia
biallelic truncating variants in VGLL2
But not phenotype in KO mouse or zebrafish models
Sources: Other
Mendeliome v1.972 RDH11 Elena Savva reviewed gene: RDH11: Rating: AMBER; Mode of pathogenicity: None; Publications: 24916380, 15634683, 30731079, 18326732, 34988992; Phenotypes: Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.972 C1GALT1C1 Zornitza Stark commented on gene: C1GALT1C1: Two maternal half-brothers with missense variant and aHUS phenotype reported, increasing evidence for association.
Mendeliome v1.969 NFE2L2 Zornitza Stark edited their review of gene: NFE2L2: Changed phenotypes: Immunodeficiency, developmental delay, and hypohomocysteinemia, MIM# 617744, Recurrent respiratory and skin infection, Growth retardation, Developmental delay, borderline ID, White matter cerebral lesions; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.969 SMAD1 Bryony Thompson Added comment: Comment on list classification: Disputed gene-disease validity curation by ClinGen PH VCEP 21/11/2022 - Only two probands reported to have PAH and SMAD1 variants. The variants are missense variants without functional data at the time of curation. Thus, SMAD1 is classified as disputed for PAH based upon insufficient genetic evidence over multiple years of research.
Mendeliome v1.967 ZNF808 Krithika Murali Marked gene: ZNF808 as ready
Mendeliome v1.966 ZNF808 Hazel Phillimore gene: ZNF808 was added
gene: ZNF808 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF808 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF808 were set to PMID: 37308312
Phenotypes for gene: ZNF808 were set to non-syndromic neonatal diabetes; MONDO:0016391
Review for gene: ZNF808 was set to GREEN
Added comment: PMID: 37308312; Alqahtani, MA. et al. (2023) Clin Genet. doi: 10.1111/cge.14389.
Three siblings in one consanguineous Saudi Arabian family with non-syndromic neonatal diabetes, all with a homozygous frameshift variant, NM_001321425.2:c.1448dupA, p.(Tyr483*), in ZNF808. (Same nucleotide and amino acid numbering as for the MANE SELECT transcript, NM_001039886.4).
This variant has been entered as likely pathogenic in ClinVar by this group.
This variant occurs in the last exon of the gene and is therefore not NMD-predicted. Instead it is predicted to cause a truncated protein.
This paper shows a diagram with several other truncating variants in this exon, which were reported in the paper by De Franco, E. et al. (2021).
(These patients also had low vitamin D levels, suggesting an association, and is consistent with other studies looking into loci that are associated with vitamin D).

De Franco, E. et al. (2021) medRxiv 08.23.21262262. (Exeter, UK):
Firstly, this group found a homozygous variant NM_001039886.3:c.637del, p.(Leu213*) that is predicted to cause a truncated protein, and also a homozygous CNV Chr19(GRCh37):g.53057128_53100968del (predicted to cause a deletion of exons 4 and 5) in two unrelated affected individuals. These patients had pancreatic agenesis, defined as insulin-dependent diabetes in the first 6 months of life (neonatal diabetes) and exocrine pancreatic insufficiency. Both were from consanguineous families. Parents were subsequently tested and shown to be heterozygous carriers.
They then investigated 232 additional patients who had been diagnosed with neonatal diabetes before the age of 6 months and found ten more homozygous ZNF808 variants. Six were nonsense: p.(Gln194*), p.(Cys233*), p.(Tyr427*), p.(Lys458*), p.(Tyr528*) and p.(Arg727*), and three were frameshift variants: p.(Ala379Valfs*157), p.(Leu588Profs*118), p.(Asn770Ilefs*98) and one was a whole-gene deletion.
All the frameshift and nonsense variants occurred in the last exon of the gene, which contains all 23 zinc finger domains; and therefore all of these variants are predicted to result in truncated proteins, and removal of some, if not all, those domains.
This group also carried out functional studies using an in vitro model of pancreas development and showed an aberrant activation of many transposable elements (mostly MER11 elements) that would be normally be repressed during early pancreas development.
Sources: Literature
Mendeliome v1.966 SART3 Krithika Murali Classified gene: SART3 as Green List (high evidence)
Mendeliome v1.966 SART3 Krithika Murali Gene: sart3 has been classified as Green List (High Evidence).
Mendeliome v1.965 SART3 Daniel Flanagan gene: SART3 was added
gene: SART3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SART3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SART3 were set to PMID: 37296101
Phenotypes for gene: SART3 were set to Neurodevelopmental disorder (MONDO#0700092), SART3-related; 46,XY disorder of sex development (MONDO:0020040), SART3-related
Review for gene: SART3 was set to GREEN
Added comment: Nine individuals from six families presenting with intellectual disability, global developmental delay, a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Additionally, two individuals had seizures and two had epileptiform activity reported on EEG.

Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro.
Sources: Expert list
Mendeliome v1.965 ARPC5 Elena Savva Classified gene: ARPC5 as Green List (high evidence)
Mendeliome v1.965 ARPC5 Elena Savva Gene: arpc5 has been classified as Green List (High Evidence).
Mendeliome v1.964 ARPC5 Elena Savva Classified gene: ARPC5 as Green List (high evidence)
Mendeliome v1.964 ARPC5 Elena Savva Gene: arpc5 has been classified as Green List (High Evidence).
Mendeliome v1.963 ARPC5 Elena Savva Marked gene: ARPC5 as ready
Mendeliome v1.963 ARPC5 Elena Savva Gene: arpc5 has been removed from the panel.
Mendeliome v1.963 NUDCD2 Krithika Murali Marked gene: NUDCD2 as ready
Mendeliome v1.963 NUDCD2 Seb Lunke Marked gene: NUDCD2 as ready
Mendeliome v1.962 NUDCD2 Ee Ming Wong gene: NUDCD2 was added
gene: NUDCD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD2 were set to 37272762
Phenotypes for gene: NUDCD2 were set to Multiple congenital anomalies (MONDO:0019042), NUDCD2-related
Penetrance for gene: NUDCD2 were set to unknown
Review for gene: NUDCD2 was set to AMBER
gene: NUDCD2 was marked as current diagnostic
Added comment: - Two unrelated probands, each biallelic for two variants in NUDCD2 (total 3x LoF variants, 1x missense variant)
- Immunoblotting of proteins extracted from the primary fibroblasts of one proband with 2x LoF variants demonstrated markedly reduced NUDCD2 levels compared to healthy individuals
Sources: Literature
Mendeliome v1.962 DCAF13 Seb Lunke Marked gene: DCAF13 as ready
Mendeliome v1.962 RAB34 Elena Savva Marked gene: RAB34 as ready
Mendeliome v1.962 RAB34 Elena Savva Phenotypes for gene: RAB34 were changed from Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies to Multiple congenital anomalies, (MONDO:0019042), RAB34-related
Mendeliome v1.961 ARPC5 Paul De Fazio gene: ARPC5 was added
gene: ARPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARPC5 were set to 37349293; 37382373
Phenotypes for gene: ARPC5 were set to Combined immunodeficiency, ARPC5-related MONDO:0015131
Review for gene: ARPC5 was set to GREEN
gene: ARPC5 was marked as current diagnostic
Added comment: 4 individuals from 3 families reported with homozygous LoF variants. All had recurrent and severe infections. Other developmental anomalies were present but seemed variable.

PMID:37349293 reports 2 unrelated patients. Both had scoliosis. One had neurodevelopmental delay and brain atrophy. Patient 1 died at 15yo after a sudden episode of hemoptysis and hematochezia. Patient 2 died at 1yo because of progressive neurologic and respiratory disease; an autopsy was not performed.

PMID:37382373 reports 2 patients from the same family. One had multiple congenital anomalies including a congenital heart defect (CHD) (patent foramen ovale), cleft palate, and hypoplastic corpus callosum. The sibling also had CHD (moderate pulmonary stenosis and atrial septal defect).

Functional studies and a mouse model were supportive of the disease association.
Sources: Literature
Mendeliome v1.961 RPH3A Seb Lunke Marked gene: RPH3A as ready
Mendeliome v1.961 DRG1 Krithika Murali Marked gene: DRG1 as ready
Mendeliome v1.958 MIR204 Elena Savva Marked gene: MIR204 as ready
Mendeliome v1.958 DCAF13 Michelle Torres gene: DCAF13 was added
gene: DCAF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DCAF13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCAF13 were set to 36797467
Phenotypes for gene: DCAF13 were set to Neuromuscular disease (MONDO#0019056), DCAF13-related
Review for gene: DCAF13 was set to RED
Added comment: One consanguineous family, 4x individuals homozygous NM_015420.7(DCAF13)c.907 G > A; p.(Asp303Asn) (3x via WES and 1x via Sanger) with a neuromuscular disorder characterized by a waddling gait, limb deformities, muscular weakness and facial palsy.

In silicos analysis of mutant DCAF13 suggests that the amino acid change is deleterious and affects a ß-hairpin turn, within a WD40 domain of the protein which may decrease protein stability. Functional studies were not performed.

Previously, a heterozygous variant in DCAF13 with or without a heterozygous missense variant in CCN3, was suggested to cause inherited cortical myoclonic tremor with epilepsy. In addition, a heterozygous DCAF13 variant has been associated with autism spectrum disorder.
Sources: Literature
Mendeliome v1.958 ERI1 Elena Savva Marked gene: ERI1 as ready
Mendeliome v1.957 ERI1 Elena Savva gene: ERI1 was added
gene: ERI1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 37352860
Phenotypes for gene: ERI1 were set to Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related
Review for gene: ERI1 was set to GREEN
Added comment: PMID: 37352860 - 8 individuals from 7 unrelated families
- Patients with biallelic missense show a MORE severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly
- Patients with biallelic null/whole gene deletion had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly
- Patient chet for a missense and PTC variant has a blended phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, mild ID and failure to thrive

- Missense variants were functionally shown to not be able to rescue 5.8S rRNA processing in KO HeLa cells
- K/O mice had neonatal lethality with growth defects, brachydactyly. Skeletal-specific K/O had mild platyspondyly, had more in keeping with patients with null variants than missense

More severe phenotype hypothesised due to "exonuclease-dead proteins may compete for the target RNA molecules with other exonucleases that have functional redundancy
with ERI1, staying bound to those RNA molecules"
Sources: Literature
Mendeliome v1.956 RAB34 Sarah Pantaleo gene: RAB34 was added
gene: RAB34 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB34 were set to PMID: 37384395
Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies
Penetrance for gene: RAB34 were set to Complete
Review for gene: RAB34 was set to GREEN
Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS.

Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher).

Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects.

RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function.

Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands.

In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth.

All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities.

All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance.
Sources: Literature
Mendeliome v1.956 DRG1 Dean Phelan gene: DRG1 was added
gene: DRG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DRG1 were set to PMID: 37179472
Phenotypes for gene: DRG1 were set to Neurodevelopmental disorder (MONDO:0700092), DRG1-related
Review for gene: DRG1 was set to GREEN
Added comment: PMID: 37179472
- Biallelic variants were identified in four affected individuals from three distinct families with neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature and craniofacial anomalies. Functional studies show the variants result in a loss of function.
Sources: Literature
Mendeliome v1.956 RPH3A Lucy Spencer gene: RPH3A was added
gene: RPH3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPH3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPH3A were set to 37403762; 29441694
Phenotypes for gene: RPH3A were set to Neurodevelopmental disorder (MONDO#0700092), RPH3A-related
Review for gene: RPH3A was set to GREEN
Added comment: PMID: 37403762- 6 patients with RPH3A variant. All 6 have ID, 4 have epilepsy, 2 with obesity, 1 with dysmorphic features. All 6 have missense variants, 3 shown to be de novo, the other 3 parents were not available for testing. I patient also had language and motor impairment, breathing issues and mixed hypo/hypertonia- he also had variants in CUL4B, PRKAG2, SCN4A, none of these genes cause seizures (which he had).

Patch clamp studies on 2 of the missense showed they increased either the number of NMDA receptors on neuron membrane surface or increased their conductance. Study suggests that the variants interrupt the normal role of RPH3A activity at the synaptic NMDAR complex which is needed for the induction of synaptic plasticity and NMDAR-dependant behaviours

Previously this gene was reported in PMID: 29441694- 1 girl with learning disabilities, tremors, ataxia, hyperglycemia and muscle fatigability. Chet for 2 RPH3A missense. Functional analysis showed strong and marginal impairment of protein binding for each variant. this is the only biallelic report currently.
Sources: Literature
Mendeliome v1.956 MIR204 Chern Lim gene: MIR204 was added
gene: MIR204 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR204 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIR204 were set to 26056285; 37321975
Phenotypes for gene: MIR204 were set to Retinal dystrophy and iris coloboma with or without cataract (MIM#616722)
Mode of pathogenicity for gene: MIR204 was set to Other
Review for gene: MIR204 was set to GREEN
gene: MIR204 was marked as current diagnostic
Added comment: PMID: 26056285
- Bilateral coloboma and rod-cone dystrophy with or without cataract in nine individuals of a five-generation family.
- Heterozygous n.37C>T segregates with the disease in all affected individuals.
- Functional analysis including transcriptome analysis showed this variant resulted in significant alterations of miR-204 targeting capabilities. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family.
- Authors suggested gain of function is the likely disease mechanism.

PMID: 37321975
- Four members of a three-generation family with early-onset chorioretinal dystrophy, heterozygous for n.37C>T.
- Additionally, four family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants.
- Haplotype analysis excluded relatedness with the family reported in PMID: 26056285.
- In silico analysis of the MIR204 n.37C>T variant reveals profound changes to its target mRNAs and suggests a gain-of-function mechanism of miR 204 variant.
Sources: Literature
Mendeliome v1.950 INTS11 Zornitza Stark Phenotypes for gene: INTS11 were changed from intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, MIM# 620428
Mendeliome v1.948 NUP54 Zornitza Stark Phenotypes for gene: NUP54 were changed from Striatonigral degeneration, MONDO:0003122, NUP54-related; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia to Dystonia 37, early-onset, with striatal lesions, MIM# 620427; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Mendeliome v1.947 BRWD1 Zornitza Stark Phenotypes for gene: BRWD1 were changed from Asthenoteratozoospermia, likely primary ciliary dyskinesia to Ciliary dyskinesia, primary, 51, MIM# 620438
Mendeliome v1.946 SMARCB1 Achchuthan Shanmugasundram reviewed gene: SMARCB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: Coffin-Siris syndrome 3, OMIM:614608; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 ARID1A Achchuthan Shanmugasundram reviewed gene: ARID1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.946 ZC4H2 Achchuthan Shanmugasundram changed review comment from: There are ten unrelated patients reported with cleft palate. Hence, this gene should be added with green rating to 'clefting disorders' panel.

PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.; to: There are ten unrelated patients reported with cleft palate. Hence, this gene should be added with green rating to 'clefting disorders' panel.

PMID:31206972 - Of 42 families identified with de novo and inherited variants in ZC4H2 gene, eight patients had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.
Mendeliome v1.944 STAG2 Achchuthan Shanmugasundram reviewed gene: STAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28296084, 29263825, 30158690, 31334757, 33014403, 37010288; Phenotypes: Holoprosencephaly 13, X-linked, OMIM:301043, Mullegama-Klein-Martinez syndrome, OMIM:301022; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.944 SMARCA4 Achchuthan Shanmugasundram reviewed gene: SMARCA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25168959, 37010288; Phenotypes: Coffin-Siris syndrome 4, OMIM:614609; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.943 POGZ Achchuthan Shanmugasundram changed review comment from: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders panel'.

PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula.

PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula.

DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288).

The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome.; to: Although there are more than three unrelated cases reported with either cleft palate or bifid uvula in total, this phenotype is not consistently present in patients with monoallelic variants in POGZ gene. Hence, this gene should only be added with amber rating in 'Clefting disorders' panel.

PMID:26739615 - Five unrelated individuals were identified with de novo truncating variants in POGZ gene, of which one individual had cleft palate and another one had bifid uvula.

PMID:31782611 - In this cohort of 22 individuals with 21 different loss of function variants in POGZ, two patients were reported with bifid uvula.

DECIPHER database - Of 42 patients with heterozygous sequence variants, one had cleft palate and another one had bifid uvula (PMID:37010288).

The OMIM entry for White-Sutton syndrome (MIM #616364) does not currently include cleft lip/ palate as one of the clinical manifestations of this syndrome.
Mendeliome v1.943 SPTSSA Zornitza Stark Phenotypes for gene: SPTSSA were changed from complex hereditary spastic paraplegia, MONDO:0015150 to Spastic paraplegia 90B, autosomal recessive , MIM# 620417; Spastic paraplegia 90A, autosomal dominant, MIM# 620416
Mendeliome v1.942 SPTSSA Zornitza Stark reviewed gene: SPTSSA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 90B, autosomal recessive , MIM# 620417, Spastic paraplegia 90A, autosomal dominant, MIM# 620416; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram changed review comment from: There are at least three unrelated cases with monoallelic variants in ARID1B gene reported with either cleft palate, cleft uvula or bifid uvula. Hence, this gene can be added with green rating in the Clefting disorders panel.

PMID:30349098 - On this web-based survey based on previously reported features of patients with variants in ARID1B gene (143 patients in total), which also included submissions to DECIPHER database, two patients were identified with cleft palate, one with cleft uvula, two with bifid uvula and three with sub mucous cleft. Although variants identified in these patients are reported in this publication, there is no association of individual patients to phenotypes available.

One patient with ARID1B variant (c.3183_3184​insT/ p.Tyr1062LeufsTer10) was reported with submucous cleft soft palate and two patients with ARID1B variants (c.4155_4156​insA/ p.Asn1386LysfsTer18 & c.2620+5G​>A) were reported with bifid uvula in DECIPHER database.; to: Although there are more than three unrelated cases with ARID1B monoallelic variants reported with either cleft palate, cleft uvula or bifid uvula, clefting isn not consistently present in patients with ARID1B variants. Hence, this gene can be added with amber rating in the Clefting disorders panel.

PMID:30349098 - On this web-based survey based on previously reported features of patients with variants in ARID1B gene (143 patients in total), which also included submissions to DECIPHER database, two patients were identified with cleft palate, one with cleft uvula, two with bifid uvula and three with sub mucous cleft. Although variants identified in these patients are reported in this publication, there is no association of individual patients to phenotypes available.

Of >100 patients with ARID1B variants in the DECIPHER database, only one patient (c.3183_3184​insT/ p.Tyr1062LeufsTer10) was reported with submucous cleft soft palate and two patients (c.4155_4156​insA/ p.Asn1386LysfsTer18 & c.2620+5G​>A) were reported with bifid uvula.
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram edited their review of gene: ARID1B: Changed rating: AMBER
Mendeliome v1.941 CHD4 Achchuthan Shanmugasundram changed review comment from: This gene should be added to the Clefting disorders panel with a green rating as there are four unrelated cases presenting with either cleft palate and/or bifid uvula.

PMID:3138819 reported a patient with heterozygous variant (p.Gln715Ter) in CHD4 that had cleft palate and pierre robin. In addition, another patient identified with heterozygous variant p.Arg1127Gln was reported with bifid uvula.

In addition, DDD study reported two patients with likely pathogenic heterozygous variants who had cleft palate in addition to several other clinical presentations including global developmental delay (PMID:37010288); to: Although there are four unrelated cases presenting with either cleft palate and/or bifid uvula, this phenotype is not consistent among patients identified with monoallelic variants in CHD4 gene. Hence, this gene should be added to the Clefting disorders panel with amber rating.

PMID:31388190 reported 32 patients with heterozygous variants in CHD4 gene, of which one patient (p.Gln715Ter) had cleft palate and pierre robin. In addition, another patient identified with heterozygous variant p.Arg1127Gln was reported with bifid uvula.

In addition, 2 out of 10 patients with pathogenic/ likely pathogenic heterozygous variants from the DDD study were reported with cleft palate in addition to several other clinical presentations including global developmental delay (PMID:37010288).
Mendeliome v1.941 ARID1B Achchuthan Shanmugasundram reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30349098, 37010288; Phenotypes: Coffin-Siris syndrome 1, OMIM:135900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.939 KLHL9 Bryony Thompson Marked gene: KLHL9 as ready
Mendeliome v1.938 KLHL9 Bryony Thompson changed review comment from: A single German family reported in 2010, segregating a missense variant c.796T>C p.Leu95Phe. In vitro functional assays demonstrated the variant diminishes the binding of KLHL9 to Cul3.
Sources: Literature; to: A single German family reported in 2010, segregating a missense variant c.796T>C p.Leu95Phe. In vitro functional assays demonstrated the variant diminishes the binding of KLHL9 to Cul3.
Ankle flexion contracture is reported in a mouse model, but there are other significant features present in the homozygous animals too - https://www.mousephenotype.org/data/genes/MGI:2180122
Sources: Literature
Mendeliome v1.938 KLHL9 Bryony Thompson gene: KLHL9 was added
gene: KLHL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLHL9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL9 were set to 20554658
Phenotypes for gene: KLHL9 were set to distal myopathy MONDO:0018949
Review for gene: KLHL9 was set to AMBER
Added comment: A single German family reported in 2010, segregating a missense variant c.796T>C p.Leu95Phe. In vitro functional assays demonstrated the variant diminishes the binding of KLHL9 to Cul3.
Sources: Literature
Mendeliome v1.937 MYMX Bryony Thompson Marked gene: MYMX as ready
Mendeliome v1.936 MYMX Bryony Thompson gene: MYMX was added
gene: MYMX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYMX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYMX were set to 35642635
Phenotypes for gene: MYMX were set to Carey-Fineman-Ziter syndrome MONDO:0009700
Review for gene: MYMX was set to AMBER
Added comment: Single family, two siblings with weakness of the facial musculature, hypomimic face, increased overbite, micrognathia, and facial dysmorphism with homozygous p.Arg46*. The phenotype resembles CFZ syndrome. The variant prevents fusion of myoblasts from patient-derived iPSCs. Mouse model recapitulates a lethal CFZS-like phenotype.
Sources: Literature
Mendeliome v1.935 NOP10 Zornitza Stark Phenotypes for gene: NOP10 were changed from Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Telomere syndrome MONDO:0100137 to Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9, MIM# 620400
Mendeliome v1.932 NOP10 Zornitza Stark edited their review of gene: NOP10: Added comment: PMID 32139460: large multiplex family with 4 affected individuals segregating a heterozygous variant.; Changed rating: AMBER; Changed publications: 17507419, 32139460; Changed phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9, MIM# 620400; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.932 MFN2 Zornitza Stark Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM #609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM #617087; Hereditary motor and sensory neuropathy VIA, OMIM #601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A 609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, MIM# 617087; Hereditary motor and sensory neuropathy VIA, MIM# 601152; Lipomatosis, multiple symmetric, with or without peripheral neuropathy, MIM# 151800
Mendeliome v1.931 MFN2 Zornitza Stark edited their review of gene: MFN2: Changed phenotypes: Charcot-Marie-Tooth disease, axonal, type 2A2A 609260, Charcot-Marie-Tooth disease, axonal, type 2A2B, MIM# 617087, Hereditary motor and sensory neuropathy VIA, MIM# 601152, Lipomatosis, multiple symmetric, with or without peripheral neuropathy, MIM# 151800
Mendeliome v1.928 RHOBTB2 Zornitza Stark reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37165955; Phenotypes: Epileptic encephalopathy, early infantile, 64, MIM#618004; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.928 NFATC1 Zornitza Stark Marked gene: NFATC1 as ready
Mendeliome v1.927 NFATC1 Zornitza Stark gene: NFATC1 was added
gene: NFATC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFATC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC1 were set to 37249233
Phenotypes for gene: NFATC1 were set to Inborn error of immunity, MONDO:0003778, NFATC1-related; Combined Immune deficiency
Review for gene: NFATC1 was set to AMBER
Added comment: 3 individuals from a multigenerational consanguineous pedigree with early-onset sinopulmonary infections and bronchiectasis, recurrent viral (warts) and bacterial (folliculitis and abscesses) skin infections, hypogammaglobulinemia, lower CD4+/CD8+ T-cell ratio and lower recent thymic emigrants compared with the age-matched controls. Lymphocyte proliferation responses to PHA and CD3/CD28 stimulations were defective.

Single pedigree with supportive functional studies.
Sources: Literature
Mendeliome v1.922 CHRM5 Zornitza Stark Marked gene: CHRM5 as ready
Mendeliome v1.922 MRPL50 Zornitza Stark Marked gene: MRPL50 as ready
Mendeliome v1.921 MOS Zornitza Stark Marked gene: MOS as ready
Mendeliome v1.921 MOS Zornitza Stark Phenotypes for gene: MOS were changed from Early embryonic arrest and fragmentation; infertility to Infertility disorder, MONDO:0005047, MOS-related; Early embryonic arrest and fragmentation
Mendeliome v1.919 HMGCR Zornitza Stark Phenotypes for gene: HMGCR were changed from [Low density lipoprotein cholesterol level QTL 3] to autosomal recessive limb-girdle muscular dystrophy (MONDO: 0015152), HMGCR-related
Mendeliome v1.915 MOS Melanie Marty gene: MOS was added
gene: MOS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MOS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOS were set to PMID: 34779126; PMID: 34997960; PMID: 36403623; PMID: 35670744
Phenotypes for gene: MOS were set to Early embryonic arrest and fragmentation; infertility
Review for gene: MOS was set to GREEN
Added comment: PMID: 34779126: 3 x females with infertility with biallelic MOS variants identified. Using oocyte-specific Erk1/2 knockout mice, they verified that MOS-ERK signal pathway inactivation in oocytes caused early embryonic arrest and fragmentation.

PMID: 34997960: 2 x females with biallelic MOS variants. Functional studies showed a reduction of protein for two of these variants (missense and frameshift). Functional studies also showed these variants reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase 1/2.

PMID: 35670744 1 x additional family (twins) with infertility and abnormal oocyte morphology with large first polar body. Functional studies showed the MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, functional studies also showed when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1.

PMID: 36403623 1 x female with primary infertility, patient’s oocytes had a large polar body and poor embryonic development, hom missense variant in MOS identified.
Sources: Literature
Mendeliome v1.911 NSUN6 Elena Savva Marked gene: NSUN6 as ready
Mendeliome v1.911 TAPT1 Paul De Fazio reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36697720, 36652330; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.910 PRSS8 Elena Savva Marked gene: PRSS8 as ready
Mendeliome v1.908 PRSS8 Lucy Spencer gene: PRSS8 was added
gene: PRSS8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRSS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRSS8 were set to 36715754
Phenotypes for gene: PRSS8 were set to ichthyosis MONDO:0019269, PRSS8-related
Review for gene: PRSS8 was set to AMBER
Added comment: PMID: 36715754
1 family with 3 affected sons with congenital ichthyosis, consanguineous parents. All 3 affected members are homozygous for a canonical splice in PRSS8, quantitative RT-PCR showed a significant reduction in normal PRSS8 transcript.

A second family with 4 affected members (proband and 3 cousins) with ichthyosis (3 also had autism), also consanguineous. Only the proband was tested who is homozygous for a missense in PTSS8. However this patient also had a TAAR1 missense (no disease association, but the paper suggests this could be responsible for the autism phenotype- KO mice have abnormal learning behaviour).
Sources: Literature
Mendeliome v1.908 UNC79 Elena Savva Marked gene: UNC79 as ready
Mendeliome v1.906 NSUN6 Michelle Torres gene: NSUN6 was added
gene: NSUN6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NSUN6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSUN6 were set to 37226891
Phenotypes for gene: NSUN6 were set to neurodevelopmental disorder MONDO:0700092, NSUN6-related
Review for gene: NSUN6 was set to AMBER
Added comment: Three unrelated consanguineous families with developmental delay, intellectual disability, motor delay, and behavioral anomalies. WES detected homozygous variants:
- p.(Leu9Glufs*3): even though authors say is is predicted to cause NMD, it actually is NMD escape. No further studies were performed. A deceased affected sibling and parents were NOT tested.
- p.(Asp323Asn): Shown to result in a misfolded protein. Methylation assay showed mutant could not catalyze m5C deposition in transcribed tRNACys and tRNAThr substrates in vitro. One of the parents and both unaffected siblings were shown to be carriers.
- p.(Glu441Profs*15): truncation (full protein is 470aa) which would result in loss of residues involved in recognition and methylation. Shown to result in a misfolded protein. Parents were shown carriers.
Sources: Literature
Mendeliome v1.906 HMGCR Naomi Baker reviewed gene: HMGCR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37167966, 36745799; Phenotypes: autosomal recessive limb-girdle muscular dystrophy (MONDO: 0015152), HMGCR-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.906 UNC79 Krithika Murali gene: UNC79 was added
gene: UNC79 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC79 were set to PMID:37183800
Phenotypes for gene: UNC79 were set to Neurodevelopmental disorderMONDO:0700092
Review for gene: UNC79 was set to AMBER
Added comment: PMID:37183800 Bayat et al 2023 report 6 unrelated patients with heterozygous NMD-predicted LoF variants in UNC79 - x1 canonical splice site variant, x5 nonsense/frameshift. 5 were confirmed de novo, 1 not identified in mother - father unavailable for testing. All variants absent in gnomAD and v2 pLI score for UNC79 is 1.

Patients with UNC79 variants were identified through GeneMatcher or an international network of Epilepsy and Genetics departments. x1 patient underwent duo exome sequencing, remaining had trio exome sequencing - no other causative variants identified.

Phenotypic features included:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal to bilateral tonic-clonic seizures)
- 5/6 hypotonia

unc79 knockdown drosophila flies exhibited significantly higher rate of seizure-like behaviour than controls. unc79 haploinsufficiency shown to lead to significant reduction in protein levels of both unc79 and unc80 in mouse brains. Unc79 haploinsufficiency associated with deficiency in hippocampal-dependent learning and memory in mice.

Authors have reviewed their own evidence in relation to the gene-disease criteria detailed by Strande et al 2017 and note that their clinical and experimental data provides moderate-level evidence supporting the association between UNC79 and a neurodevelopment disorder including ASD.

Amber association favoured due to clinical phenotypic range reported between affected individuals and their lack of specificity.
Sources: Literature
Mendeliome v1.904 NPR1 Zornitza Stark Marked gene: NPR1 as ready
Mendeliome v1.903 MRPL50 Anna Ritchie gene: MRPL50 was added
gene: MRPL50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL50 were set to PMID: 37148394
Phenotypes for gene: MRPL50 were set to Mitochondrial disease, MONDO: 004470, MRPL50-related
Added comment: A homozygous missense variant (c.335T>A; p.Val112Asp) shared by twin sisters presenting with premature ovarian insufficiency, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction.
Quantitative proteomics data demonstrated a significant reduction in abundance of MRPL50 protein when compared with controls.
Patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. This data supports a biochemical phenotype associated with MRPL50 variants.
Knockdown/knockout of mRpL50 in Drosophila, resulted abnormal ovarian development.
Sources: Literature
Mendeliome v1.903 POU3F2 Ain Roesley Marked gene: POU3F2 as ready
Mendeliome v1.903 ACBD6 Elena Savva Marked gene: ACBD6 as ready
Mendeliome v1.903 ACBD6 Elena Savva Marked gene: ACBD6 as ready
Mendeliome v1.901 ACBD6 Elena Savva Marked gene: ACBD6 as ready
Mendeliome v1.898 NPR1 Lilian Downie gene: NPR1 was added
gene: NPR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPR1 were set to PMID: 37080586
Phenotypes for gene: NPR1 were set to Genetic hypertension MONDO:0015512
Review for gene: NPR1 was set to GREEN
Added comment: 4 sibs with systemic hypertension in the neonatal period - presenting with cardiogenic shock, with homozygous variants (consanguineous parents), parents confirmed heterozygotes. 3/4 infants had increased NT (>3.5) in utero
RT-PCR shows dramatic reduction of RNA levels
2 sibs in a second family, normal NT and pregnancy, neonatal systematic hypertension presenting with cardiogenic shock,
Sources: Literature
Mendeliome v1.898 POU3F2 Sarah Pantaleo gene: POU3F2 was added
gene: POU3F2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POU3F2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU3F2 were set to PMID: 37207645
Phenotypes for gene: POU3F2 were set to Autism spectrum disorder, NDD, and adolescent-onset obesity
Penetrance for gene: POU3F2 were set to unknown
Mode of pathogenicity for gene: POU3F2 was set to Other
Review for gene: POU3F2 was set to GREEN
Added comment: We associate ultra-rare variants in POU3F2, encoding a central nervous system transcription factor, with syndromic obesity and neurodevelopment delay in 12 individuals. Demonstrate variant pathogenicity through in vitro analysis. Used exome sequencing, GeneMatcher and Genomics England 100,000 Genomes Project rare disease database.

Both truncating and missense variants in over 10 individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity (may have had other features eg. CAKUT in 2 individuals, diabetes in two) . Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperplasia during childhood. With the exception of an early truncating variant, the variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promoter activation.

Variants absent from population and clinical databases. Almost all constituted putatively non-inherited de novo variants (8/10).

Functional studies provide evidence for loss of function in eight and gain of function in one obesity-associated POU3F2 variant. One variant did not impact POU3F2-promoter activation, leaving the possibility for further path-mechanisms.
Sources: Literature
Mendeliome v1.897 ACBD6 Lucy Spencer gene: ACBD6 was added
gene: ACBD6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 36457943; 21937992; 35446914
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder (MONDO#0700092), ACBD6-related
Review for gene: ACBD6 was set to GREEN
Added comment: PMID: 36457943
2 siblings with a neurodevelopmental disorder: severely delayed development, obesity, pancytopenia, diabetes, liver cirrhosis, intravertebral disc herniation, mild brain atrophy. Consanguineous family both siblings found to have a homozygous frameshift.

This paper also mentioned 3 other reported variants in 6 individuals (only 3 unrelated) all homozygous, 2 frameshift, 1 canonical splice. All reported to have a neurodevelopmental disorder, some with limited information but one family also has obesity, spasticity, and dysmorphism. PMIDs: 21937992, 35446914
Sources: Literature
Mendeliome v1.896 CHRM5 Elena Savva gene: CHRM5 was added
gene: CHRM5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHRM5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRM5 were set to 37213061
Phenotypes for gene: CHRM5 were set to Congenital anomaly of kidney and urinary tract, (MONDO:0019719), CHRM5-related
Review for gene: CHRM5 was set to RED
Added comment: PMID: 37213061
- homozygous missense p.(Q184R) in a proband with neurogenic bladder and CAKUT. Additional features were small trabeculated urinary bladder, bilateral severe hydronephrosis, grade V VUR right, chronic kidney disease (stage 4).
- Radioligand binding experiments were inconclusive - the missense variant had no effect on receptor expression or binding affinity.
- ACh binding assay did show a 2-fold increase (borderline significant), but no effect in secondary messenger accumulation.
- Transfected CHO line showed no effect on receptor expression
- Described a mouse K/O as having a bladder overactivity

No hom PTCs in gnomAD
Sources: Literature
Mendeliome v1.894 AMFR Zornitza Stark Marked gene: AMFR as ready
Mendeliome v1.894 AMFR Zornitza Stark Phenotypes for gene: AMFR were changed from Hereditary spastic paraplegia, MONDO:0019064 to Spastic paraplegia 89, autosomal recessive, MIM# 620379
Mendeliome v1.892 AMFR Zornitza Stark reviewed gene: AMFR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 89, autosomal recessive, MIM# 620379; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.891 ATP11A Zornitza Stark edited their review of gene: ATP11A: Added comment: PMID 35278131 reports three additional families with deafness, including segregation in a large pedigree.; Changed rating: GREEN; Changed publications: 35278131
Mendeliome v1.891 SCN4A Zornitza Stark Phenotypes for gene: SCN4A were changed from Hyperkalemic periodic paralysis, type 2, MIM# 170500; Hypokalemic periodic paralysis, type 2, MIM# 613345; Myasthenic syndrome, congenital, 16, MIM# 614198; Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390; Paramyotonia congenita , MIM#168300 to Congenital myopathy 22A, classic, MIM# 620351; Congenital myopathy 22B, severe fetal, MIM# 620369; Hyperkalemic periodic paralysis, type 2, MIM# 170500; Hypokalemic periodic paralysis, type 2, MIM# 613345; Myasthenic syndrome, congenital, 16, MIM# 614198; Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390; Paramyotonia congenita , MIM#168300
Mendeliome v1.890 SCN4A Zornitza Stark edited their review of gene: SCN4A: Changed phenotypes: Congenital myopathy 22A, classic, MIM# 620351, Congenital myopathy 22B, severe fetal, MIM# 620369, Hyperkalemic periodic paralysis, type 2, MIM# 170500, Hypokalemic periodic paralysis, type 2, MIM# 613345, Myasthenic syndrome, congenital, 16, MIM# 614198, Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390, Paramyotonia congenita , MIM#168300
Mendeliome v1.885 GIGYF2 Bryony Thompson reviewed gene: GIGYF2: Rating: RED; Mode of pathogenicity: None; Publications: 18358451, 33239198, 25279164, 20060621, 19250854, 26152800; Phenotypes: {Parkinson disease 11} , OMIM # 607688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.885 NDUFA13 Lucy Spencer reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.879 GATAD2A Bryony Thompson changed review comment from: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature; to: PMID: 37181331 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.879 NAF1 Zornitza Stark Phenotypes for gene: NAF1 were changed from Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148 to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365
Mendeliome v1.878 NAF1 Zornitza Stark reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.877 ARFGEF3 Ain Roesley reviewed gene: ARFGEF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.877 RRAGC Zornitza Stark Phenotypes for gene: RRAGC were changed from Dilated cardiomyopathy; cataract to Dilated cardiomyopathy (MONDO:0005021), RRAGC-related
Mendeliome v1.873 ATP5O Zornitza Stark Phenotypes for gene: ATP5O were changed from mitochondrial disease, ATP5F1E-related MONDO:0044970 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359
Mendeliome v1.870 ATP5O Zornitza Stark reviewed gene: ATP5O: Rating: GREEN; Mode of pathogenicity: None; Publications: 35621276; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.869 AMFR Yetong Chen gene: AMFR was added
gene: AMFR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMFR were set to 37119330
Phenotypes for gene: AMFR were set to Hereditary spastic paraplegia, MONDO:0019064
Review for gene: AMFR was set to GREEN
Added comment: PMID 37119330 reports 20 individuals harbouring AMFR variants from 8 unrelated, consanguineous families. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature
Mendeliome v1.868 POLD3 Bryony Thompson Marked gene: POLD3 as ready
Mendeliome v1.868 POLD3 Bryony Thompson gene: POLD3 was added
gene: POLD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLD3 were set to 37030525; 36395985; 27524497
Phenotypes for gene: POLD3 were set to Severe combined immunodeficiency MONDO:0015974
Review for gene: POLD3 was set to AMBER
Added comment: Homozygous missense variant (NM_006591.3; p.Ile10Thr) identified in a single Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency with neurodevelopmental delay and hearing loss. POLD3 as well as POLD1 and POLD2 expression was abolished in the patient's cells. Null mouse models are embryonic lethal and demonstrate Pold3 is essential for DNA replication in murine B cells.
Sources: Literature
Mendeliome v1.864 SLC4A2 Zornitza Stark Marked gene: SLC4A2 as ready
Mendeliome v1.863 SLC4A2 Zornitza Stark gene: SLC4A2 was added
gene: SLC4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A2 were set to 34668226; 20507629
Phenotypes for gene: SLC4A2 were set to Osteopetrosis, autosomal recessive 9, MIM# 620366
Review for gene: SLC4A2 was set to AMBER
Added comment: Single individual reported with homozygous missense variant. However, cattle and mouse models support gene-disease association.
Sources: Literature
Mendeliome v1.862 ZCCHC8 Bryony Thompson Phenotypes for gene: ZCCHC8 were changed from Pulmonary fibrosis to pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Mendeliome v1.861 ZCCHC8 Bryony Thompson edited their review of gene: ZCCHC8: Changed phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Mendeliome v1.858 ACD Bryony Thompson Phenotypes for gene: ACD were changed from Dyskeratosis congenita, MIM# 616553 to telomere syndrome MONDO:0100137; dyskeratosis congenita, autosomal dominant 6 MONDO:0014690; Hoyeraal-Hreidarsson syndrome MONDO:0018045
Mendeliome v1.855 ACD Bryony Thompson reviewed gene: ACD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807141, 31515401, 30995915, 27528712, 25205116, 24316971, 30064976, 33446513, 25233904; Phenotypes: telomere syndrome MONDO:0100137, dyskeratosis congenita, autosomal dominant 6 MONDO:0014690, Hoyeraal-Hreidarsson syndrome MONDO:0018045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.855 RRAGC Naomi Baker reviewed gene: RRAGC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:37057673, 27234373, 33057194; Phenotypes: Dilated cardiomyopathy (MONDO:0005021), RRAGC-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.855 MCAT Zornitza Stark reviewed gene: MCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.855 MCAT Zornitza Stark Phenotypes for gene: MCAT were changed from progressive autosomal recessive optic neuropathy to Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309
Mendeliome v1.854 DNAH7 Zornitza Stark Phenotypes for gene: DNAH7 were changed from non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related to Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related
Mendeliome v1.853 DNAH7 Zornitza Stark reviewed gene: DNAH7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.853 RARA Zornitza Stark commented on gene: RARA: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.
Mendeliome v1.853 RARA Zornitza Stark Phenotypes for gene: RARA were changed from Syndromic chorioretinal coloboma to Craniosynostosis - MONDO:0015469; Syndromic chorioretinal coloboma
Mendeliome v1.852 RARA Zornitza Stark Publications for gene: RARA were set to 31343737
Mendeliome v1.851 RARA Zornitza Stark Classified gene: RARA as Amber List (moderate evidence)
Mendeliome v1.851 RARA Zornitza Stark Gene: rara has been classified as Amber List (Moderate Evidence).
Mendeliome v1.850 RARA Zornitza Stark edited their review of gene: RARA: Added comment: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.; Changed rating: AMBER; Changed publications: 31343737, 37086723; Changed phenotypes: Craniosynostosis - MONDO:0015469, Syndromic chorioretinal coloboma; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.850 PMEPA1 Zornitza Stark Phenotypes for gene: PMEPA1 were changed from Familial thoracic aortic aneurysm disease (FTAAD); Loeys-Dietz syndrome to Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related
Mendeliome v1.849 PMEPA1 Zornitza Stark reviewed gene: PMEPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.849 NAF1 Bryony Thompson Marked gene: NAF1 as ready
Mendeliome v1.848 NAF1 Bryony Thompson gene: NAF1 was added
gene: NAF1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NAF1 were set to 27510903
Phenotypes for gene: NAF1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Review for gene: NAF1 was set to GREEN
Added comment: At least 3 probands/families with telomere-related pulmonary fibrosis and a supporting mouse model
PMID: 27510903 - 5 individuals from 2 unrelated families with pulmonary fibrosis-emphysema and extrapulmonary manifestations including myelodysplastic syndrome and liver disease, with LoF variants. Truncated NAF1 was detected in cells derived from patients, and, in cells in which a frameshift mutation was introduced by genome editing telomerase RNA levels were reduced. Shortened telomere length also segregated with the variants. A Naf1+/- mouse model had reduced telomerase RNA levels

ClinVar - 1 nonsense and 2 splice site variants (ID: 2443185, 1338525, 2443184) called LP by the Genetic Services Laboratory, University of Chicago but no clinical details were provided
- SCV002547372.1 - Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center - at least one individual with pulmonary fibrosis and leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Sources: Expert list
Mendeliome v1.847 PMEPA1 Hazel Phillimore changed review comment from: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature; to: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
(Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.).

Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Mendeliome v1.847 PMEPA1 Seb Lunke Marked gene: PMEPA1 as ready
Mendeliome v1.846 LHX2 Zornitza Stark Marked gene: LHX2 as ready
Mendeliome v1.845 CNOT9 Zornitza Stark Marked gene: CNOT9 as ready
Mendeliome v1.845 CBX1 Seb Lunke Marked gene: CBX1 as ready
Mendeliome v1.842 LHX2 Manny Jacobs gene: LHX2 was added
gene: LHX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LHX2 were set to PMID: 37057675
Phenotypes for gene: LHX2 were set to Neurodevelopmental disorder (MONDO: 0700092)
Review for gene: LHX2 was set to GREEN
Added comment: PMID: 37057675

Case series of 19 individuals across 18 families.
1 whole gene deletion, 7 missense, 10 predicted LoF variants.
Proposed loss-of-function mechanism.
Variable phenotype, with variable intellectual disability and behavioural (ASD/ADHD) features.
Microcephaly in 7 individuals.
1 variant inherited from a mildly affected parent, all other variants with parental genotype available shown to be de novo.
Sources: Literature
Mendeliome v1.842 DNAH7 Seb Lunke Marked gene: DNAH7 as ready
Mendeliome v1.841 PMEPA1 Hazel Phillimore gene: PMEPA1 was added
gene: PMEPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to PMID: 36928819
Phenotypes for gene: PMEPA1 were set to Familial thoracic aortic aneurysm disease (FTAAD); Loeys-Dietz syndrome
Mode of pathogenicity for gene: PMEPA1 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: PMEPA1 was set to AMBER
Added comment: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Mendeliome v1.841 GPR156 Zornitza Stark Marked gene: GPR156 as ready
Mendeliome v1.839 CBX1 Daniel Flanagan gene: CBX1 was added
gene: CBX1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBX1 were set to PMID: 37087635
Phenotypes for gene: CBX1 were set to Neurodevelopmental disorder (MONDO#0700092), CBX1-related
Review for gene: CBX1 was set to GREEN
Added comment: Three different de novo missense variants identified in three unrelated individuals with developmental delay, hypotonia, autistic features, and variable dysmorphic features such as broad forehead and head circumference above average. Mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Functional studies confirmed the reduction of mutant HP1β binding to heterochromatin.
Sources: Expert list
Mendeliome v1.838 SRSF1 Zornitza Stark Marked gene: SRSF1 as ready
Mendeliome v1.838 CNOT9 Karina Sandoval gene: CNOT9 was added
gene: CNOT9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CNOT9 were set to PMID: 37092538
Phenotypes for gene: CNOT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CNOT9 was set to GREEN
Added comment: 7 individuals with de novo variants. In silico predictions of functional relevance. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include.

Symptoms: Neuro dev disorder. ID, Epilepsy. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities.
Sources: Literature
Mendeliome v1.837 DNAH7 Chern Lim gene: DNAH7 was added
gene: DNAH7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH7 were set to 34476482; 35543642
Phenotypes for gene: DNAH7 were set to non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related
Review for gene: DNAH7 was set to GREEN
gene: DNAH7 was marked as current diagnostic
Added comment: PMID: 34476482 (Wei et al 2021):
- Hom/chet missense DNAH7 variants in three unrelated infertile patients with idiopathic asthenozoospermia, presented with primary ciliary dyskinesia (PCD)-associated symptoms.
- Functional studies showed expression of DNAH7 in the spermatozoa from the DNAH7-defective patients was significantly decreased.

PMID: 35543642 (Gao et al 2022):
- One proband with idiopathic asthenozoospermia, presented a history of PCD-like symptoms. Hom frameshift variant predicted to cause NMD, both parents are heterozygous.
- Immunofluorescent staining showed DNAH7 signal significantly decreased or was even completely absent in the sperm from the investigated patient.
Sources: Literature
Mendeliome v1.837 INTS11 Seb Lunke Marked gene: INTS11 as ready
Mendeliome v1.837 MRPL39 Lilian Downie changed review comment from: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature; to: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.836 INTS11 Melanie Marty changed review comment from: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.; to: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages.
Mendeliome v1.836 SRSF1 Paul De Fazio gene: SRSF1 was added
gene: SRSF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SRSF1 were set to 37071997
Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092
Review for gene: SRSF1 was set to GREEN
gene: SRSF1 was marked as current diagnostic
Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism.

Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS.

Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms.

Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17).
Sources: Literature
Mendeliome v1.835 SLC30A9 Zornitza Stark Marked gene: SLC30A9 as ready
Mendeliome v1.834 SLC30A9 Lucy Spencer gene: SLC30A9 was added
gene: SLC30A9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A9 were set to 37041080
Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome (MIM#617595)
Review for gene: SLC30A9 was set to GREEN
Added comment: PMID:37041080 - 2 families previously reported and this paper describes 4 more with biallelic SLC30A9 variants. Original 2 families: 6 affected members all hom for Ala350del, and 1 affected member chet for 2 frameshifts. 4 families from this paper: 2 families have the same homozygous missense (Gly418Val), family 3 has 4 affected sibs hom for Ala350del, family 4 1 affected chet for a frameshift and a synonymous. So 2 fams homs for Ala350del and 2 fams hom for Gly418Val.
All have Brik-Landau-Perez syndrome: all with ID, movement disorder and dystonia, and many with oculomotor apraxia, renal abnormalitie, ptosis, some had hearing impairment.
Sources: Literature
Mendeliome v1.834 GPR156 Anna Ritchie gene: GPR156 was added
gene: GPR156 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPR156 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPR156 were set to PMID: 36928819
Phenotypes for gene: GPR156 were set to Sensorineural hearing loss, MONDO:60700002, GPR156-related
Review for gene: GPR156 was set to GREEN
Added comment: Eight affected individuals from three unrelated families with congenital nonsyndromic bilateral sensorineural hearing loss. Homozygous or compound heterozygous loss of function variants were reported in these families.
Sources: Literature
Mendeliome v1.834 MRPL39 Lilian Downie changed review comment from: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000)
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature; to: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.834 MRPL39 Lilian Downie gene: MRPL39 was added
gene: MRPL39 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL39 were set to PMID: 37133451
Phenotypes for gene: MRPL39 were set to Leigh syndrome MONDO:0009723
Added comment: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000)
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.833 ERG Ain Roesley Phenotypes for gene: ERG were changed from to primary lymphoedema MONDO#0019175, ERG-related
Mendeliome v1.831 ERG Ain Roesley reviewed gene: ERG: Rating: GREEN; Mode of pathogenicity: None; Publications: 36928819; Phenotypes: primary lymphoedema MONDO#0019175, ERG-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.831 GATAD2A Bryony Thompson Marked gene: GATAD2A as ready
Mendeliome v1.830 GATAD2A Bryony Thompson gene: GATAD2A was added
gene: GATAD2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related
Review for gene: GATAD2A was set to GREEN
Added comment: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.828 KDM5A Zornitza Stark Marked gene: KDM5A as ready
Mendeliome v1.827 YWHAE Zornitza Stark Marked gene: YWHAE as ready
Mendeliome v1.826 YWHAE Zornitza Stark gene: YWHAE was added
gene: YWHAE was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: YWHAE.
Mode of inheritance for gene: YWHAE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAE were set to 36999555
Phenotypes for gene: YWHAE were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: YWHAE was set to GREEN
Added comment: PMID 36999555 reports 10 patients with YWHAE variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1) who have mild to severe intellectual disability. 3 individuals with SNVs. Mouse model supports gene-disease association.
Sources: Literature
Mendeliome v1.824 KPNA7 Zornitza Stark Phenotypes for gene: KPNA7 were changed from Epilepsy; intellectual disability to Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Neurodevelopmental disorder
Mendeliome v1.821 KPNA7 Zornitza Stark reviewed gene: KPNA7: Rating: AMBER; Mode of pathogenicity: None; Publications: 36647821; Phenotypes: Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.821 ACSL5 Zornitza Stark Phenotypes for gene: ACSL5 were changed from severe FTT (no OMIM #) to Diarrhoea 13, MIM# 620357
Mendeliome v1.819 INTS11 Achchuthan Shanmugasundram gene: INTS11 was added
gene: INTS11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to 37054711
Review for gene: INTS11 was set to GREEN
Added comment: Comment on gene rating: This gene should be rated GREEN in Intellectual disability panel as it has 10 unrelated cases and functional evidence in support of this association.

PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants.
Sources: Literature
Mendeliome v1.817 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Mendeliome v1.816 MED11 Zornitza Stark reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.816 MARS Zornitza Stark Phenotypes for gene: MARS were changed from Interstitial lung and liver disease, MIM#615486; Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Trichothiodystrophy 9, nonphotosensitive, MIM# 619692 to Interstitial lung and liver disease, MIM#615486; Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Trichothiodystrophy 9, nonphotosensitive, MIM# 619692; Spastic paraplegia 70, autosomal recessive, MIM# 620323
Mendeliome v1.815 MARS Zornitza Stark Publications for gene: MARS were set to 23729695; 24354524; 29655802; 24103465; 25913036; 33909043
Mendeliome v1.814 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Six individuals from two unrelated families reported with SPG.; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036, 24482476, 34585293; Changed phenotypes: Interstitial lung and liver disease, MIM#615486, Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280, Spastic paraplegia 70, autosomal recessive, MIM# 620323
Mendeliome v1.814 WARS Zornitza Stark Phenotypes for gene: WARS were changed from Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder (MONDO:0700092), WARS-related to Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities, MIM# 620317
Mendeliome v1.812 DNAJB4 Zornitza Stark Phenotypes for gene: DNAJB4 were changed from Congenital myopathy 21 with early respiratory failure, MIM# 620326 to Congenital myopathy 21 with early respiratory failure, MIM# 620326; distal myopathy MONDO:0018949
Mendeliome v1.809 DNAJB4 Zornitza Stark Phenotypes for gene: DNAJB4 were changed from Myopathy, MONDO:0005336, DNAJB4-related to Congenital myopathy 21 with early respiratory failure, MIM# 620326
Mendeliome v1.808 DNAJB4 Zornitza Stark reviewed gene: DNAJB4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 21 with early respiratory failure, MIM# 620326; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.807 KDM5A Achchuthan Shanmugasundram gene: KDM5A was added
gene: KDM5A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM5A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KDM5A were set to 21937992; 33350388
Phenotypes for gene: KDM5A were set to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Review for gene: KDM5A was set to GREEN
Added comment: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Sources: Literature
Mendeliome v1.807 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071 to Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.806 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.805 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies to Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071
Mendeliome v1.803 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Added comment: Association with ID: GREEN for bi-allelic variants:

PMID:28286008 reported a boy with compound heterozygous variants that was presented with developmental delay in 13 months and had severe intellectual disability and hyperactivity at nine years of age. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia.

PMID:30692597 reported a five year old boy identified with a homozygous ROBO1 variant who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus and characteristic facial features.

PMID:35227688 reported eight patients including the boy reported in PMID:30692597. Of the other seven patients, three were presented with intellectual disability. Of these three patients, two harboured compound heterozygous and one harboured homozygous variants.

PMID:35348658 reported a patient identified with monoallelic de novo variant (p.D422G) who presented with early-onset epileptic encephalopathy and had severe developmental delay.; Changed phenotypes: Congenital heart disease, Pituitary anomalies, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, intellectual disability, MONDO:0001071
Mendeliome v1.803 ROBO1 Zornitza Stark changed review comment from: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu.; to: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu. This association is RED.
Mendeliome v1.803 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Added comment: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu.; Changed publications: 28592524, 30530901, 30692597, 33270637, 28402530, 35348658; Changed phenotypes: Congenital heart disease, Pituitary anomalies, Nystagmus 8, congenital, autosomal recessive, MIM# 257400
Mendeliome v1.799 RYR3 Zornitza Stark Phenotypes for gene: RYR3 were changed from Nemaline myopathy; fetal akinesia; arthrogryposis to Congenital myopathy 20, MIM# 620310
Mendeliome v1.794 MAP3K3 Zornitza Stark Marked gene: MAP3K3 as ready
Mendeliome v1.793 MAP3K3 Zornitza Stark gene: MAP3K3 was added
gene: MAP3K3 was added to Mendeliome. Sources: Literature
somatic tags were added to gene: MAP3K3.
Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K3 were set to 33729480; 35355835; 33891857; 36995941; 10700190; 25728774
Phenotypes for gene: MAP3K3 were set to Cerebral malformation, MONDO:0016054, MAP3K3-related
Mode of pathogenicity for gene: MAP3K3 was set to Other
Review for gene: MAP3K3 was set to GREEN
Added comment: Recurrent somatic missense variant (p.I441M) identified in sporadic cases of cerebral and spinal cavernous malformation. Recent publication demonstrates that this missense variant can drive CCM formation (in vitro and in vivo studies).
Sources: Literature
Mendeliome v1.792 VWA8 Zornitza Stark Marked gene: VWA8 as ready
Mendeliome v1.791 MKL2 Zornitza Stark Marked gene: MKL2 as ready
Mendeliome v1.790 ACTC1 Zornitza Stark Marked gene: ACTC1 as ready
Mendeliome v1.789 ACTC1 Zornitza Stark reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.785 POLR1A Zornitza Stark commented on gene: POLR1A: Evidence for association of bi-allelic variants with leukodystrophy is moderate.
Mendeliome v1.785 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Mendeliome v1.785 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Mendeliome v1.782 BIN1 Bryony Thompson Added comment: Comment on mode of inheritance: ClinGen Definititive for semidominant for centronuclear myopathy by the Congenital myopathy GCEP - Classification - 04/27/2020
Mendeliome v1.781 VWA8 Dean Phelan gene: VWA8 was added
gene: VWA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VWA8 were set to PMID: 37012052
Phenotypes for gene: VWA8 were set to Retinitis pigmentosa (MONDO:0019200), VWA8-related
Review for gene: VWA8 was set to AMBER
Added comment: PMID: 37012052
- Single family with 11 affected patients, 9 - 87y, all presented initial symptoms of night blindness, visual field defects and reduced visual acuity later, macular changes, including macular degeneration and dystrophy. A heterozygous two-loci variant in VWA8 c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter) was identified and segregated with disease. Expression studies showed reduced protein expression. Zebrafish knockout model displayed an RP phenotype.
Sources: Literature
Mendeliome v1.781 MKL2 Dean Phelan gene: MKL2 was added
gene: MKL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID: 37013900
Phenotypes for gene: MKL2 were set to Neurodevelopmental disorder (MONDO:0700092), MKL2-related
Mode of pathogenicity for gene: MKL2 was set to Other
Review for gene: MKL2 was set to AMBER
Added comment: PMID: 37013900
- de novo missense variants in MKL2 (now known as MRTFB) were identified in two patients with mild dysmorphic features, intellectual disability, global developmental delay, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Sources: Literature
Mendeliome v1.781 RNH1 Seb Lunke Marked gene: RNH1 as ready
Mendeliome v1.780 ESAM Seb Lunke Marked gene: ESAM as ready
Mendeliome v1.777 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Mendeliome v1.776 CRIPT Karina Sandoval changed review comment from: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome, two new identified and 4 were already published. 5 were hom, 1 was chet, all with different variants. Additionally all presented with neuro dev delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom; to: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants.
All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom
Mendeliome v1.776 CEP162 Paul De Fazio gene: CEP162 was added
gene: CEP162 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP162 were set to 36862503
Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related
Penetrance for gene: CEP162 were set to unknown
Review for gene: CEP162 was set to AMBER
gene: CEP162 was marked as current diagnostic
Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior.

Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation.

Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients.

Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background).
Sources: Literature
Mendeliome v1.776 ACTC1 Lilian Downie gene: ACTC1 was added
gene: ACTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to PMID: 36945405
Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 MIM#612794; Cardiomyopathy, dilated, 1R MIM#613424; Cardiomyopathy, hypertrophic, 11 MIM#612098; ACTC1 related distal arthrogryposis MONDO:0019942
Review for gene: ACTC1 was set to GREEN
Added comment: ClinGen definitive association with HCM, moderate for DCM
5 new families (8 individuals) with a distral arthrogryposis phenotype (PMID: 36945405)
multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy
facial features: microretrognathia, ptosis, downslanting palpebral fissures, low-set ears, and a long nasal bridge
All missense variants
Sources: Literature
Mendeliome v1.776 DOCK11 Seb Lunke Marked gene: DOCK11 as ready
Mendeliome v1.775 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Mendeliome v1.775 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Mendeliome v1.774 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.774 DOCK11 Lucy Spencer gene: DOCK11 was added
gene: DOCK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related
Review for gene: DOCK11 was set to GREEN
Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls.

6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild.
Sources: Literature
Mendeliome v1.774 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Mendeliome v1.774 RNH1 Krithika Murali changed review comment from: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature; to: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis. No antenatal features reported.
Sources: Literature
Mendeliome v1.774 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.773 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.769 MB Elena Savva Marked gene: MB as ready
Mendeliome v1.769 MB Elena Savva gene: MB was added
gene: MB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MB were set to 35527200; 30918256
Phenotypes for gene: MB were set to Myopathy, sarcoplasmic body MIM#620286
Mode of pathogenicity for gene: MB was set to Other
Review for gene: MB was set to GREEN
Added comment: PMID: 30918256:
- Recurrent c.292C>T (p.His98Tyr) in fourteen members of six European families with AD progressive myopathy.
- Mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin.
- GOF hypothesised
- 2/3 of myoglobin knockout mice die in utero, 1/3 live to adulthood with little sign of functional effects, likely due to multiple compensatory mechanisms.

PMID: 35527200:
- single adult patient with myoglobinopathy
- same recurring p.His98Tyr variant
Sources: Literature
Mendeliome v1.768 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Mendeliome v1.765 NPPA Chern Lim changed review comment from: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has 195 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).; to: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has >200 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).
Mendeliome v1.763 PPCS Bryony Thompson reviewed gene: PPCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35616428, 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.763 PPCDC Bryony Thompson Marked gene: PPCDC as ready
Mendeliome v1.763 PPCDC Bryony Thompson gene: PPCDC was added
gene: PPCDC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPCDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPCDC were set to 36564894
Phenotypes for gene: PPCDC were set to dilated cardiomyopathy MONDO:0005021
Review for gene: PPCDC was set to RED
Added comment: Single family reported with two siblings with a fatal cardiac phenotype including dilated cardiomyopathy with biallelic variants p.Thr53Pro and p.Ala95Val. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant.
Sources: Literature
Mendeliome v1.762 ELOC Bryony Thompson Marked gene: ELOC as ready
Mendeliome v1.761 EPHA10 Bryony Thompson Marked gene: EPHA10 as ready
Mendeliome v1.760 RNF212B Bryony Thompson Marked gene: RNF212B as ready
Mendeliome v1.759 SLC25A36 Bryony Thompson Marked gene: SLC25A36 as ready
Mendeliome v1.757 NCAPG2 Zornitza Stark changed review comment from: Two families and functional evidence (zebrafish model).
Sources: Literature; to: Two families and functional evidence (zebrafish model). Rated as LIMITED by ClinGen; one of the families had a homozygous missense variant. Internal case identified by VCGS but dual diagnosis.
Sources: Literature
Mendeliome v1.757 NPPA Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.757 RNF212B Sangavi Sivagnanasundram gene: RNF212B was added
gene: RNF212B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: RNF212B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Phenotypes for gene: RNF212B were set to Infertility disorder, MONDO:0005047
Review for gene: RNF212B was set to AMBER
Added comment: Homozygous nonsense mutation (R150X) causative of oligoasthenotheratozoospermia (OAT) identified in three unrelated individuals (two of Jewish decent from the same consanguineous family).

Drosophila ZIP3/RNF212 related gene paralogs (vilya, narya, nenya) showed loss of function in the RNF212B protein and promoted formation of DNA double-stand breaks. The mutant was shown to result in a reduction in fertility in the Drosophila paralogs.

Note: RNF212B is reported to be exclusively expressed in the testes only compared to RNF212 which is reported in both the testes and ovaries.
Sources: Other
Mendeliome v1.756 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammatory syndrome, MONDO:0019751, HCK-related to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Mendeliome v1.755 HCK Zornitza Stark edited their review of gene: HCK: Changed phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Mendeliome v1.755 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related to Möbius syndrome, MONDO:0008006; Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.754 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.753 PRDM10 Zornitza Stark Marked gene: PRDM10 as ready
Mendeliome v1.752 PRDM10 Achchuthan Shanmugasundram gene: PRDM10 was added
gene: PRDM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRDM10 were set to 36440963
Phenotypes for gene: PRDM10 were set to Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086
Review for gene: PRDM10 was set to RED
Added comment: PMID:36440963 reported a family presenting with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with Birt-Hogg-Dubé syndrome (BHD, MIM #135150) based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. A heterozygous missense variant (p.Cys677Tyr) was identified, which co-segregated with the phenotype in the family.

Functional studies show that Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.752 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Mendeliome v1.748 STX4 Zornitza Stark Phenotypes for gene: STX4 were changed from to Non-syndromic genetic hearing loss, MONDO:0019497, STX4-related.
Mendeliome v1.744 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862
Mendeliome v1.743 STX4 Achchuthan Shanmugasundram reviewed gene: STX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36355422; Phenotypes: Hearing impairment, HP:0000365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram edited their review of gene: ARF1: Changed publications: 36345169
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram reviewed gene: ARF1: Rating: ; Mode of pathogenicity: None; Publications: 3634516; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.743 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Mendeliome v1.743 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
Mendeliome v1.742 RNPC3 Zornitza Stark Phenotypes for gene: RNPC3 were changed from Growth hormone deficiency; Intellectual disability to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Mendeliome v1.741 RNPC3 Zornitza Stark edited their review of gene: RNPC3: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Mendeliome v1.738 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from Currarino syndrome, MIM# 176450 to Currarino syndrome, MIM# 176450; Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Mendeliome v1.736 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Mendeliome v1.735 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.
Sources: Expert Review
Mendeliome v1.734 HECTD4 Zornitza Stark Marked gene: HECTD4 as ready
Mendeliome v1.734 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.733 HECTD4 Zornitza Stark reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.732 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v1.731 SPTLC1 Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Juvenile amyotrophic lateral sclerosis-27, MIM#620285, Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v1.727 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Mendeliome v1.727 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Mendeliome v1.722 TLN1 Zornitza Stark Phenotypes for gene: TLN1 were changed from idiopathic spontaneous coronary artery dissection MONDO:0007385 to idiopathic spontaneous coronary artery dissection MONDO:0007385; thrombocytopenia, MONDO:0002049, TLN1-related
Mendeliome v1.720 DPYSL2 Zornitza Stark Marked gene: DPYSL2 as ready
Mendeliome v1.719 DPYSL2 Zornitza Stark gene: DPYSL2 was added
gene: DPYSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071, DPYSL2-related
Review for gene: DPYSL2 was set to AMBER
Added comment: Two unrelated cases with monoallelic variants in DPYSL2/ CRMP2, supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature
Mendeliome v1.718 RBSN Zornitza Stark Marked gene: RBSN as ready
Mendeliome v1.717 RBSN Zornitza Stark gene: RBSN was added
gene: RBSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071, RBSN-related
Review for gene: RBSN was set to GREEN
Added comment: Four unrelated families reported, consistent feature is ID.

PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.
Sources: Literature
Mendeliome v1.716 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Mendeliome v1.715 SRPRA Zornitza Stark gene: SRPRA was added
gene: SRPRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to 36223592
Phenotypes for gene: SRPRA were set to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Review for gene: SRPRA was set to AMBER
Added comment: De novo variant; zebrafish model. Schwachman-Diamond like.
Sources: Literature
Mendeliome v1.714 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature; to: PMID 36860166: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature; to: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. Particularly, Eph overexpressed flies had a poorer performance compared to controls in negative geotaxis assay. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.; to: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.

This gene has not yet been associated with hearing loss either in OMIM or in Gene2Phenotype.
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram reviewed gene: OXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36130215; Phenotypes: sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram gene: EPHA10 was added
gene: EPHA10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPHA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA10 were set to 36048850
Phenotypes for gene: EPHA10 were set to postlingual non-syndromic genetic hearing loss, MONDO:0016298
Mode of pathogenicity for gene: EPHA10 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: EPHA10 was set to RED
Added comment: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Mendeliome v1.708 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Added comment: Fourth family reported in PMID 36847845 with hypotonia and paroxysmal dyskinesia.; Changed publications: 34542157, 29178645, 36847845
Mendeliome v1.708 YWHAZ Zornitza Stark Marked gene: YWHAZ as ready
Mendeliome v1.708 YWHAZ Zornitza Stark gene: YWHAZ was added
gene: YWHAZ was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members. In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
Mendeliome v1.706 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome to Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related
Mendeliome v1.703 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart disease, MONDO:0005453, PLXND1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.703 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
Mendeliome v1.703 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Literature
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram edited their review of gene: PLXND1: Changed phenotypes: Truncus arteriosus, HP:0001660
Mendeliome v1.702 KIF5B Achchuthan Shanmugasundram reviewed gene: KIF5B: Rating: ; Mode of pathogenicity: None; Publications: 36018820; Phenotypes: dilated cardiomyopathy, MONDO:0005021, ophthalmoplegia, MONDO:0003425, myopathy, MONDO:0005336, Hypotonia, HP:0001252, Seizure, HP:0001250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.702 CYB561 Zornitza Stark Marked gene: CYB561 as ready
Mendeliome v1.701 CYB561 Zornitza Stark gene: CYB561 was added
gene: CYB561 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB561 were set to 29343526; 31822578
Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182
Review for gene: CYB561 was set to GREEN
Added comment: Three families reported.

Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood.

Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa)
Sources: Expert Review
Mendeliome v1.699 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Mendeliome v1.698 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Mendeliome v1.698 TEFM Zornitza Stark Marked gene: TEFM as ready
Mendeliome v1.697 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Mendeliome v1.695 TEFM Ee Ming Wong gene: TEFM was added
gene: TEFM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related
Review for gene: TEFM was set to GREEN
gene: TEFM was marked as current diagnostic
Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families
- Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts
- TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function
Sources: Literature
Mendeliome v1.691 HMGB1 Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093
4 new families with de novo protein truncating variants.

In addition with PMID 34159400 ( all de novos)

c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family
c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Set current diagnostic: yes
Mendeliome v1.689 LGR4 Elena Savva changed review comment from: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; to: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).
Mendeliome v1.689 LGR4 Elena Savva edited their review of gene: LGR4: Added comment: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; Changed publications: PMID: 32493844, 36538378; Changed phenotypes: {Bone mineral density, low, susceptibility to} MIM#615311; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.689 USMG5 Bryony Thompson Marked gene: USMG5 as ready
Mendeliome v1.688 USMG5 Bryony Thompson gene: USMG5 was added
gene: USMG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 29917077; 30240627
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6 MIM#618683
Review for gene: USMG5 was set to AMBER
Added comment: A homozygous splice site mutation in 4 patients from 3 unrelated families of Ashkenazi Jewish descent. Experimental analyses demonstrated that the splice variant leads to loss of protein expression and haplotype analysis suggested a founder effect. In situ cryo-ET analysis of the mitochondria of a homozygous affected case showed profound disturbances of mitochondrial crista ultrastructure.
Sources: Literature
Mendeliome v1.686 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Mendeliome v1.684 ELOC Achchuthan Shanmugasundram gene: ELOC was added
gene: ELOC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELOC was set to Unknown
Publications for gene: ELOC were set to 35323939
Phenotypes for gene: ELOC were set to von Hippel-Lindau disease, MONDO:0008667; renal cell carcinoma, MONDO:0005086; retinal hemangioblastoma, MONDO:0003343
Review for gene: ELOC was set to RED
Added comment: Comment on gene classification: This gene should be rated red as there is only one case with germline variant found so far.

A female patient was identified with a germline de novo missense variant in ELOC gene (c.236A>G/ p.Tyr79Cys) and satisfied the clinical diagnostic criteria for von Hippel-Lindau (VHL) disease. The patient had left retinal haemangioblastomas, renal cell carcinomas, cyst of the right kidney, spinal haemangioblastoma, a haemangioblastoma at the cervicomedullary junction and Henoch-Schonlein purpura (PMID:35323939).

This is the only germline variant detected in ELOC gene and was associated with VHL so far. However, ~20 somatic ELOC variants have been reported to be associated with renal cell carcinomas so far.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.684 ATG4D Suliman Khan gene: ATG4D was added
gene: ATG4D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to PMID: 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder; Abnormal facial shape
Penetrance for gene: ATG4D were set to unknown
Review for gene: ATG4D was set to GREEN
Added comment: PMID: 36765070 reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment with a similar facial gestalt comprising almond-shaped eyes, depressed nasal bridge, and a prominent Cupid’s bow with variable disease severity and progression. NGS analysis revealed bi-allelic loss-of-function variants in ATG4D gene. Based on the clinical, bioinformatic, and functional data, the author concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.684 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224 to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224; Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.682 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Added comment: Publications 25090642; 33484482: Single multi-generational family reported with a missense variant in this gene and cataract. Mouse model of same variant supports association. Amber for this association.; Changed publications: 31278393, 25090642, 33484482; Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224, Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.680 PPM1K Zornitza Stark edited their review of gene: PPM1K: Added comment: PMID: 36706222 reported a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K; Changed rating: AMBER; Changed publications: 23086801, 36706222
Mendeliome v1.680 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.679 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194; 36450800
Mendeliome v1.678 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: 36178483; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.678 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Mendeliome v1.678 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Mendeliome v1.677 EFCAB1 Zornitza Stark reviewed gene: EFCAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.677 CST6 Zornitza Stark Marked gene: CST6 as ready
Mendeliome v1.671 WNT11 Zornitza Stark Marked gene: WNT11 as ready
Mendeliome v1.668 MRPS7 Zornitza Stark edited their review of gene: MRPS7: Added comment: Now second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants.; Changed rating: AMBER; Changed publications: 25556185, 36421788
Mendeliome v1.668 STAT6 Zornitza Stark Marked gene: STAT6 as ready
Mendeliome v1.667 STAT6 Zornitza Stark gene: STAT6 was added
gene: STAT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT6 were set to 36216080; 36758835
Phenotypes for gene: STAT6 were set to Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies
Review for gene: STAT6 was set to GREEN
Added comment: Two families reported with GoF variants and extensive functional data.
Sources: Literature
Mendeliome v1.666 LTV1 Zornitza Stark Marked gene: LTV1 as ready
Mendeliome v1.665 LTV1 Achchuthan Shanmugasundram gene: LTV1 was added
gene: LTV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LTV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTV1 were set to 34999892
Phenotypes for gene: LTV1 were set to Inflammatory poikiloderma with hair abnormalities and acral keratoses, OMIM:620199
Review for gene: LTV1 was set to AMBER
Added comment: Comment on classification of gene: This gene should be rated amber as it has been implicated in inflammatory poikiloderma with hair abnormalities and acral keratoses as identified from two unrelated families harbouring the same biallelic variant and supported by functional studies.

PMID:34999892 reported four UK women of South Asian origin (three Pakistani sisters and an unrelated Indian woman) identified with homozygous variant c.503A>G, (p.Asn168Ser) and presented with poikiloderma, hair abnormalities, and acral keratoses, which the authors named as inflammatory poikiloderma with hair abnormalities and acral keratoses (IPHAK).

Both in silico modelling and splicing assays from a patient sample showed that this variant is responsible for splicing defects and defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm in yeast.

This gene has already been associated with relevant phenotype (MIM #620199) in OMIM, but not in Gene2Phenotype.
Sources: Literature
Mendeliome v1.665 WNT11 Achchuthan Shanmugasundram gene: WNT11 was added
gene: WNT11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WNT11 were set to 34875064
Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures
Review for gene: WNT11 was set to GREEN
Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene.

Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures.

A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures.

A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met).

This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells.

This gene has not yet been reported with any phenotypes either in OMIM or in G2P.
Sources: Literature
Mendeliome v1.663 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Mendeliome v1.656 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Mendeliome v1.654 KBTBD13 Bryony Thompson reviewed gene: KBTBD13: Rating: AMBER; Mode of pathogenicity: None; Publications: 36335629; Phenotypes: Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.654 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Hypertrophic cardiomyopathy to Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MIM# 620236
Mendeliome v1.653 ASNA1 Zornitza Stark Marked gene: ASNA1 as ready
Mendeliome v1.651 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Mendeliome v1.651 RRAGD Zornitza Stark Phenotypes for gene: RRAGD were changed from Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Mendeliome v1.650 PMEL Zornitza Stark Marked gene: PMEL as ready
Mendeliome v1.649 ASNA1 Naomi Baker gene: ASNA1 was added
gene: ASNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to 31461301; 16797549
Phenotypes for gene: ASNA1 were set to Dilated cardiomyopathy, MONDO:0001644, ASNA1-related
Review for gene: ASNA1 was set to RED
Added comment: Two siblings reported with biallelic variants - there were two variants on the paternal allele (c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*)) and one variant on the maternal allele (c.488T>C p.(Val163Ala)). Unaffected sibling was heterozygous for maternal allele. Western blotting demonstrated reduced protein expression. Knockout of asna1 in zebrafish mode resulted in cardiac defects and early lethality. The Asna1 knockout mice displayed early embryonic lethality, consistent with a role of Asna1 in early embryonic development.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore gene: RRAGD was added
gene: RRAGD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to PMID: 34607910
Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100; 36207673
Phenotypes for gene: PMEL were set to Oculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.

Some evidence that polymorphisms in this gene influence pigmentation in cattle.
Sources: Literature
Mendeliome v1.649 SPTSSA Seb Lunke Marked gene: SPTSSA as ready
Mendeliome v1.649 SPTSSA Seb Lunke Added comment: Comment on list classification: Three individuals but only two variants with different inheritance. Amber despite functional data.
Mendeliome v1.648 SPTSSA Seb Lunke gene: SPTSSA was added
gene: SPTSSA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to complex hereditary spastic paraplegia, MONDO:0015150
Review for gene: SPTSSA was set to AMBER
Added comment: Three unrelated individuals with common neurological features of developmental delay, progressive motor impairment, progressive lower extremity spasticity, and epileptiform activity or seizures. Other additional features varied.

Two of the individuals had the same de-novo missense, Thr51Ile, while the third was homozygous for a late truncating variant, Gln58AlafsTer10. The patient with the hom variant was described as less severe.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in flies, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA.

The de-novo missense were shown to impact regulation more than the hom truncation, while the truncated region was shown to previously to be important for ORMDL regulation.

Mice with a hom KO of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Mendeliome v1.647 MIR145 Zornitza Stark Marked gene: MIR145 as ready
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Marked gene: TRU-TCA1-1 as ready
Mendeliome v1.642 CAMLG Seb Lunke Marked gene: CAMLG as ready
Mendeliome v1.636 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Mendeliome v1.635 MIR145 Lucy Spencer gene: MIR145 was added
gene: MIR145 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR145 were set to 36649075
Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related
Review for gene: MIR145 was set to RED
Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p.

Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts.
Sources: Literature
Mendeliome v1.632 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to PMID: 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Mendeliome v1.630 HTR2C Zornitza Stark Marked gene: HTR2C as ready
Mendeliome v1.630 TRU-TCA1-1 Paul De Fazio gene: TRU-TCA1-1 was added
gene: TRU-TCA1-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927
Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425
Review for gene: TRU-TCA1-1 was set to AMBER
gene: TRU-TCA1-1 was marked as current diagnostic
Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA.

PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy.
Sources: Literature
Mendeliome v1.629 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Mendeliome v1.628 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Mendeliome v1.628 THBS1 Zornitza Stark Marked gene: THBS1 as ready
Mendeliome v1.627 OGDH Sarah Pantaleo reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, MIM# 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.627 NPTX1 Ain Roesley Marked gene: NPTX1 as ready
Mendeliome v1.626 THBS1 Zornitza Stark gene: THBS1 was added
gene: THBS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS1 were set to 36453543
Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related
Review for gene: THBS1 was set to GREEN
Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma.

Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure.
Sources: Literature
Mendeliome v1.625 NPTX1 Ain Roesley gene: NPTX1 was added
gene: NPTX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related
Review for gene: NPTX1 was set to GREEN
gene: NPTX1 was marked as current diagnostic
Added comment: PMID:34788392
5 families with multigenerational segregations - late onset ataxia
4 families with p.(Gly389Arg) + 1x p.(Glu327Gly)
functional studies done

Note: case report of a family member published elsewhere (PMID:35288776)

PMID:35285082
1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome
p.(Arg143Leu)

PMID:35560436
1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy
p.(Gln370Arg)
Sources: Literature
Mendeliome v1.624 GET4 Elena Savva Marked gene: GET4 as ready
Mendeliome v1.623 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Mendeliome v1.621 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.620 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.619 SARS Zornitza Stark Phenotypes for gene: SARS were changed from neurodevelopmental disorder MONDO#070009, SARS1-related to neurodevelopmental disorder MONDO#070009, SARS1-related; Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.618 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048; 36041817
Mendeliome v1.617 SARS Zornitza Stark Mode of inheritance for gene: SARS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.616 DRC1 Zornitza Stark Phenotypes for gene: DRC1 were changed from Ciliary dyskinesia, primary, 21, MIM# 615294; Male infertility to Ciliary dyskinesia, primary, 21, MIM# 615294; Spermatogenic failure 80, MIM# 620222
Mendeliome v1.615 DRC1 Zornitza Stark edited their review of gene: DRC1: Changed phenotypes: Ciliary dyskinesia, primary, 21, MIM# 615294, Spermatogenic failure 80, MIM# 620222
Mendeliome v1.614 LY96 Zornitza Stark Marked gene: LY96 as ready
Mendeliome v1.614 LY96 Zornitza Stark gene: LY96 was added
gene: LY96 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to 36462957
Phenotypes for gene: LY96 were set to Inborn error of immunity, MONDO:0003778, LY96-related
Review for gene: LY96 was set to RED
Added comment: Single individual with infantile colitis associated with failure-to-thrive, bloody diarrhoea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Found to have homozygous inflame deletion. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation.
Sources: Expert Review
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986
Mendeliome v1.611 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Mendeliome v1.610 ZNF668 Zornitza Stark reviewed gene: ZNF668: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.608 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Mendeliome v1.607 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Mendeliome v1.606 SLC26A6 Zornitza Stark Marked gene: SLC26A6 as ready
Mendeliome v1.606 SLC26A6 Zornitza Stark Phenotypes for gene: SLC26A6 were changed from Enteric hyperoxaluria and nephrolithiasis to Primary hyperoxaluria, MONDO:0002474, SLC26A6-related
Mendeliome v1.604 SLC26A6 Zornitza Stark reviewed gene: SLC26A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary hyperoxaluria, MONDO:0002474, SLC26A6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.604 TRPC5 Zornitza Stark Marked gene: TRPC5 as ready
Mendeliome v1.601 TRPC5 Hazel Phillimore gene: TRPC5 was added
gene: TRPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.601 ZMYM3 Zornitza Stark Marked gene: ZMYM3 as ready
Mendeliome v1.601 BSN Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature; to: Ye et al 2022, Neurogenetics - https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865
Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Mendeliome v1.597 BSN Zornitza Stark Marked gene: BSN as ready
Mendeliome v1.597 BSN Zornitza Stark Added comment: Comment when marking as ready: We are aware of additional mono-allelic cases.
Mendeliome v1.595 UHRF1 Chern Lim changed review comment from: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense.; to: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense. Her cotwin was clinically and epigenetically normal
Mendeliome v1.595 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092 to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.594 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194
Mendeliome v1.593 ARHGEF38 Zornitza Stark Marked gene: ARHGEF38 as ready
Mendeliome v1.593 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022
- One patient with compound het missense and nonsense variants, both parents are carriers (hets).
- The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical.
- Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes.
- Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.593 ARHGEF38 Zornitza Stark Mode of inheritance for gene: ARHGEF38 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.592 ARHGEF38 Zornitza Stark Classified gene: ARHGEF38 as Amber List (moderate evidence)
Mendeliome v1.592 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.591 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Mendeliome v1.590 ARHGAP35 Dean Phelan reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36450800; Phenotypes: Developmental defect of the eye (MONDO:0020145), ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.589 ARHGEF38 Paul De Fazio gene: ARHGEF38 was added
gene: ARHGEF38 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGEF38 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARHGEF38 were set to 36493769
Phenotypes for gene: ARHGEF38 were set to Cleft lip/palate MONDO:0016044, ARHGEF38-related
Review for gene: ARHGEF38 was set to AMBER
gene: ARHGEF38 was marked as current diagnostic
Added comment: PMID:36493769 identified an intragenic deletion by high-res microarray of the same exon (exon 3) in 4 individuals with non-syndromic cleft lip/palate. Deletion of exon 3 is present in 6 individuals in gnomAD. Inheritance information was not available.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.589 COBLL1 Zornitza Stark Marked gene: COBLL1 as ready
Mendeliome v1.588 COBLL1 Paul De Fazio gene: COBLL1 was added
gene: COBLL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COBLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COBLL1 were set to 36493769
Phenotypes for gene: COBLL1 were set to Cleft lip/palate MONDO:0016044, COBLL1-related
gene: COBLL1 was marked as current diagnostic
Added comment: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father. Note that the gene is not quite LOF constrained in gnomAD.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.588 BSN Krithika Murali gene: BSN was added
gene: BSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BSN were set to Epilepsy MONDO:0005027
Review for gene: BSN was set to GREEN
Added comment: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Mendeliome v1.588 EIF4A2 Dean Phelan gene: EIF4A2 was added
gene: EIF4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to PMID: 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related
Mode of pathogenicity for gene: EIF4A2 was set to Other
Review for gene: EIF4A2 was set to GREEN
Added comment: PMID: 36528028
- EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms.
Sources: Literature
Mendeliome v1.588 PHLDB1 Seb Lunke Marked gene: PHLDB1 as ready
Mendeliome v1.587 PHLDB1 Seb Lunke gene: PHLDB1 was added
gene: PHLDB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PHLDB1 were set to 36543534
Phenotypes for gene: PHLDB1 were set to osteogenesis imperfecta, MONDO:0019019
Review for gene: PHLDB1 was set to AMBER
Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment.

Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided.
Sources: Literature
Mendeliome v1.586 OXGR1 Zornitza Stark Marked gene: OXGR1 as ready
Mendeliome v1.583 OXGR1 Sarah Pantaleo gene: OXGR1 was added
gene: OXGR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OXGR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OXGR1 were set to PMID:35671463
Phenotypes for gene: OXGR1 were set to Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related
Penetrance for gene: OXGR1 were set to unknown
Review for gene: OXGR1 was set to AMBER
Added comment: Candidate disease gene for human calcium oxalate nephrolithiasis.

Performed exome sequencing and directed sequencing of the OXGR1 locus in a worldwide nephrolithiasis/nephrocalcinosis (NL/NC) cohort, and putatively deleterious rare OXGR1 variants were functionally characterised.

A heterozygous OXGR1 missense variant (c.371T>G; p.Leu124Arg) co-segregated with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals.

Interrogation of the OXGR1 locus in 1,107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls. Four missense variants and one frameshift variant.

Four of five NL/NC-associated missense variants revealed impaired AKG-dependent calcium ion uptake, demonstrating loss of function.

Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Six potentially deleterious variants were identified in six of 1,108 NL/NC families (0.54%).

Limitations: only probands were able to be recruited for four of six families. In the future, it will be important to determine whether any of the affected family members share the identified OXGR1 variant. They also observe OXGR1 variants in 0.16% of ExAC subjects (selected on the basis of the absence of paediatric disease).
Sources: Literature
Mendeliome v1.582 CCIN Seb Lunke Marked gene: CCIN as ready
Mendeliome v1.580 CCIN Chern Lim gene: CCIN was added
gene: CCIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCIN were set to 36546111; 36527329
Phenotypes for gene: CCIN were set to Teratozoospermia
Review for gene: CCIN was set to GREEN
gene: CCIN was marked as current diagnostic
Added comment: Two papers with three unrelated patients with teratozoospermia:

PMID: 36546111
- Two families reported: One with homozygous missense (fam is consanguineous) and another with compound heterozygous missense + nonsense variants, patients suffering from teratozoospermia.
- Homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* knock-in mice generated. Spermatozoa from homozygous male mice exhibited abnormalities of sperm head shape revealed by Diff-Quick staining. When mated with WT mice, both homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* male mice were infertile, whereas the mutant female mice could generate offspring and displayed no defects in fertility.

PMID: 36527329
- One consanguineous family reported: homozygous missense, with asthenoteratozoospermia.
- Transfected HEK cells showed reduced CCIN protein level.
Sources: Literature
Mendeliome v1.580 TRA2B Seb Lunke Marked gene: TRA2B as ready
Mendeliome v1.576 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Mendeliome v1.574 TUFT1 Zornitza Stark Marked gene: TUFT1 as ready
Mendeliome v1.573 TUFT1 Zornitza Stark gene: TUFT1 was added
gene: TUFT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUFT1 were set to https://doi.org/10.1093/bjd/ljac026
Phenotypes for gene: TUFT1 were set to Ectodermal dysplasia, MONDO:0019287, TUFT1-related
Review for gene: TUFT1 was set to AMBER
Added comment: 9 individuals from three families reported with woolly hair and skin fragility. One of the variants, c.60+1G>A was present in two of the families, founder effect demonstrated by haplotype analysis. Another loss of function variant present in the third family. Some functional data but mostly expression studies.
Sources: Literature
Mendeliome v1.572 ZMYM3 Belinda Chong gene: ZMYM3 was added
gene: ZMYM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYM3 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: ZMYM3 were set to 36586412; 24721225
Phenotypes for gene: ZMYM3 were set to Neurodevelopmental disorders (NDDs)
Review for gene: ZMYM3 was set to GREEN
Added comment: PMID: 36586412
Using the MatchMaker Exchange - Described 27 individuals with rare, variation in the ZMYM3. Most individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) with de novo variants.
Overlapping features included developmental delay, intellectual disability, behavioural abnormalities, and a specific facial gestalt in a subset of males.
Variants in almost all individuals are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441 (R441W), a site at which variation has been previously seen in NDD-affected siblings (24721225), and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T).
ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect.
Sources: Literature
Mendeliome v1.572 KMT2D Zornitza Stark Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920; KMT2D-associated syndrome to Kabuki syndrome 1, MIM# 147920; Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Mendeliome v1.571 KMT2D Zornitza Stark edited their review of gene: KMT2D: Changed phenotypes: Kabuki syndrome 1, MIM# 147920, Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Mendeliome v1.571 BUB1 Zornitza Stark Phenotypes for gene: BUB1 were changed from Neurodevelopmental disorder, BUB1-related MONDO:0700092 to Primary microcephaly-30 (MCPH30), MIM#620183
Mendeliome v1.570 BUB1 Zornitza Stark edited their review of gene: BUB1: Changed phenotypes: primary microcephaly-30 (MCPH30), MIM#620183
Mendeliome v1.570 GOSR2 Zornitza Stark Phenotypes for gene: GOSR2 were changed from Epilepsy, progressive myoclonic 6 , MIM#614018 to Epilepsy, progressive myoclonic 6 , MIM#614018; Muscular dystrophy, congenital, with or without seizures, MIM# 620166
Mendeliome v1.569 GOSR2 Zornitza Stark edited their review of gene: GOSR2: Added comment: PMIDs 29855340; 33639315: at least three families reported with a muscular dystrophy presentation as well as seizures.; Changed publications: 21549339, 24458321, 30363482, 29855340, 33639315; Changed phenotypes: Epilepsy, progressive myoclonic 6 , MIM#614018, Muscular dystrophy, congenital, with or without seizures, MIM# 620166
Mendeliome v1.567 TSPEAR Zornitza Stark Phenotypes for gene: TSPEAR were changed from Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180 to Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, MIM#618180; Selective tooth agenesis-10 (STHAG10), MIM#620173
Mendeliome v1.566 TSPEAR Zornitza Stark Publications for gene: TSPEAR were set to 27736875; 30046887
Mendeliome v1.565 TSPEAR Zornitza Stark edited their review of gene: TSPEAR: Added comment: More than 5 individuals reported with selective tooth agenesis.; Changed rating: GREEN; Changed publications: 30046887, 32112661, 34042254; Changed phenotypes: Selective tooth agenesis-10 (STHAG10), MIM#620173; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.563 SLC26A6 Arina Puzriakova gene: SLC26A6 was added
gene: SLC26A6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC26A6 were set to 35115415; 21170874; 32660969
Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)

SLC26A6 is currently not associated with any human phenotype in OMIM or G2P.
Sources: Literature
Mendeliome v1.563 WDFY3 Zornitza Stark Phenotypes for gene: WDFY3 were changed from Microcephaly 18, primary, autosomal dominant, MIM#617520 to Microcephaly 18, primary, autosomal dominant, MIM#617520; Neurodevelopmental disorder with macrocephaly
Mendeliome v1.559 CLDN5 Zornitza Stark Mode of pathogenicity for gene: CLDN5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mendeliome v1.554 SETD2 Zornitza Stark edited their review of gene: SETD2: Added comment: PMID 32710489: 12 unrelated patients, ranging from 1 month to 12 years of age, with a multisystemic neurodevelopmental disorder associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740W).

Key clinical features: severely impaired global development apparent from infancy, feeding difficulties with failure to thrive, small head circumference, and dysmorphic facial features. Affected individuals have impaired intellectual development and hypotonia; they do not achieve walking or meaningful speech. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and possibly endocrine.

Further 3 unrelated patients identified with mild to moderately impaired intellectual development associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740Q).

These are distinct clinically from Luscan-Lumish syndrome, which is characterised by overgrowth.; Changed publications: 29681085, 32710489; Changed phenotypes: Luscan-Lumish syndrome, MIM#616831, Rabin-Pappas syndrome,MIM# 620155, Intellectual developmental disorder, autosomal dominant 70, MIM# 620157
Mendeliome v1.554 RPS15 Zornitza Stark Marked gene: RPS15 as ready
Mendeliome v1.552 CLDN5 Suliman Khan reviewed gene: CLDN5: 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: 36477332; Phenotypes: seizures, developmental delay, microcephaly, brain calcifications; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.548 HSPG2 Zornitza Stark Phenotypes for gene: HSPG2 were changed from Dyssegmental dysplasia, Silverman-Handmaker type; Schwartz-Jampel syndrome, type 1 to Schwartz-Jampel syndrome, type 1, MIM# 255800; MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, MIM# 224410; MONDO:0009140
Mendeliome v1.547 IL2RB Zornitza Stark changed review comment from: Five families reported.
Sources: Expert list; to: Five families reported.

Affected individuals present in infancy with features of both abnormal activation of certain immune signaling pathways, resulting in lymphoid proliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, especially CMV. Laboratory studies show increased NK cells that show impaired differentiation, as well as abnormal T cell populations or responses. Some patients may die in childhood; hematopoietic bone marrow transplantation is curative.

Sources: Expert list
Mendeliome v1.544 RPS6KB1 Zornitza Stark Marked gene: RPS6KB1 as ready
Mendeliome v1.544 RPS6KB1 Zornitza Stark Phenotypes for gene: RPS6KB1 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, MONDO:0005045, RPS6KB1-related
Mendeliome v1.542 TNNC2 Zornitza Stark Marked gene: TNNC2 as ready
Mendeliome v1.541 TNNC2 Zornitza Stark gene: TNNC2 was added
gene: TNNC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNNC2 were set to 33755597
Phenotypes for gene: TNNC2 were set to Congenital myopathy, MONDO:0019952, TNNC2-related
Review for gene: TNNC2 was set to GREEN
Added comment: Two families reported: Family 1: 4 individuals, three generations; missense variant p.(Asp34Tyr) Family 2: de novo variant, missense p.(Met79Ile)

Physiological studies in myofibers isolated from patients’ biopsies revealed a markedly reduced force response of the sarcomeres to [Ca2+]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC.

Borderline Green: sufficient segregation in Fam 1 plus de novo status in Fam 2, plus functional data.
Sources: Literature
Mendeliome v1.540 CHUK Zornitza Stark Phenotypes for gene: CHUK were changed from Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339; Cocoon syndrome, MIM# 613630; AEC-like syndrome to Combined immunodeficiency, MONDO:0015131, CHUK-related; Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339; Cocoon syndrome, MIM# 613630; AEC-like syndrome
Mendeliome v1.538 CHUK Zornitza Stark edited their review of gene: CHUK: Changed phenotypes: Combined immunodeficiency, MONDO:0015131, CHUK-related, Popliteal pterygium syndrome, Bartsocas-Papas type 2, MIM# 619339, Cocoon syndrome, MIM# 613630, AEC-like syndrome
Mendeliome v1.538 CHUK Zornitza Stark edited their review of gene: CHUK: Added comment: PMID 34533979: single individual reported with homozygous missense variant in this gene and recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine. Supportive functional data.; Changed publications: 25691407, 20961246, 10195895, 10195896, 29523099, 28513979, 34533979
Mendeliome v1.535 LIG1 Zornitza Stark Phenotypes for gene: LIG1 were changed from Combined immunodeficiency; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis to Immunodeficiency 96, MIM# 619774; Lymphopaenia; Hypogammaglobulinaemia; Recurrent bacterial and viral infections; Growth retardation; Sun sensitivity, radiation sensitivity; Macrocytosis
Mendeliome v1.534 NLGN4X Zornitza Stark Marked gene: NLGN4X as ready
Mendeliome v1.534 NLGN4X Zornitza Stark Added comment: Comment when marking as ready: Definitive assessment by ClinGen noted, as well as 'limited' assessments by G2P and Genomics England. Many of the variants are multi-gene deletions; phenotypes are not well delineated, with several individuals not having ID.
Mendeliome v1.531 MPC2 Zornitza Stark Marked gene: MPC2 as ready
Mendeliome v1.530 MPC2 Zornitza Stark gene: MPC2 was added
gene: MPC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPC2 were set to 36417180
Phenotypes for gene: MPC2 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related
Review for gene: MPC2 was set to AMBER
Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels.
Sources: Literature
Mendeliome v1.528 ARF3 Zornitza Stark Publications for gene: ARF3 were set to 34346499
Mendeliome v1.527 ARF3 Zornitza Stark Classified gene: ARF3 as Green List (high evidence)
Mendeliome v1.527 ARF3 Zornitza Stark Gene: arf3 has been classified as Green List (High Evidence).
Mendeliome v1.526 TIMMDC1 Paul De Fazio reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36349561, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31 MIM#618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.526 LEMD2 Seb Lunke Phenotypes for gene: LEMD2 were changed from Marbach-Rustad progeroid syndrome, OMIM# 619322; progeroid disorder to Marbach-Rustad progeroid syndrome, OMIM# 619322; arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587; Cataract 46, juvenile-onset, OMIM# 212500
Mendeliome v1.523 LEMD2 Seb Lunke reviewed gene: LEMD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31061923, 26788539, 30905398, 36377660; Phenotypes: Marbach-Rustad progeroid syndrome, OMIM# 619322, arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587, Cataract 46, juvenile-onset, OMIM# 212500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.523 NUP54 Zornitza Stark Marked gene: NUP54 as ready
Mendeliome v1.523 NUP54 Zornitza Stark Phenotypes for gene: NUP54 were changed from Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia to Striatonigral degeneration, MONDO:0003122, NUP54-related; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Mendeliome v1.520 FEM1C Zornitza Stark Marked gene: FEM1C as ready
Mendeliome v1.519 DCLRE1B Zornitza Stark Phenotypes for gene: DCLRE1B were changed from Dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome to Dyskeratosis congenita, autosomal recessive 8, MIM# 620133
Mendeliome v1.515 NUP54 Zornitza Stark Mode of pathogenicity for gene: NUP54 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mendeliome v1.513 NUP54 Hazel Phillimore gene: NUP54 was added
gene: NUP54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP54 were set to PMID: 36333996
Phenotypes for gene: NUP54 were set to Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Mode of pathogenicity for gene: NUP54 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: NUP54 was set to AMBER
Added comment: From PMID: 36333996.; Harrer, P. et al. (2022) Ann Neurol. doi: 10.1002/ana.26544.

Three patients from unrelated families with dystonia and/or Leigh(-like) syndromes, with biallelic variants in NUP54, in the C-terminal protein region that interacts with NUP62. Onset was between 12 months and 5 years. All had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

Patient / Family A (consanguineous) was homozygous for c.1073T>G p.(Ile358Ser).

Patient / Family B was compound heterozygous for c.1073T>G p.(Ile358Ser) and c.1126A>G p.(Lys376Glu).

Patient / Family C was compound heterozygosity for c.1410_1412del p.(Gln471del) and two missense variants c.1414G>A, p.(Glu472Lys); c.1420C>T, p.(Leu474Phe)

The phenotypes were similar to those of NUP62 including early-onset dystonia with dysphagic choreoathetosis, and T2-hyperintense lesions in striatum.

Brain MRIs showed T2/FLAIR hyperintensities in the dorsal putamina.

Western blots showing reduced expression of NUP54 and its interaction partners NUP62/NUP58 in patient fibroblasts.
Sources: Literature
Mendeliome v1.513 GABRA3 Zornitza Stark Marked gene: GABRA3 as ready
Mendeliome v1.512 ARF3 Dean Phelan reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36369169, 34346499; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), ARF3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.511 NPC1 Naomi Baker gene: NPC1 was added
gene: NPC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPC1 were set to 36417180
Phenotypes for gene: NPC1 were set to mitochondrial pyruvate carrier deficiency, MONDO:0013877, MPC2-related
Review for gene: NPC1 was set to AMBER
Added comment: Four patients from two unrelated consanguineous families reported with homozygous variants (missense and stop-loss). Siblings from family 1 were diagnosed prenatally with diffuse subcutaneous oedema, cardiomegaly, corpus callosum agenesis, ventriculomegaly and hypoplasia of the cerebellum. Siblings from family 2 had slightly different presentations, which included anoxo-ischemic encephalopathy, isolated dyspnea, neonatal respiratory distress, neonatal jaundice, hypotonia, visual impairment, microcephaly; both siblings had severe delayed psychomotor development. Immunoblot analysis of protein expression in lysates from patient-derived fibroblasts demonstrated reduced MPC1 and MPC2 protein levels.
Sources: Literature
Mendeliome v1.510 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from Neuronopathy, distal hereditary motor, type X, MIM# 620080 to Neuronopathy, distal hereditary motor, type X, MIM# 620080; Aortic aneurysm, MONDO:0005160, EMILIN2-related
Mendeliome v1.507 EMILIN1 Karina Sandoval reviewed gene: EMILIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36351433; Phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy, aortic aneurysm; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.507 GABRA3 Sarah Pantaleo gene: GABRA3 was added
gene: GABRA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRA3 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: GABRA3 were set to PMID: 29053855
Phenotypes for gene: GABRA3 were set to Epilepsy, intellectual disability, dysmorphic features,
Penetrance for gene: GABRA3 were set to Incomplete
Review for gene: GABRA3 was set to GREEN
Added comment: Six variants in GABRA3 encoding the alpha3-subunit of the GABA(A) receptor.
Five missense variants and one micro duplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus.
The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies.
Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype.
Mechanism suggested - three detected missense variants are localised in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the alpha3-subunit. Functional studies in Xenopus leaves oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype.
Results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.
Sources: Literature
Mendeliome v1.507 TCEAL1 Zornitza Stark Marked gene: TCEAL1 as ready
Mendeliome v1.505 TCEAL1 Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.504 TCEAL1 Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.504 TCEAL1 Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.504 SHROOM4 Alison Yeung reviewed gene: SHROOM4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36379543, 35663265; Phenotypes: Congenital anomaly of the kidney and urinary tracy (CAKUT), SHROOM4-related, MONDO:0019719, epilepsy, idiopathic generalised, SHROOM4-related, MONDO:0005579; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.504 UQCRH Chern Lim gene: UQCRH was added
gene: UQCRH was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UQCRH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UQCRH were set to 34750991
Phenotypes for gene: UQCRH were set to Mitochondrial complex III deficiency, nuclear type 11, MIM#620137
Review for gene: UQCRH was set to AMBER
gene: UQCRH was marked as current diagnostic
Added comment: PMID: 34750991:
- Two affected cousins, presented with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy.
- Both have a 2.2 kb homozygous deletion of exons 2 and 3 of UQCRH, predicted to culminate in an in-frame deletion exons 2 and 3 of the four-exon UQCRH gene, resulting in a shortened product.
- Mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/-) also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death.
- Patient fibroblasts and Uqcrh-/- mouse tissues showed a CIII defect.
- Expression of wild-type UQCRH in patient fibroblasts ameliorates the CIII defect.
Sources: Literature
Mendeliome v1.504 FEM1C Paul De Fazio gene: FEM1C was added
gene: FEM1C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FEM1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FEM1C were set to 36336956; 28135719; 33398170; 33398168
Phenotypes for gene: FEM1C were set to Neurodevelopmental disorder, FEM1C-related MONDO:0700092
Review for gene: FEM1C was set to GREEN
gene: FEM1C was marked as current diagnostic
Added comment: PMID:36336956 describes a 9-year-old boy with severe DD, lack of speech, pyramidal signs, and limb ataxia who had a de novo missense variant Asp126His in FEM1C ascertained by WES. The equivalent variant introduced into the nematode C.elegans resulted in disabled locomotion caused by synaptic abnormalities and not muscle dysfunction.

An alternate change Asp126Val was reported in the DDD study de novo in a patient with uncharacterised developmental delay (PMID:28135719).

The Asp126 residue (but not either of the variants above specifically) was shown to be functionally important by in vitro studies (PMID:33398170;33398168). The residue is highly conserved and located in a region of missense constraint.

Borderline green, 2 patients and an animal model. Note all evidence points to the Asp126 residue being of specific importance.
Sources: Literature
Mendeliome v1.504 TCEAL1 Melanie Marty gene: TCEAL1 was added
gene: TCEAL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCEAL1 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: TCEAL1 were set to PMID: 36368327
Phenotypes for gene: TCEAL1 were set to hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features.
Review for gene: TCEAL1 was set to GREEN
Added comment: 7 individuals (males and females) with de novo variants involving TCEAL1. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.
Sources: Literature
Mendeliome v1.504 KDM2B Ain Roesley changed review comment from: 27 individuals from 22 families were recruited
12 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature; to: 27 individuals from 22 families were recruited
13 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature
Mendeliome v1.504 KDM2B Ain Roesley Marked gene: KDM2B as ready
Mendeliome v1.503 MAN2A2 Zornitza Stark Marked gene: MAN2A2 as ready
Mendeliome v1.503 KDM2B Ain Roesley gene: KDM2B was added
gene: KDM2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related
Review for gene: KDM2B was set to GREEN
gene: KDM2B was marked as current diagnostic
Added comment: 27 individuals from 22 families were recruited
12 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)
Sources: Literature
Mendeliome v1.502 MAN2A2 Zornitza Stark gene: MAN2A2 was added
gene: MAN2A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAN2A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2A2 were set to 36357165
Phenotypes for gene: MAN2A2 were set to Congenital disorder of glycosylation, MONDO:0015286, MAN2A2-reated
Review for gene: MAN2A2 was set to RED
Added comment: Single consanguineous family reported with homozygous truncating variant in two brothers with ID. Supportive biochemical data only.
Sources: Literature
Mendeliome v1.501 ARPC4 Zornitza Stark Phenotypes for gene: ARPC4 were changed from Neurodevelopmental disorder, ARPC4-related MONDO#0700092 to Developmental delay, language impairment, and ocular abnormalities, MIM# 620141
Mendeliome v1.500 ARPC4 Zornitza Stark edited their review of gene: ARPC4: Changed phenotypes: Developmental delay, language impairment, and ocular abnormalities, MIM# 620141
Mendeliome v1.499 UBE3C Zornitza Stark Marked gene: UBE3C as ready
Mendeliome v1.498 KIF26A Zornitza Stark Marked gene: KIF26A as ready
Mendeliome v1.495 UBE3C Chirag Patel gene: UBE3C was added
gene: UBE3C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBE3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE3C were set to PMID: 36401616
Phenotypes for gene: UBE3C were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: UBE3C was set to GREEN
Added comment: 3 patients/2 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in UBE3C. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Mendeliome v1.493 HECTD4 Chirag Patel gene: HECTD4 was added
gene: HECTD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to PMID: 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM#
Review for gene: HECTD4 was set to GREEN
Added comment: 7 patients/5 families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. WES found bi-allelic variants in HECTD4. The RNA studies in some patients with LoF variants provided evidence for the LoF effect.
Sources: Literature
Mendeliome v1.491 KIF26A Chirag Patel gene: KIF26A was added
gene: KIF26A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to PMID: 36228617
Phenotypes for gene: KIF26A were set to Congenital brain malformations, no OMIM #
Review for gene: KIF26A was set to GREEN
Added comment: 5 unrelated patients with biallelic loss-of-function variants in KIF26A (found through WES), exhibiting a spectrum of congenital brain malformations (schizencephaly, corpus callosum anomalies, polymicrgyria, and ventriculomegaly). Combining mice and human iPSC-derived organoid models, they discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways.
Sources: Literature
Mendeliome v1.489 PIGN Zornitza Stark edited their review of gene: PIGN: Added comment: Large cohort study of 21 new and review of 40 previously published cases in PMID 36322149

Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon.; Changed publications: 36322149; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563, Fryns syndrome
Mendeliome v1.486 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Added comment: PMID 36331550: further 31 individuals reported with mono-allelic variants. Three phenotypes observed:
1. DEE
2. Isolated DD/ID
3. HSP or ataxia; Changed publications: 20493457, 22258530, 32811770, 35150594, 34526651, 31515523, 36331550
Mendeliome v1.486 SEC16B Zornitza Stark Marked gene: SEC16B as ready
Mendeliome v1.483 NDUFB7 Zornitza Stark Phenotypes for gene: NDUFB7 were changed from Congenital lactic acidosis; hypertrophic cardiomyopathy to Mitochondrial complex I deficiency nuclear type 39 (MC1DN39), MIM#620135; Congenital lactic acidosis; hypertrophic cardiomyopathy
Mendeliome v1.482 NDUFB7 Zornitza Stark reviewed gene: NDUFB7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency nuclear type 39 (MC1DN39), MIM#620135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.481 KCNJ16 Zornitza Stark Phenotypes for gene: KCNJ16 were changed from Renal tubulopathy; deafness to Inherited renal tubular disease, MONDO:0015962, KCNJ16-related; Renal tubulopathy; deafness
Mendeliome v1.480 KCNJ16 Zornitza Stark edited their review of gene: KCNJ16: Changed phenotypes: Inherited renal tubular disease, MONDO:0015962, KCNJ16-related, Renal tubulopathy, deafness
Mendeliome v1.480 AFDN Zornitza Stark Marked gene: AFDN as ready
Mendeliome v1.480 AFDN Zornitza Stark gene: AFDN was added
gene: AFDN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AFDN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AFDN were set to 36384317
Phenotypes for gene: AFDN were set to Cleft lip/palate, MONDO:0016044, AFDN-related
Review for gene: AFDN was set to RED
Added comment: Over-representation of rare AFDN missense variants reported in a cohort of CL/P individuals of African and Brazilian origin. However, almost all of the variants reported have hets in gnomad. The one that is novel has alternative missense at the same aa position.
Sources: Literature
Mendeliome v1.478 FOXI1 Zornitza Stark reviewed gene: FOXI1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.478 CLEC3B Zornitza Stark Marked gene: CLEC3B as ready
Mendeliome v1.477 CLEC3B Chirag Patel gene: CLEC3B was added
gene: CLEC3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLEC3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLEC3B were set to PMID: 35331648
Phenotypes for gene: CLEC3B were set to Macular dystrophy, retinal, 4, OMIM #619977
Review for gene: CLEC3B was set to GREEN
Added comment: 12 affected individuals from 5 multigenerational Japanese families in a small village in Miyazaki diagnosed with autosomal dominant maculoretinopathy. WES identified a pathogenic variant (p.Ala180Asp) in CLEC3B, which encodes tetranectin, a plasminogen kringle-4 binding protein. Variant cosegregated with the ocular phenotype.

Mice that received subretinal injections with CLEC3B variant displayed multiple subretinal hyperreflective deposits, reduced retinal thickness, and decreased electroretinographic responses. The optokinetic tracking response indicated that spatial frequency was significantly lower (P < .05), implying impaired visual function in the mice.
Sources: Literature
Mendeliome v1.476 PDIA6 Chirag Patel edited their review of gene: PDIA6: Added comment: 2nd patient with large polycystic kidneys, death and end stage renal failure at 18 months, microcephaly, bilateral inguinal hernias, umbilical hernia, developmental delay, bilateral sensorineural hearing loss, visual impairment, steatorrhea, fibrotic changes in liver, and insulin-dependent diabetes. WGS found homozygous stop-gain variant (Tyr368*) in PDIA6. Segregation not performed.; Changed rating: AMBER; Changed publications: PMID: 35856135; Changed phenotypes: Polycystic kidney disease, infancy-onset diabetes, and microcephaly
Mendeliome v1.476 ARPC4 Zornitza Stark Phenotypes for gene: ARPC4 were changed from Microcephaly; mild motor delays; significant speech impairment to Neurodevelopmental disorder, ARPC4-related MONDO#0700092
Mendeliome v1.475 ARPC4 Zornitza Stark reviewed gene: ARPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35047857; Phenotypes: Neurodevelopmental disorder, ARPC4-related MONDO#0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.474 SPTBN5 Zornitza Stark edited their review of gene: SPTBN5: Added comment: Some of the missense variants are present at high population frequencies, not compatible with Mendelian disease. Gene is tolerant of LoF in gnomad, raising questions about the pathogenicity of the LoF variant.
Commentaries questioning gene-disease relationship PMID: 36117916; 36238261; Changed rating: RED
Mendeliome v1.473 MTSS1 Zornitza Stark Marked gene: MTSS1 as ready
Mendeliome v1.472 MTSS1 Zornitza Stark gene: MTSS1 was added
gene: MTSS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTSS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTSS1 were set to 36067766
Phenotypes for gene: MTSS1 were set to Intellectual disability, MTSS1-related (MONDO#0001071)
Review for gene: MTSS1 was set to GREEN
Added comment: Five individuals with the same heterozygous de novo variant in MTSS2 (NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing.

The individuals presented with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms.

Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies.
Sources: Literature
Mendeliome v1.471 TPR Zornitza Stark Phenotypes for gene: TPR were changed from intellectual disability, MONDO:0001071; cerebellar ataxia, MONDO:0000437; microcephaly, MONDO:0001149 to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, TPR-related
Mendeliome v1.470 TPR Zornitza Stark Marked gene: TPR as ready
Mendeliome v1.469 SMC5 Zornitza Stark Marked gene: SMC5 as ready
Mendeliome v1.468 SMC5 Zornitza Stark gene: SMC5 was added
gene: SMC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMC5 were set to 36333305
Phenotypes for gene: SMC5 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SMC5 was set to GREEN
Added comment: Four individuals from three families with a chromosome breakage disorder and bi-allelic variants in this gene. However, three of the individuals had the same homozygous missense variant. Evidence for functional impact of the variant was limited. However, zebrafish model recapitulated the phenotype and was not rescued by the introduction of this variant, arguing for functional effect. Borderline Amber/Green
Sources: Literature
Mendeliome v1.467 SLF2 Zornitza Stark Marked gene: SLF2 as ready
Mendeliome v1.466 SLF2 Zornitza Stark gene: SLF2 was added
gene: SLF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLF2 were set to 36333305
Phenotypes for gene: SLF2 were set to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID
Review for gene: SLF2 was set to GREEN
Added comment: Seven individuals from 6 families with a chromosome breakage disorder and bi-allelic variants in this gene (LoF). Functional data including zebrafish model.
Sources: Literature
Mendeliome v1.465 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to intellectual disability, MONDO:0001071; cerebellar ataxia, MONDO:0000437; microcephaly, MONDO:0001149
Review for gene: TPR was set to RED
Added comment: This gene should be added to the following diseases: Intellectual disability, microcephaly and ataxia.

Comment on classification of this gene: This gene should be added with a RED rating as the association is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.465 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34476477; Phenotypes: Neurofibromatosis, type 1, MIM# 162200, MONDO:0018975, renovascular hypertension, MONDO:0006947; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.463 IRF2BP2 Zornitza Stark edited their review of gene: IRF2BP2: Added comment: Reports of additional patients: 4yo with chronic diarrhea, severe eczema, anemia, failure to thrive, fevers, short stature, recurrent infections, cataracts, hypodontia, hypotrichosis alopecia, hypogammaglobulinemia. The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years.; Changed rating: GREEN; Changed publications: 27016798, 32048120, 36193988, 33864888; Changed phenotypes: Immunodeficiency, common variable, 14, MIM# 617765
Mendeliome v1.462 ATP5F1 Zornitza Stark Marked gene: ATP5F1 as ready
Mendeliome v1.462 ATP5F1 Zornitza Stark gene: ATP5F1 was added
gene: ATP5F1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATP5F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5F1 were set to 36239646
Phenotypes for gene: ATP5F1 were set to Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation-2 (HUMOP2), MIM#620085
Review for gene: ATP5F1 was set to RED
Added comment: Identical twins reported with a de novo missense variant in this gene and hyper metabolism: normal thyroid function, hyperphagia, tachypnea, increased basal temperature, and increased sweating. Biochemical studies demonstrated increased mitochondrial oxygen consumption with inefficient production of ATP in the final steps of oxidative phosphorylation due to an uncoupling defect
Sources: Expert list
Mendeliome v1.460 CACNA1I Zornitza Stark Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with variable intellectual disability and speech impairment, with or without seizures (NEDISS), MIM#620114
Mendeliome v1.459 CACNA1I Zornitza Stark reviewed gene: CACNA1I: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with variable intellectual disability and speech impairment, with or without seizures (NEDISS), MIM#620114; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.459 RPS6KB1 Arina Puzriakova gene: RPS6KB1 was added
gene: RPS6KB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPS6KB1 were set to 34916228
Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy
Review for gene: RPS6KB1 was set to GREEN
Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640)
Sources: Literature
Mendeliome v1.459 HK1 Zornitza Stark edited their review of gene: HK1: Added comment: PMID 36333503: 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1) identified in individuals with hyperinsulinism.; Changed publications: 19536174, 30778173, 25316723, 25190649, 31621442, 32814480, 7655856, 12393545, 33361148, 31119733, 27282571, 36333503; Changed phenotypes: Hyperinsulinism MONDO:0002177, HK1-related, Neuropathy, hereditary motor and sensory, Russe type , MIM#605285, Haemolytic anaemia due to hexokinase deficiency, MIM# 235700, Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547, Retinitis pigmentosa 79, MIM# 617460
Mendeliome v1.459 FRA10AC1 Zornitza Stark Phenotypes for gene: FRA10AC1 were changed from Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related to Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113
Mendeliome v1.458 FRA10AC1 Zornitza Stark edited their review of gene: FRA10AC1: Changed phenotypes: Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113
Mendeliome v1.458 ITPR3 Zornitza Stark Phenotypes for gene: ITPR3 were changed from Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111
Mendeliome v1.455 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Added comment: Additional family with 3 individuals in 2 generations reported in PMID 24627108.; Changed rating: GREEN; Changed publications: 32949214, 24627108; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111
Mendeliome v1.453 WDR5 Bryony Thompson Marked gene: WDR5 as ready
Mendeliome v1.452 WDR5 Bryony Thompson gene: WDR5 was added
gene: WDR5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Phenotypes for gene: WDR5 were set to Neurodevelopmental disorder MONDO:0700092, WDR5-related
Mode of pathogenicity for gene: WDR5 was set to Other
Review for gene: WDR5 was set to GREEN
Added comment: Six different missense variants were identified (de novo) in 11 affected individuals with neurodevelopmental disorders, with a broad spectrum of additional features, including epilepsy, aberrant growth parameters, skeletal and cardiac abnormalities. In vivo and in vitro functional suggest that loss-of-function is not the mechanism of disease. The mechanism of disease is yet to be established.
Sources: Literature
Mendeliome v1.451 KPNA3 Zornitza Stark Phenotypes for gene: KPNA3 were changed from Hereditary Spastic Paraplegia, infantile onset to Spastic paraplegia-88 (SPG88), MIM#620106
Mendeliome v1.450 KPNA3 Zornitza Stark reviewed gene: KPNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia-88 (SPG88), MIM#620106; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.450 JARID2 Zornitza Stark Phenotypes for gene: JARID2 were changed from Intellectual disability to Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF), MIM#620098
Mendeliome v1.449 JARID2 Zornitza Stark edited their review of gene: JARID2: Changed phenotypes: Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF), MIM#620098
Mendeliome v1.447 DNAJB4 Zornitza Stark Marked gene: DNAJB4 as ready
Mendeliome v1.446 DNAJB4 Karina Sandoval gene: DNAJB4 was added
gene: DNAJB4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJB4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJB4 were set to PMID: 36264506
Phenotypes for gene: DNAJB4 were set to Myopathy, MONDO:0005336, DNAJB4-related
Review for gene: DNAJB4 was set to GREEN
Added comment: 4 individuals from 3 unrelated families with bi-allelic LoF/missense variants in this gene, and either childhood/adult onset of muscle weakness and respiratory failure. One had HCM.

Functional studies including mouse model.
Sources: Literature
Mendeliome v1.444 MYCBP2 Zornitza Stark Marked gene: MYCBP2 as ready
Mendeliome v1.443 CAMSAP1 Zornitza Stark Marked gene: CAMSAP1 as ready
Mendeliome v1.442 THAP1 Michelle Torres commented on gene: THAP1: Monoallelic is well established with reduced penetrance.

Biallelic was seen in 3 families generally with severe and early onset dystonia:

PMID: 36205328: consanguineous family (gene panel), proband homozygous for p.Lys162Asn with early onset multifocal dystonia with severe oromandibular/laryngeal dysfunction; both parents were confirmed carriers with milder features (47 yo father with tightness and difficulty with fine motor tasks, 41 yo mother with tightness).

PMID: 21425335: 3 siblings are homozygous for the p.Leu32His with early-onset generalized dystonia. Carriers were unaffected.

PMID: 20211909: a homozygous variant was identified in an individual with with writer's dystonia initially and then developing segmental dystonia, onset at 57 yo, parents could not be tested.
Mendeliome v1.442 CAMSAP1 Naomi Baker gene: CAMSAP1 was added
gene: CAMSAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related
Review for gene: CAMSAP1 was set to GREEN
Added comment: Five unrelated families with bi-allelic loss-of-function variants. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe neurodevelopmental delay, cortical visual impairment, and seizures.
Sources: Literature
Mendeliome v1.442 MYCBP2 Suliman Khan gene: MYCBP2 was added
gene: MYCBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYCBP2 were set to PMID: 36200388
Phenotypes for gene: MYCBP2 were set to Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related; corpus callosum abnormalities
Penetrance for gene: MYCBP2 were set to Complete
Review for gene: MYCBP2 was set to GREEN
Added comment: PMID: 36200388 reported eight patients with neurodevelopmental disorder including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy, and autistic features. Each patient harbored a de novo LOF variant in MYCBP2 gene. Functional study supported a direct link between MYCBP2 and neurodevelopmental spectrum disorder specifically corpus callosum defects.
Sources: Literature
Mendeliome v1.442 KLHL20 Zornitza Stark Marked gene: KLHL20 as ready
Mendeliome v1.441 KLHL20 Dean Phelan gene: KLHL20 was added
gene: KLHL20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to PMID: 36214804
Phenotypes for gene: KLHL20 were set to Neurodevelopmental disorder (MONDO:0700092), KLHL20-related
Review for gene: KLHL20 was set to GREEN
Added comment: PMID: 36214804
- 14 patients with de novo missense variants in KLHL20. The patients had mild to severe ID, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity and subtle dysmorphic facial features.
Sources: Literature
Mendeliome v1.441 FICD Alison Yeung Marked gene: FICD as ready
Mendeliome v1.440 FICD Alison Yeung gene: FICD was added
gene: FICD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36136088
Phenotypes for gene: FICD were set to Hereditary motor neurone disease, FICD-related, MONDO:0024257
Review for gene: FICD was set to GREEN
Added comment: Three unrelated families with recurrent homozygous missense variant: p.Arg374His
One further family with Chet variants: p.Arg 374His and p.Gly370GlufsTer53

Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP.

Onset of symptoms in childhood with progressive course. Presentation with severe lower limb spasticity and mild upper limb spascticity, nerve conduction test shows motor neuropathy.
Sources: Literature
Mendeliome v1.439 FOXI3 Zornitza Stark Marked gene: FOXI3 as ready
Mendeliome v1.437 FOXI3 Paul De Fazio gene: FOXI3 was added
gene: FOXI3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 36260083
Phenotypes for gene: FOXI3 were set to Dysostosis with predominant craniofacial involvement (MONDO:0800085)
Penetrance for gene: FOXI3 were set to Incomplete
Review for gene: FOXI3 was set to GREEN
gene: FOXI3 was marked as current diagnostic
Added comment: Ten affected individuals from 4 families reported with monoallelic variants, 2 with missense variants affecting the nuclear localisation sequence and 2 with frameshift variants.

The missense variants were associated with isolated microtia with aural atresia and affected subcellular localisation of the protein, while the frameshift variants were associated with microtia and mandubular hypoplasia, suggesting dosage sensitivity.

Rated green but CAUTION for incomplete penetrance. 3 of the 4 families had unaffected carriers. Family 1 in particular had 25 genotyped individuals, of which 15 were carriers, of which 5 were affected.
Sources: Literature
Mendeliome v1.436 TOMM7 Zornitza Stark edited their review of gene: TOMM7: Added comment: Second family reported in PMID 36282599: single affected individual with homozygous missense variant; clinical presentation with progeroid features but functional data supports underlying mitochondrial aetiology.

Maintain Amber rating as the two patients have quite disparate clinical presentations.; Changed publications: 36282599
Mendeliome v1.436 CBFB Ain Roesley Marked gene: CBFB as ready
Mendeliome v1.435 CBFB Ain Roesley gene: CBFB was added
gene: CBFB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBFB were set to 36241386
Phenotypes for gene: CBFB were set to cleidocranial dysplasia (MONDO#0007340), CBFB-related
Penetrance for gene: CBFB were set to Complete
Review for gene: CBFB was set to GREEN
gene: CBFB was marked as current diagnostic
Added comment: 5 families with 8 individuals, including 2 de novos and 1 intragenic exon 4 deletion

In 1 family, the mother did not report skeletal concerns but had dental abnormalities during childhood
Sources: Literature
Mendeliome v1.430 SFTPA1 Zornitza Stark edited their review of gene: SFTPA1: Added comment: Additional 3 families reported with mono-allelic variants.; Changed rating: GREEN; Changed publications: 31601679, 30854216, 28869238, 26792177, 32855221
Mendeliome v1.428 FGL2 Zornitza Stark Marked gene: FGL2 as ready
Mendeliome v1.427 FGL2 Zornitza Stark gene: FGL2 was added
gene: FGL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGL2 were set to 36243222
Phenotypes for gene: FGL2 were set to Autoinflammatory syndrome, MONDO:0019751, FGL2-related
Review for gene: FGL2 was set to AMBER
Added comment: Child with early onset systemic inflammation, autoantibodies, and vasculitis. Homozygous truncating variant, functional studies include rescue experiments.
Sources: Literature
Mendeliome v1.421 CLCN7 Zornitza Stark changed review comment from: Two individuals reported with same missense variant and hypopigmentation, organomegaly, and delayed myelination and development. Variant is GoF. No osteopetrosis, biopsy findings from skin and other organs are consistent with a lysosomal storage disorder. IUGR, prematurity and polyhydramnios are features.

Bi-allelic variants in this gene are associated with osteopetrosis.; to: Two individuals reported with same missense variant and hypopigmentation, organomegaly, and delayed myelination and development. Variant is GoF. No osteopetrosis, biopsy findings from skin and other organs are consistent with a lysosomal storage disorder. IUGR, prematurity and polyhydramnios are features.

Mono- and bi-allelic variants in this gene are associated with osteopetrosis.
Mendeliome v1.421 HNRNPH1 Zornitza Stark Phenotypes for gene: HNRNPH1 were changed from HNRNPH1‐related syndromic intellectual disability; early onset high myopia, MONDO:0001384 to Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, MIM# 620083
Mendeliome v1.418 PRDM16 Paul De Fazio reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 29367541, 29447731, 30847666, 33082984, 32183154, 33500567, 34540771, 34350506, 34935411; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.418 WNK4 Zornitza Stark changed review comment from: More than 5 unrelated families reported.; to: More than 5 unrelated families reported.

Caution: assessed as MODERATE by ClinGen. Although at least 9 individuals have been reported, all the reported variants are missense without other supportive functional or segregation data.
Mendeliome v1.418 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from peripheral neuropathy to Neuronopathy, distal hereditary motor, type X, MIM# 620080
Mendeliome v1.417 EMILIN1 Zornitza Stark reviewed gene: EMILIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.416 CCDC34 Zornitza Stark Marked gene: CCDC34 as ready
Mendeliome v1.415 CCDC34 Zornitza Stark gene: CCDC34 was added
gene: CCDC34 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CCDC34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC34 were set to 34348960
Phenotypes for gene: CCDC34 were set to Spermatogenic failure 76, MIM# 620084
Review for gene: CCDC34 was set to GREEN
Added comment: Two unrelated individuals reported with homozygous frameshift variants. Mouse model recapitulated phenotype.
Sources: Expert list
Mendeliome v1.414 ACTN2 Bryony Thompson reviewed gene: ACTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17097056, 20022194, 25173926, 25224718, 22767232, 27287556, 28436997, 31333075, 31956495, 32973354, 34802252, 33500567, 36078153, 36116040; Phenotypes: intrinsic cardiomyopathy MONDO:0000591; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.411 NFAT5 Zornitza Stark edited their review of gene: NFAT5: Added comment: Two additional individuals with missense variants reported in PMID 36238298: one with EBV infection with hepatitis and enterocolitis, and one with fatal HLH.; Changed rating: AMBER; Changed publications: 25667416, 36238298; Changed phenotypes: Immune deficiency disease, MONDO:0003778, NFAT5-related, Recurrent infections, Autoimmune enterocolopathy, EBV susceptibility, HLH
Mendeliome v1.411 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from 35861243; spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes to Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071
Mendeliome v1.410 PSMC1 Zornitza Stark edited their review of gene: PSMC1: Changed phenotypes: Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071
Mendeliome v1.408 FGF14 Zornitza Stark Phenotypes for gene: FGF14 were changed from Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003 to Spinocerebellar ataxia 27, MIM# 609307; Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Mendeliome v1.407 FGF14 Zornitza Stark edited their review of gene: FGF14: Changed phenotypes: Spinocerebellar ataxia 27, MIM# 609307, Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Mendeliome v1.407 FGF14 Zornitza Stark Phenotypes for gene: FGF14 were changed from Spinocerebellar ataspinocerebellar ataxia type 27 MONDO:0012247; hereditary episodic ataxia MONDO:0016227 to Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003
Mendeliome v1.406 FGF14 Zornitza Stark reviewed gene: FGF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vestibulocerebellar disorder with predominant ocular signs, MIM# 193003; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.406 IMPA1 Bryony Thompson Marked gene: IMPA1 as ready
Mendeliome v1.405 IMPA1 Bryony Thompson gene: IMPA1 was added
gene: IMPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IMPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IMPA1 were set to 26416544; 24554717; 32839513; 17460611
Phenotypes for gene: IMPA1 were set to intellectual disability, autosomal recessive 59 MONDO:0015020
Review for gene: IMPA1 was set to AMBER
Added comment: A homozygous frameshift variant identified in a large Brazilian consanguineous family with ID, also supporting functional studies and null mouse models.
Sources: Literature
Mendeliome v1.404 ARNT2 Bryony Thompson Marked gene: ARNT2 as ready
Mendeliome v1.404 ARNT2 Bryony Thompson Gene: arnt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.404 ARNT2 Bryony Thompson Classified gene: ARNT2 as Amber List (moderate evidence)
Mendeliome v1.404 ARNT2 Bryony Thompson Gene: arnt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.403 ARNT2 Bryony Thompson gene: ARNT2 was added
gene: ARNT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARNT2 were set to 11381139; 24022475
Phenotypes for gene: ARNT2 were set to Webb-Dattani syndrome MONDO:0014404
Review for gene: ARNT2 was set to AMBER
Added comment: A homozygous frameshift (c.1373_1374dupTC) in six affected children from a highly consanguineous family with a syndromic phenotype including microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract. In a Arnt2(-/-) mouse model embryos die perinatally and exhibit impaired hypothalamic development.
Sources: Literature
Mendeliome v1.402 FRMD5 Zornitza Stark Marked gene: FRMD5 as ready
Mendeliome v1.401 FRMD5 Zornitza Stark gene: FRMD5 was added
gene: FRMD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder MONDO:0700092, FRMD5-related
Review for gene: FRMD5 was set to GREEN
Added comment: Eight individuals reported with missense variants in this gene, de novo in 6 where parents were available. Clinical presentation was with ID, seizures, ataxia. Fly model.
Sources: Literature
Mendeliome v1.397 TOMM7 Zornitza Stark Phenotypes for gene: TOMM7 were changed from growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy MONDO:0014911 to Inborn mitochondrial disorder MONDO:0004069, TOMM7-related
Mendeliome v1.396 TOMM7 Bryony Thompson Marked gene: TOMM7 as ready
Mendeliome v1.395 TOMM7 Bryony Thompson gene: TOMM7 was added
gene: TOMM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOMM7 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100148
Phenotypes for gene: TOMM7 were set to growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy MONDO:0014911
Review for gene: TOMM7 was set to AMBER
Added comment: A single case identified with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. A mouse model of the missense variant demonstrated a bioenergetic defect and a phenotype of mitochondrial diseases. It also strongly suggested that the variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with a homozygous Tomm7 deletion.
Sources: Literature
Mendeliome v1.393 SEPT4 Bryony Thompson Marked gene: SEPT4 as ready
Mendeliome v1.392 SEPT4 Bryony Thompson gene: SEPT4 was added
gene: SEPT4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEPT4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEPT4 were set to 36135717; 15737931; 15737930
Phenotypes for gene: SEPT4 were set to male infertility MONDO:0005372
Review for gene: SEPT4 was set to GREEN
Added comment: Two unrelated cases with primary male infertility (asthenoteratozoospermia) from consanguineous Chinsese families with 2 difference homozygous stopgain variants (Patient 1: c.721A>T, p.R241* and Patient 2: c.205C>T, p.R69*). Multiple supporting mouse models where the male mice are sterile.
Sources: Literature
Mendeliome v1.391 FAM20B Bryony Thompson Marked gene: FAM20B as ready
Mendeliome v1.390 FAM20B Bryony Thompson gene: FAM20B was added
gene: FAM20B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FAM20B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM20B were set to 30847897; 30105814; 22732358; 27405802
Phenotypes for gene: FAM20B were set to Desbuquois dysplasia MONDO:0015426
Review for gene: FAM20B was set to AMBER
Added comment: Two siblings from a single family with neonatal short limb dysplasia resembling Desbuquois dysplasia. One of the siblings underwent genetic testing and compound heterozygous variants were identified in FAM20B ((NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). Multiple mouse models reported with skeletal abnormalities.
Sources: Other
Mendeliome v1.389 EXOC6B Bryony Thompson Marked gene: EXOC6B as ready
Mendeliome v1.388 EXOC6B Bryony Thompson gene: EXOC6B was added
gene: EXOC6B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC6B were set to 26669664; 30284759; 36150098
Phenotypes for gene: EXOC6B were set to Spondyloepimetaphyseal dysplasia with joint laxity MONDO:0019675
Review for gene: EXOC6B was set to GREEN
Added comment: 6 affected individuals from 4 families, and supporting assays in patient cells
PMID: 26669664 - 2 brothers with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones from a consanguineous family, with a homozygous nonsense variant [c.906T>A/p.(Tyr302*)]
PMID: 30284759 - 2 sisters with dislocations of the hips and knees, long slender fingers with distal tapering, significant motor disability but normal (older sister) or low-normal intelligence (younger sister), with a homozygous in-frame deletion of exons 9-20
PMID: 36150098 - 2 unrelated probands from consanguineous families, one with a homozygous frameshift exon 20 deletion and one with a homozygous nonsense variant (c.401T>G p.Leu134Ter). Function assessment of patient fibroblast cell lines indicated abrogation of exocytosis leading to impaired primary ciliogenesis
Sources: Literature
Mendeliome v1.385 VPS33A Bryony Thompson changed review comment from: PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells.
PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family
PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family
PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts; to: Now two missense variants reported with disease in at least 15 probands/families
PMID: 28013294 - 13 cases homozygous for VPS33A c.1492C>T p.(Arg498Trp) from non-consanguineous Yakuti families with a Mucopolysaccharidoses-like disease (coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, intellectual disability, and excess secretion of urinary glycosaminoglycans). Lysosomal over-acidification and heparan sulphate accumulation were detected in patient-derived and VPS33A-depleted HeLa cells.
PMID: 27547915 - 2 affected siblings homozygous for VPS33A p.(Arg498Trp) from a consanguineous Turkish family
PMID: 31936524 - 1 homozygous case from a non-consanguineous Yakuti family
PMID: 36153662 - an attenuated juvenile case with a new homozygous missense variant VPS33A c.599G>C p.(Arg200Pro). Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid and decreased abundance of VPS33A in patient-derived fibroblasts
Mendeliome v1.385 DPH5 Zornitza Stark Marked gene: DPH5 as ready
Mendeliome v1.383 VPS33A Bryony Thompson reviewed gene: VPS33A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28013294, 27547915, 31936524, 36153662; Phenotypes: Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders MONDO:0015012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.383 SLC12A6 Zornitza Stark Phenotypes for gene: SLC12A6 were changed from Andermann syndrome; Agenesis of the corpus callosum with peripheral neuropathy, MIM#21800; Intermediate CMT to Andermann syndrome; Agenesis of the corpus callosum with peripheral neuropathy, MIM#21800; Charcot-Marie-Tooth disease, axonal, type 2II , MIM#620068
Mendeliome v1.382 SLC12A6 Zornitza Stark edited their review of gene: SLC12A6: Changed phenotypes: Andermann syndrome, Agenesis of the corpus callosum with peripheral neuropathy, MIM#21800, Charcot-Marie-Tooth disease, axonal, type 2II , MIM#620068
Mendeliome v1.376 SCNM1 Elena Savva Marked gene: SCNM1 as ready
Mendeliome v1.375 SCNM1 Elena Savva gene: SCNM1 was added
gene: SCNM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to PMID: 36084634
Phenotypes for gene: SCNM1 were set to Ciliopathy, SCNM1-related, MONDO:0005308
Review for gene: SCNM1 was set to GREEN
Added comment: Iturrate (2022): three unrelated families (4 affected) w/ OFD, polydactyly, syndactyly and brachydactyly. All had biallelic variants (fs, missense, AluYc1 sequence insertion) and were consanguinous
- the missense variant was shown to have a splice outcome
Sources: Literature
Mendeliome v1.374 LETM1 Zornitza Stark Marked gene: LETM1 as ready
Mendeliome v1.372 LETM1 Ee Ming Wong gene: LETM1 was added
gene: LETM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214
Phenotypes for gene: LETM1 were set to Mitochondrial disease MONDO#0044970, LETM1-related
gene: LETM1 was marked as current diagnostic
Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants
-Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation,
and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years
-Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect
-From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components
Sources: Literature
Mendeliome v1.372 GABRG1 Seb Lunke Marked gene: GABRG1 as ready
Mendeliome v1.372 GABBR1 Zornitza Stark Marked gene: GABBR1 as ready
Mendeliome v1.371 GABBR1 Zornitza Stark gene: GABBR1 was added
gene: GABBR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABBR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABBR1 were set to 36103875
Phenotypes for gene: GABBR1 were set to Neurodevelopmental disorder, GABBR1-related, MONDO:0700092
Review for gene: GABBR1 was set to GREEN
Added comment: Four individuals with de novo variants in this gene and varying severity of DD/ID, seizures and hypotonia.
Sources: Literature
Mendeliome v1.370 DUT Seb Lunke Marked gene: DUT as ready
Mendeliome v1.369 DUT Daniel Flanagan gene: DUT was added
gene: DUT was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DUT were set to 28073829; 35611808
Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome (MIM#620044)
Review for gene: DUT was set to GREEN
Added comment: Homozygous missense (p.(Tyr142Cys)) identified in eight affected individuals from four unrelated consanguineous families (French, Egyptian, two Libyan) with diabetes and bone marrow failure. DUT silencing in human and rat pancreatic b-cells results in apoptosis via the intrinsic cell death pathway.

p.(Tyr142Cys) has 11 heterozygotes and no homozygotes in gnomAD.
Sources: Expert list
Mendeliome v1.369 CENPP Seb Lunke Marked gene: CENPP as ready
Mendeliome v1.369 CENPP Seb Lunke changed review comment from: Sources: Literature; to: Single family with dominant SNHL segregated through 5 family members. Truncating variant in NM_001012267.3(CENPP):c.849T>A (p.Cys283Ter). Note: misannotated as nonsense variant in paper.
Sources: Literature
Mendeliome v1.369 CENPP Seb Lunke gene: CENPP was added
gene: CENPP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CENPP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CENPP were set to 36071244
Phenotypes for gene: CENPP were set to autosomal dominant nonsyndromic hearing loss; MONDO:0019587
Review for gene: CENPP was set to RED
Added comment: Sources: Literature
Mendeliome v1.368 SLC13A1 Zornitza Stark Marked gene: SLC13A1 as ready
Mendeliome v1.368 GABRG1 Anna Ritchie gene: GABRG1 was added
gene: GABRG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRG1 were set to PMID: 36121006
Phenotypes for gene: GABRG1 were set to Developmental and epileptic encephalopathy MONDO:0100062
Added comment: 2-year-old patient with epileptic encephalopathy, hypotonia, and global developmental delays. Clinical trio exome sequencing showed a novel, de novo missense variant in the GABRG1 gene.
Sources: Literature
Mendeliome v1.367 MED11 Ain Roesley Marked gene: MED11 as ready
Mendeliome v1.366 MED11 Ain Roesley gene: MED11 was added
gene: MED11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related
Review for gene: MED11 was set to GREEN
gene: MED11 was marked as current diagnostic
Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*).

Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes

NO evidence of founder effect from haplotype analysis

7/7 cerebral dysgyria, cortical atrophy
5/7 limb contracture
4/7 epilepsy
3/7 families with IUGR
3/7 GDD
3/7 hearing loss
3/7 undescended testis
2/7 nystagmus
1/7 congenital cataract
Sources: Literature
Mendeliome v1.364 SLC13A1 Lucy Spencer gene: SLC13A1 was added
gene: SLC13A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A1 were set to 36175384
Phenotypes for gene: SLC13A1 were set to sulfation-related bone disorder MONDO:0019688, SLC13A1-related
Review for gene: SLC13A1 was set to RED
Added comment: PMID: 36175384- 1 patient with a homozygous nonsense variant in SLC13A1. Patient has enlargements of the joints, and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. Also autistic features and hyposulfatemia and hypersulfaturia, and reduced serum cholesterol sulfate. However the variant in this individual (Arg12Ter) has 569 hets and 1 hom in gnomad.

Also this patient was homozygous for CFTR Ala455Gly which is a known pathogenic variant associated with a less severe CF phenotype.
Sources: Literature
Mendeliome v1.363 NAPB Alison Yeung Marked gene: NAPB as ready
Mendeliome v1.362 FKBP6 Zornitza Stark Marked gene: FKBP6 as ready
Mendeliome v1.361 MTSS1L Elena Savva Marked gene: MTSS1L as ready
Mendeliome v1.361 SARS Ee Ming Wong edited their review of gene: SARS: Added comment: -Two missense variants within the aminoacylation domain identified in 16 affected individuals from 3 distinct CMT families
-Mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation; Changed rating: GREEN; Changed publications: 36088542; Changed phenotypes: Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.361 FOSL2 Zornitza Stark Marked gene: FOSL2 as ready
Mendeliome v1.359 MTSS1L Elena Savva gene: MTSS1L was added
gene: MTSS1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTSS1L were set to PMID: 36067766
Phenotypes for gene: MTSS1L were set to Intellectual disability, MTSS2-related (MONDO#0001071)
Review for gene: MTSS1L was set to GREEN
Added comment: Alt gene name: MTSS2

Huang (2022): recurring de novo missense variant (p.R671W) causing syndromic intellectual disability in 5 unrelated individuals.
- Individuals present with GDD, mild ID (5/5), nystagmus (3/5), optic atrophy (1/5), ptosis (2/5), sensorineural hearing loss (2/4), microcephaly or relative microcephaly (5/5), and shared mild facial dysmorphisms.
- Overexpression supports a DN mechanism
Sources: Literature
Mendeliome v1.358 DAW1 Alison Yeung Marked gene: DAW1 as ready
Mendeliome v1.357 DAW1 Alison Yeung gene: DAW1 was added
gene: DAW1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124
Phenotypes for gene: DAW1 were set to Primary ciliary dyskinesia, MONDO:0016575; Visceral heterotaxy, MONDO:0018677
Review for gene: DAW1 was set to GREEN
Added comment: Biallelic variants identified in two unrelated families. Zebrafish model recapitulates PCD and heterotaxy phenotype
Sources: Literature
Mendeliome v1.356 RABGAP1 Zornitza Stark Marked gene: RABGAP1 as ready
Mendeliome v1.354 NAPB Paul De Fazio gene: NAPB was added
gene: NAPB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 26235277; 28097321; 33189936
Phenotypes for gene: NAPB were set to Developmental and epileptic encephalopathy 107 MIM#620033
Review for gene: NAPB was set to GREEN
gene: NAPB was marked as current diagnostic
Added comment: PMID 26235277: homozygous nonsense variant identified in a 6 year old girl by trio WES with early-onset epileptic encephalopathy characterised by multifocal seizures and profound GDD

PMID 28097321: exome sequencing in 152 consanguineous families with at least one member affected with ID. Homozygous nonsense variant identified in a patient with profound ID, seizures, feeding difficulties in infancy, muscularhypotonia, microcephaly, and impaired vision

PMID 33189936: homozygous canonical splice variant identified by trio exome sequencing in two siblings with seizures, intellectual disability and global developmental delay, microcephaly (<-3SD), and muscular hypotonia.
Sources: Literature
Mendeliome v1.354 FKBP6 Dean Phelan gene: FKBP6 was added
gene: FKBP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FKBP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FKBP6 were set to PMID: 36150389
Phenotypes for gene: FKBP6 were set to Spermatogenic failure (MONDO:0004983), FKBP6-related
Review for gene: FKBP6 was set to GREEN
Added comment: PMID: 36150389 - large cohort study of men with severe spermatogenic failure (SPGF), identified six individuals with rare bi-allelic loss of function variants in FKBP6. RT-qPCR and immunofluorescence confirmed lack of FKBP6 expression. In mice, Fkbp6 has also been shown to be essential for spermatogenesis.
Sources: Literature
Mendeliome v1.348 NSD2 Zornitza Stark edited their review of gene: NSD2: Added comment: PMID 36189577: two individuals reported with a GoF variant, p.Glu1099Lys, and a distinct phenotype: intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly.; Changed phenotypes: Rauch-Steindl syndrome, MIM# 619695, Microcephaly, intellectual disability, Neurodevelopmental disorder, NSD2-associated, GoF, MONDO:0700092
Mendeliome v1.348 FOSL2 Krithika Murali gene: FOSL2 was added
gene: FOSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOSL2 were set to 36197437
Phenotypes for gene: FOSL2 were set to Neurodevelopmental disorder, MONDO:0700092, FOSL2-related
Review for gene: FOSL2 was set to GREEN
Added comment: PMID 36197437 Cospain et al 2022 report 11 individuals from 10 families with heterozygous PTC variants in exon 4/4 of the FOSL2 gene. All variants were predicted to escape NMD resulting in a truncated protein, with the truncation occurring proximal to the C-terminal domain (supportive functional studies).

In 10/11 families the variant occurred de novo in a single affected proband. In one family with 2 affected siblings, the variant was present in the siblings but absent in the unaffected parent likely due to gonadal mosaicism.

Clinical features included:
- Cutis aplasia congenital of the scalp (10/11)
- Tooth enamel hypoplasia and discolouration (8/9)
- Multiple other ectodermal features also noted e.g. small brittle nails, hypotrichosis/hypertrichosis, lichen sclerosis
- 5 individuals had cataracts (mostly bilateral, congenital/early childhood onset)
- 6/9 IUGR
- 5/9 postnatal growth restriction
- 7/9 developmental delay/ID
- 5/7 ADHD/ASD
- 2/9 seizures
Sources: Literature
Mendeliome v1.346 TRAF3 Zornitza Stark edited their review of gene: TRAF3: Added comment: PMID 35960817: Nine individuals from five unrelated families with childhood-onset immune diseases and recurrent infections. All patients had suffered recurrent ear and sinopulmonary infections, including pneumonias from encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenza, resulting in early-onset bronchiectasis in several individuals; Changed rating: GREEN; Changed publications: 20832341, 35960817; Changed phenotypes: Autoinflammatory syndrome, TRAF3-related, MONDO:0019751, hypergammaglobulinemia, lymphadenopathy, splenomegaly, Sjögren’s syndrome, {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5}, MIM# 614849
Mendeliome v1.346 KCNK3 Krithika Murali reviewed gene: KCNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36195757; Phenotypes: eurodevelopmental disorder, MONDO:0700092, KCNK3-related, developmental delay with sleep apnoea (DDSA), Pulmonary hypertension, primary, 4-MIM#615344; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.346 COQ4 Zornitza Stark changed review comment from: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. At least 9 unrelated families reported.; to: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. At least 9 unrelated families reported.

Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations.
Mendeliome v1.346 ADAMTS19 Zornitza Stark Phenotypes for gene: ADAMTS19 were changed from Non-syndromic heart valve disease to Cardiac valvular dysplasia 2, MIM# 620067
Mendeliome v1.345 ADAMTS19 Zornitza Stark edited their review of gene: ADAMTS19: Changed phenotypes: Cardiac valvular dysplasia 2, MIM# 620067
Mendeliome v1.344 DPH2 Zornitza Stark Phenotypes for gene: DPH2 were changed from Diphthamide-deficiency syndrome to Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MIM# 620062; Diphthamide-deficiency syndrome
Mendeliome v1.343 DPH2 Zornitza Stark reviewed gene: DPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MIM# 620062; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.343 ARSB Zornitza Stark Tag clinical trial tag was added to gene: ARSB.
Mendeliome v1.343 ARSB Zornitza Stark Tag treatable tag was added to gene: ARSB.
Mendeliome v1.343 ARG1 Zornitza Stark Tag treatable tag was added to gene: ARG1.
Mendeliome v1.342 ACVR1 Zornitza Stark changed review comment from: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner.

Multiple unrelated families reported. The R206H variant is recurrent.

Note variants in this gene are also associated with congenital heart disease, PMID 29089047.; to: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner.

Multiple unrelated families reported. The R206H variant is recurrent.

Clinical trial with palovarotene

Note variants in this gene are also associated with congenital heart disease, PMID 29089047.
Mendeliome v1.342 ALDOB Zornitza Stark reviewed gene: ALDOB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fructose intolerance, hereditary, MIM# 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.342 ATP7A Zornitza Stark changed review comment from: ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein.; to: ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein.

Treatment for Menkes disease: subcutaneous injections of copper histidine or copper chloride

ClinGen has assessed as moderate evidence for actionability.

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.
Mendeliome v1.342 ATRX Zornitza Stark Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome; Mental retardation-hypotonic facies syndrome, X-linked to Alpha-thalassemia/mental retardation syndrome, MIM# 301040; Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580
Mendeliome v1.341 PDCD6IP Zornitza Stark Phenotypes for gene: PDCD6IP were changed from Neurodevelopmental disorder MONDO:0700092; Microcephaly; intellectual disability to Microcephaly 29, primary, autosomal recessive, MIM# 620047; Microcephaly; intellectual disability
Mendeliome v1.340 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Changed phenotypes: Microcephaly 29, primary, autosomal recessive, MIM# 620047, Microcephaly, intellectual disability
Mendeliome v1.340 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Changed phenotypes: Microcephaly 29, primary, autosomal recessive , MIM# 620047, Microcephaly, intellectual disability
Mendeliome v1.340 DPP9 Zornitza Stark Marked gene: DPP9 as ready
Mendeliome v1.339 DPP9 Zornitza Stark gene: DPP9 was added
gene: DPP9 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPP9 were set to 36112693
Phenotypes for gene: DPP9 were set to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias
Review for gene: DPP9 was set to GREEN
Added comment: Three unrelated families with Hatipoğlu syndrome with biochemical and cellular assays, mouse and zebrafish models. Immunological features of recurrent fevers, repeated infections, herpes susceptibility, cytopenias.
Sources: Expert Review
Mendeliome v1.338 ARSA Zornitza Stark Tag treatable tag was added to gene: ARSA.
Tag clinical trial tag was added to gene: ARSA.
Mendeliome v1.338 ARPC1B Zornitza Stark Tag treatable tag was added to gene: ARPC1B.
Mendeliome v1.338 AQP2 Zornitza Stark changed review comment from: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants.; to: Dominant disease is caused by variants exerting a dominant negative effect, whereas recessive disease is caused by bi-allelic loss of function variants.

Onset in infancy. Causes severe dehydration, can be life-threatening.

Treatment: hydration, low-salt, low-protein diet, thiazide diuretics, amiloride, indomethacin.

Clinical trials.
Mendeliome v1.338 APRT Zornitza Stark changed review comment from: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic.; to: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic.

Treatable: allopurinol or febuxostat, low purine diet.
Mendeliome v1.338 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features to Intestinal dysmotility syndrome, MIM# 620045; Impaired intestinal peristalsis; haemorrhagic diarrhoea; dysmorphic features
Mendeliome v1.337 ABCC6 Zornitza Stark Phenotypes for gene: ABCC6 were changed from Pseudoxanthoma elasticum, MIM# 264800; Pseudoxanthoma elasticum, forme fruste, MIM#177850 to Arterial calcification, generalized, of infancy, 2, MIM# 614473; Pseudoxanthoma elasticum, MIM# 264800; Pseudoxanthoma elasticum, forme fruste, MIM#177850
Mendeliome v1.335 ABCC6 Zornitza Stark edited their review of gene: ABCC6: Added comment: GACI is a treatable disorder.; Changed rating: GREEN; Changed publications: 33005041, 34355424; Changed phenotypes: Arterial calcification, generalized, of infancy, 2, MIM# 614473; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.333 GIF Zornitza Stark Marked gene: GIF as ready
Mendeliome v1.333 GIF Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CBLIF.
Mendeliome v1.333 PTPA Zornitza Stark Marked gene: PTPA as ready
Mendeliome v1.332 PTPA Zornitza Stark gene: PTPA was added
gene: PTPA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability, MONDO: 36073231, PTPA-related
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

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Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Mendeliome v1.328 PKHD1 Zornitza Stark edited their review of gene: PKHD1: Added comment: Notę heterozygous carriers reported to have liver cysts and nephrocalcinosis, gene-disease association considered MODERATE by ClinGen.; Changed publications: 28375157, 21945273; Changed phenotypes: Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200, Nephrocalcinosis, MONDO:0001567, PKHD1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.325 PPP2R5C Teresa Zhao changed review comment from: - ClinVar: two de novo missense variants (p.E177K and p.H188R), one has been reported for intellectual disability

- PMID 25972378: inframe del (T157del) found in a de novo individual with ID, facial asymmetry, conductive HL, overgrowth

- VCGS proband: additional de novo missense variant (p.K299E) found in one individual with syndromic intellectual disability; to: - ClinVar: two de novo missense variants (p.E177K and p.H188R), one has been reported for intellectual disability

- PMID 25972378: inframe del (T157del) found in a de novo individual with ID, facial asymmetry, conductive HL, overgrowth

- VCGS proband: additional de novo missense variant (p.K299E) found in one individual with syndromic intellectual disability
Mendeliome v1.325 MYH8 Ain Roesley reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: 15590965, 17041932, 15282353; Phenotypes: Carney complex variant MIM#60883; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v1.323 NODAL Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad.

The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED.

A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance.

Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987
Mendeliome v1.323 OOEP Bryony Thompson Phenotypes for gene: OOEP were changed from Multi locus imprinting disturbance in offspring to Multi locus imprinting disturbance in offspring; female infertility due to oocyte meiotic arrest MONDO:0044626
Mendeliome v1.320 OOEP Bryony Thompson reviewed gene: OOEP: Rating: AMBER; Mode of pathogenicity: None; Publications: 35946397, 18804437; Phenotypes: female infertility due to oocyte meiotic arrest MONDO:0044626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.318 UBAP2L Zornitza Stark changed review comment from: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).
Sources: Literature; to: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in 11 individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).
Sources: Literature
Mendeliome v1.318 UBAP2L Zornitza Stark Marked gene: UBAP2L as ready
Mendeliome v1.317 UBAP2L Zornitza Stark gene: UBAP2L was added
gene: UBAP2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).
Sources: Literature
Mendeliome v1.316 ALDH1A2 Zornitza Stark Phenotypes for gene: ALDH1A2 were changed from congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features to Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025
Mendeliome v1.315 ALDH1A2 Zornitza Stark reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.314 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Mendeliome v1.312 PDZD8 Zornitza Stark Marked gene: PDZD8 as ready
Mendeliome v1.310 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to RED
Added comment: SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Mendeliome v1.310 HNRNPH1 Zornitza Stark Phenotypes for gene: HNRNPH1 were changed from HNRNPH1‐related syndromic intellectual disability to HNRNPH1‐related syndromic intellectual disability; early onset high myopia, MONDO:0001384
Mendeliome v1.308 TMEM163 Zornitza Stark Marked gene: TMEM163 as ready
Mendeliome v1.304 NBAS Zornitza Stark edited their review of gene: NBAS: Added comment: PMID 35902954 - Biallelic NBAS variants identifed in three HLH patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS-defcient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus.; Changed publications: 31761904, 35902954; Changed phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, Infantile liver failure syndrome 2, MIM# 616483, Haemophagocytic lymphohistiocytosis (HLH), MONDO:0015541
Mendeliome v1.304 TYMS Zornitza Stark Marked gene: TYMS as ready
Mendeliome v1.303 COX11 Zornitza Stark Marked gene: COX11 as ready
Mendeliome v1.302 COX11 Zornitza Stark gene: COX11 was added
gene: COX11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551
Phenotypes for gene: COX11 were set to Mitochondrial disease (MONDO:0044970), COX11-related
Review for gene: COX11 was set to GREEN
Added comment: PMID: 36030551
- Biallelic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated consanguineous families, one with homozygous missense variant, another with homozygous frameshift variant.
- Functional studies supported pathogenicity of the missense variant, and showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10.
- RNA studies suggested the mutant transcript with p.(Val12Glyfs*21) is not degraded by nonsense mediated decay.
Sources: Literature
Mendeliome v1.301 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048
Mendeliome v1.300 TMEM147 Zornitza Stark Marked gene: TMEM147 as ready
Mendeliome v1.299 SAT1 Zornitza Stark Phenotypes for gene: SAT1 were changed from to Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Keratosis follicularis spinulosa decalvans
Mendeliome v1.291 GATA1 Zornitza Stark edited their review of gene: GATA1: Added comment: PMID 36029112: De novo GATA1 initiation codon variant (c.3G>A) identified in a Diamond-Blackfan Anaemia patient. Functional evidence showed that the variant does not affect the GATA1 mRNA but brings about a shorter GATA1 isoform (GATA1s) and reduced full-length functional GATA1 protein (GATA1fl), thereby contributing to an erythropoietic defect. Four other GATA1 variants (c.2T>C, c.220G>C, c.220delG, c.220+2T>C) found in eight families have been described as DBA phenotype.; Changed publications: 36029112; Changed phenotypes: Thrombocytopaenia, X-linked, with or without dyserythropoietic anaemia, MIM# 300367, Haemolytic anaemia due to elevated adenosine deaminase, MIM# 301083, Anemia, X-linked, with/without neutropenia and/or platelet abnormalities, MIM# 300835, Diamond-Blackfan anemia (MONDO:0015253)
Mendeliome v1.291 LGI3 Zornitza Stark Marked gene: LGI3 as ready
Mendeliome v1.291 LGI3 Zornitza Stark Phenotypes for gene: LGI3 were changed from Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi to Neurodevelopmental disorder, MONDO:0700092, LGI3-related; Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi
Mendeliome v1.289 TMEM147 Naomi Baker gene: TMEM147 was added
gene: TMEM147 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM147 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM147 were set to PMID: 36044892
Phenotypes for gene: TMEM147 were set to Neurodevelopmental disorder (MONDO:0700092), TMEM147-related
Review for gene: TMEM147 was set to GREEN
Added comment: PMID: 36044892; Twelve different variants reported in 23 affected individuals from 15 unrelated families with biallelic variants. All individuals had global developmental delay and intellectual disability. Consistent facial dysmorphisms included coarse facies, prominent forehead, board depressed nasal root, tented mouth, long smooth philtrum, and low-set ears. In vitro studies of missense variants demonstrated accelerated protein degradation via the autophagy-lysosomal pathway, while analysis of primary fibroblasts and granulocytes provided functional evidence of ER and nuclear envelope dysfunction.
Sources: Literature
Mendeliome v1.289 SARS Ee Ming Wong reviewed gene: SARS: Rating: RED; Mode of pathogenicity: Other; Publications: 36041817; Phenotypes: neurodevelopmental disorder, MONDO#070009, SARS1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.289 ADAMTS15 Zornitza Stark Marked gene: ADAMTS15 as ready
Mendeliome v1.288 CAPRIN1 Zornitza Stark Marked gene: CAPRIN1 as ready
Mendeliome v1.287 CBLB Alison Yeung Marked gene: CBLB as ready
Mendeliome v1.286 CBLB Alison Yeung gene: CBLB was added
gene: CBLB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBLB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBLB were set to 36006710
Phenotypes for gene: CBLB were set to Autoimmune disease, MONDO:0007179
Review for gene: CBLB was set to GREEN
Added comment: Distinct homozygous mutations in CBLB were identified in three unrelated children with early onset autoimmunity. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyper-proliferation in response to antigen receptor cross-linking.
Sources: Literature
Mendeliome v1.285 TYMS Lucy Spencer gene: TYMS was added
gene: TYMS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TYMS was set to Other
Publications for gene: TYMS were set to 35931051
Phenotypes for gene: TYMS were set to Dyskeratosis congenita MONDO:0015780
Review for gene: TYMS was set to RED
Added comment: 8 families with dyskeratosis congenita and heterozygous variants in TYMS. 4 PTCs, 2 missense and 1 splice (2 families had the same frameshift). However in all families 1 unaffected parent was also heterozygous for the same TYSM variant.

The other parent in 3 of these families was then shown to carry a heterozygous variant in ENOSF1 which each affected child was also heterozygous for. ENOSF1 has been shown to modify TYMS expression at the RNA level by acting as an antisense molecule to TYMS. ENOSF1 partially overlaps TYMS on chromosome 18 and is transcribed in the opposite direction to TYMS. This paper is suggesting digenic inheritance.

The TYMS wild type parent from another family was seen to have a TYMSOS variant which was also observed along with the TYMS variant in their 2 affected children.

Immunoblotting showed a stark reduction in TYMS protein level in the cells of affected probands when compared to the parent carrier, wild-type parent, and the controls.

Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1.
Sources: Literature
Mendeliome v1.285 LGI3 Melanie Marty edited their review of gene: LGI3: Changed phenotypes: Global developmental delay, Intellectual disability, Distal deformities, Diminished reflexes, Facial myokymia, Hyporeflexia/areflexia
Mendeliome v1.285 HNRNPH1 Hazel Phillimore changed review comment from: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2).
In gnomAD, there are very few LOF variants. (LOF shows pLI = 1).
The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.; to: PMID: 35989590; Ouyang, J. et al. (2022): Two loss of function variants c.2dup, p.(M1?) and c.121dup, p.(Q41Pfs*20), were found in two individuals with early onset high myopia. They were in cohort of 928 probands with early onset high myopia. The pedigrees for these probands indicate that no other relatives were affected. However, it does not appear that any relatives were tested for these variants. These variants were reported to be absent in gnomAD. Note: there is actually 1 heterozygote for an alternative variant that is predicted to cause p.(Met1?) in gnomADv2.
In gnomAD, there are very few LOF variants. (LOF shows pLI = 1).
The group also studied knockdown of this gene in zebrafish, which resulted in ocular coloboma.
Mendeliome v1.285 HNRNPH1 Hazel Phillimore reviewed gene: HNRNPH1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35989590; Phenotypes: early onset high myopia, blindness; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.285 TMEM163 Teresa Zhao changed review comment from: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures and two have ID.
Sources: Literature; to: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures.
Sources: Literature
Mendeliome v1.285 MET Zornitza Stark Phenotypes for gene: MET were changed from Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884 to Arthrogryposis, distal, type 11 (MIM#620019), AD; Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884
Mendeliome v1.283 MET Zornitza Stark changed review comment from: PMID 30777867:
Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.; to: PMID 30777867:
Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.

AMBER for this association
Mendeliome v1.283 MET Zornitza Stark edited their review of gene: MET: Added comment: PMID 30777867:
Four-generation Chinese arthrogryposis pedigree with only upper limb involvement. MET c.3701A>G p.Y1234C segregated as heterozygous in 11 affected family members and was absent from 12 unaffected family members. Variant is absent from gnomad. Functional studies showed this variant caused failure of phosphorylation and loss of tyrosine kinase activity of MET receptor. A mouse model was also created with this variant, mutated mice were found to be smaller than WT mice and had reduced myofibres. These mouse models also had defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. Phenotypes in this family included camptodactyly, absent flexion crease, and limited forearm supination.; Changed publications: 30777867
Mendeliome v1.283 TMEM163 Teresa Zhao gene: TMEM163 was added
gene: TMEM163 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM163 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM163 were set to PMID: 35953447
Phenotypes for gene: TMEM163 were set to Hypomyelinating leukodystrophy
Review for gene: TMEM163 was set to GREEN
Added comment: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures and two have ID.
Sources: Literature
Mendeliome v1.283 LGI3 Melanie Marty gene: LGI3 was added
gene: LGI3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to PMID: 35948005
Phenotypes for gene: LGI3 were set to Global developmental delay; Intellectual disability; Distal deformities; Diminished reflexes; Facial myokymia; Hyporeflexia/areflexi
Review for gene: LGI3 was set to GREEN
Added comment: Sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3.
Lgi3-null mice showed reduced and mis-local-ized Kv1 channel complexes in myelinated peripheral axons.
Sources: Literature
Mendeliome v1.280 BUD13 Alison Yeung Marked gene: BUD13 as ready
Mendeliome v1.279 BUD13 Alison Yeung gene: BUD13 was added
gene: BUD13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BUD13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUD13 were set to 35670808
Phenotypes for gene: BUD13 were set to Lipodystrophy, MONDO:0006573
Review for gene: BUD13 was set to AMBER
Added comment: 5 individuals with a lipodystrophy phenotype with a typical facial appearance, corneal clouding, achalasia, progressive hearing loss, and variable severity. Although 3 individuals showed stunted growth, intellectual disability, and died within the first decade of life, 2 are adults with normal intellectual development. All individuals harbored an identical homozygous nonsense variant affecting the retention and splicing complex component BUD13. Individuals from only two Algerian families.
Sources: Literature
Mendeliome v1.276 NOTCH1 Chern Lim changed review comment from: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Missense and small inframe insertion variants in the negative regulatory region.; to: PMID: 35947102:
- Seven unrelated patients with leukoencephalopathy and calcifications, germline heterozygous de novo gain-of-function variants in NOTCH1.
- Other clinical features include intellectual disability, spasticity and etc. Childhood onset in most individuals however 15y and 40y reported in two individuals.
- Missense and small inframe insertion variants in the negative regulatory region.
Mendeliome v1.276 ADAMTS15 Naomi Baker changed review comment from: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature; to: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: contractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature
Mendeliome v1.276 ADAMTS15 Naomi Baker gene: ADAMTS15 was added
gene: ADAMTS15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS15 were set to PMID: 35962790
Phenotypes for gene: ADAMTS15 were set to Arthrogryposis (MONDO:0008779), ADMATS15-related
Review for gene: ADAMTS15 was set to GREEN
Added comment: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature
Mendeliome v1.276 CAPRIN1 Paul De Fazio gene: CAPRIN1 was added
gene: CAPRIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPRIN1 were set to 35979925
Phenotypes for gene: CAPRIN1 were set to Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092
Review for gene: CAPRIN1 was set to GREEN
gene: CAPRIN1 was marked as current diagnostic
Added comment: 12 individuals reported with ID and language impairment. Other features included seizures (4 individuals), hands and feet malformations (5 individuals), breathing problems (6 individuals), ocular problems (4 individuals) and hearing problems (3 individuals).

All of the variants were nonsense (NMD-predicted) or splicing variants. 10 were de novo, 1 was inherited from an affected father. Functional studies supported pathogenicity.
Sources: Literature
Mendeliome v1.276 LHX8 Alison Yeung gene: LHX8 was added
gene: LHX8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LHX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LHX8 were set to 36029299
Phenotypes for gene: LHX8 were set to Inherited premature ovarian failure, MONDO:0019852, LHX8-related
Review for gene: LHX8 was set to GREEN
Added comment: Heterozygous LOF variants identified in 6 families with premature ovarian failure due to oocyte maturation arrest.
Sources: Literature
Mendeliome v1.271 LEF1 Zornitza Stark edited their review of gene: LEF1: Added comment: Monoallelic variants in LEF1 reported in 11 affected individuals from 4 unrelated families, and a biallelic variant reported in an affected individual from a consanguineous family. The phenotypic spectrum included various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Haploinsufficiency or loss of DNA binding postulated to be responsible for a mild to moderate phenotype, whereas loss of β-catenin binding caused by biallelic variants postulated to be associated with a severe phenotype.; Changed rating: GREEN; Changed publications: 32022899, 35583550; Changed phenotypes: Syndromic disease, MONDO:0002254, LEF1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.271 REEP1 Zornitza Stark Phenotypes for gene: REEP1 were changed from Neuronopathy, distal hereditary motor, type VB MIM#614751; Spastic paraplegia 31, autosomal dominant MIM#610250; Charcot-Marie-Tooth; severe congenital distal SMA with diaphragmatic paralysis; congenital axonal neuropathy and diaphragmatic palsy to Spinal muscular atrophy, distal, autosomal recessive, 6, MIM#620011; Neuronopathy, distal hereditary motor, type VB MIM#614751; Spastic paraplegia 31, autosomal dominant MIM#610250
Mendeliome v1.270 REEP1 Zornitza Stark reviewed gene: REEP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy, distal, autosomal recessive, 6, MIM#620011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.270 CCDC82 Zornitza Stark Marked gene: CCDC82 as ready
Mendeliome v1.270 CCDC82 Zornitza Stark Phenotypes for gene: CCDC82 were changed from Intellectual disability and spastic paraparesis, no OMIM # to Neurodevelopmental disorder, MONDO:0700092, CCDC82-related
Mendeliome v1.268 NPNT Zornitza Stark Marked gene: NPNT as ready
Mendeliome v1.265 KIF5B Zornitza Stark Marked gene: KIF5B as ready
Mendeliome v1.264 COL9A3 Zornitza Stark Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome AR; Deafness AD; Peripheral vitreoretinal degeneration and retinal detachment, AD to Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome, type VI, MIM# 620022; Deafness AD; Peripheral vitreoretinal degeneration and retinal detachment, AD
Mendeliome v1.261 CCDC82 Chirag Patel gene: CCDC82 was added
gene: CCDC82 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to PMID: 35373332, 35118659, 27457812
Phenotypes for gene: CCDC82 were set to Intellectual disability and spastic paraparesis, no OMIM #
Review for gene: CCDC82 was set to GREEN
Added comment: 4 consanguineous families with 9 affected individuals with developmental delay/intellectual disability, and 2 families had spasticity and 1 had epilepsy. WES identified 3 homozgyous truncating variants, segregating with disease and parents as carriers. No functional studies.
Sources: Literature
Mendeliome v1.259 NPNT Chirag Patel gene: NPNT was added
gene: NPNT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPNT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792
Phenotypes for gene: NPNT were set to Renal agenesis, no OMIM #
Review for gene: NPNT was set to GREEN
Added comment: 3 consanguineous families with multiple affecteds with bilateral renal agenesis. Whole-exome sequencing (WES)-based homozygosity mapping identified 2 homozygous truncating variants. Reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Loss of nephronectin (NPNT) is known to lead to failure of metanephric kidney development with resulting renal agenesis in murine models.
Sources: Literature
Mendeliome v1.257 KIF5B Chirag Patel gene: KIF5B was added
gene: KIF5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5B were set to PMID: 35342932
Phenotypes for gene: KIF5B were set to Kyphomelic dysplasia, no OMIM #
Review for gene: KIF5B was set to GREEN
Added comment: 4 individuals with Kyphomelic dysplasia (severe bowing of the limbs, sharp angulation of the femora and humeri, short stature, narrow thorax, distinctive facial features, and neonatal respiratory distress. WES found de novo heterozygous missense variants in KIF5B encoding kinesin-1 heavy chain. All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. No functional studies of variants. Previously 2 animal model experiments showed that loss of function of KIF5B can cause kyphomelic dysplasia. First, chondrocyte-specific knockout of Kif5b in mice was shown to produce a disorganized growth plate, leading to bone deformity. Second, double mutants disrupting the two zebrafish kif5b caused abnormal skeletal morphogenesis and the curvature of Meckel's and ceratohyal cartilages.
Sources: Literature
Mendeliome v1.253 ACADS Zornitza Stark changed review comment from: Definitive by ClinGen.; to: Definitive by ClinGen. However, largely just causes a biochemical abnormality, and association with clinical disease is debated.
Mendeliome v1.253 FOCAD Zornitza Stark Marked gene: FOCAD as ready
Mendeliome v1.252 FOCAD Zornitza Stark gene: FOCAD was added
gene: FOCAD was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOCAD were set to 35864190
Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, MIM# 619991
Review for gene: FOCAD was set to GREEN
Added comment: Moreno Traspas et al 2022 reported 14 children from ten unrelated families with syndromic form of pediatric liver cirrhosis. Genome/exome sequencing analysis reveled biallelic variants in the FOCAD gene. Most of the mutations were nonsense, frameshift, or splice site alterations, predicted to result in a loss of function, but there were also 3 missense variants at highly conserved residues. Western blot analysis of dermal fibroblasts derived from 2 patients showed near absent FOCAD expression in cellular extracts. There were also decreased levels of the SKIC2 protein, suggesting that FOCAD may contribute to the stability of RNA helicase (OMIM: 619991).
Sources: Expert Review
Mendeliome v1.248 ZMYND8 Zornitza Stark Marked gene: ZMYND8 as ready
Mendeliome v1.247 ZMYND8 Zornitza Stark gene: ZMYND8 was added
gene: ZMYND8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Expert Review
Mendeliome v1.246 TRAC Seb Lunke Added comment: Comment on list classification: Single variant reported to date in 6 patients; 2 unrelated children from consanguineous families of Pakistani descent (PMID: 21206088); 1 non-consanguineous family from North-west India (PMID: 33909184) and 1 consanguineous parents of East Indian (https://lymphosign.com/doi/10.14785/lymphosign-2022-0001) Also note annotation issues in certain variant curation and annotation tools.
Mendeliome v1.242 PRIM1 Zornitza Stark Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, MIM# 620005
Mendeliome v1.241 PRIM1 Zornitza Stark edited their review of gene: PRIM1: Changed phenotypes: Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, MIM# 620005
Mendeliome v1.241 SMG9 Zornitza Stark Phenotypes for gene: SMG9 were changed from Heart and brain malformation syndrome, MIM# 616920 to Heart and brain malformation syndrome, MIM# 616920; Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Mendeliome v1.239 SMG9 Zornitza Stark edited their review of gene: SMG9: Added comment: PMID 35087184: 5 individuals from 3 unrelated Finnish families reported with same homozygous missense variant (founder effect) and predominantly neurological phenotype. Uncertain if this is a distinct disorder or part of a spectrum with the previously reported cases.; Changed publications: 27018474, 31390136, 35087184; Changed phenotypes: Heart and brain malformation syndrome, MIM# 616920, Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Mendeliome v1.239 THUMPD1 Zornitza Stark Phenotypes for gene: THUMPD1 were changed from Syndromic disease, MONDO:0002254, THUMPD1-related to Neurodevelopmental disorder with speech delay and variable ocular anomalies, MIM# 619989
Mendeliome v1.238 THUMPD1 Zornitza Stark reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and variable ocular anomalies, MIM# 619989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.238 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Susceptibility to infection with Staphylococcus aureus; Hereditary predisposition to infections, MONDO:0015979, OTULIN-related to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.233 SPTBN5 Zornitza Stark changed review comment from: Identified as a candidate gene in a sacral agenesis cohort.

PMID 32732226: compound het variants identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis.
Sources: Literature; to: Bi-allelic variants: Identified as a candidate gene in a sacral agenesis cohort.

PMID 32732226: compound het variants identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis.
Sources: Literature
Mendeliome v1.233 SPTBN5 Zornitza Stark edited their review of gene: SPTBN5: Added comment: Monoallelic variants:
- Four probands from unrelated families (1x Pakistani and 3x Italian) with de novo heterozygous SPTBN5 variants
- 3x missense variants and 1x LoF variant were reported
- Phenotypes include intellectual disability (mild to severe), aggressive tendencies and variable features such as craniofacial and physical dysmorphisms, autistic behavior, and gastroesophageal reflux; Changed rating: GREEN; Changed publications: 35782384, 32732226, 28007035; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SPTBN5-related, Sacral agenesis, congenital anomalies; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.233 CPS1 Zornitza Stark Phenotypes for gene: CPS1 were changed from to Carbamoylphosphate synthetase I deficiency MIM#237300
Mendeliome v1.231 CPS1 Zornitza Stark reviewed gene: CPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Pulmonary hypertension, neonatal, susceptibility to} 615371; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.231 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099 to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Susceptibility to infection with Staphylococcus aureus; Hereditary predisposition to infections, MONDO:0015979, OTULIN-related
Mendeliome v1.228 OTULIN Zornitza Stark changed review comment from: Autoinflammatory disorder presenting in the newborn period with recurrent fever, erythematous rash with painful nodules, painful joints, diarrhoea and lipodystrophy.; to: Bi-allelic variants: Autoinflammatory disorder presenting in the newborn period with recurrent fever, erythematous rash with painful nodules, painful joints, diarrhoea and lipodystrophy.
Mendeliome v1.228 OTULIN Zornitza Stark edited their review of gene: OTULIN: Added comment: PMID 35587511: Multiple individuals reported with haploinsufficiency of OTULIN and severe staphylococcal disease, with life-threatening skin or pulmonary necrosis. Functional data.; Changed publications: 27523608, 27559085, 35587511; Changed phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099, Susceptibility to infection with Staphylococcus aureus, Hereditary predisposition to infections, MONDO:0015979, OTULIN-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.228 NOX1 Zornitza Stark gene: NOX1 was added
gene: NOX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOX1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NOX1 were set to 29091079; 32064493
Phenotypes for gene: NOX1 were set to Inflammatory bowel disease, MONDO:0005265, NOX1-related
Review for gene: NOX1 was set to AMBER
Added comment: 8 IBD patients with early onset of IBD with progressive and severe colonic disease, refractory to conventional therapy and functional studies suggesting variant-dependent loss of NOX1-mediated superoxide generation. However, high frequency of nonsynonymous mutations in NOX1 suggests that NOX1 is not a highly penetrant Mendelian disorder and that other genetic modifiers or environmental factors may contribute to disease pathogenesis.

The variant reported in PMID 32064493 is present in 6 hets in gnomad.
Sources: Literature
Mendeliome v1.227 BICD2 Zornitza Stark Phenotypes for gene: BICD2 were changed from Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290; MONDO:0014121; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291 to Neurodevelopmental disorder (MONDO#0700092), BICD2-related; Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM# 615290; MONDO:0014121; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, MIM# 618291
Mendeliome v1.224 KIF15 Alison Yeung Phenotypes for gene: KIF15 were changed from ?Braddock-Carey syndrome 2 - MIM#619981 to Braddock-Carey syndrome 2 - MIM#619981
Mendeliome v1.223 KIF15 Alison Yeung Marked gene: KIF15 as ready
Mendeliome v1.222 SARS Ain Roesley Publications for gene: SARS were set to 28236339; 34570399
Mendeliome v1.222 SARS Ain Roesley Classified gene: SARS as Green List (high evidence)
Mendeliome v1.222 SARS Ain Roesley Gene: sars has been classified as Green List (High Evidence).
Mendeliome v1.222 SARS Ain Roesley Phenotypes for gene: SARS were changed from Intellectual disability to neurodevelopmental disorder MONDO#070009, SARS1-related
Mendeliome v1.221 PSMC1 Zornitza Stark Marked gene: PSMC1 as ready
Mendeliome v1.221 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes to 35861243; spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes
Mendeliome v1.220 SARS Ain Roesley reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: neurodevelopmental disorder MONDO#070009, SARS1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.220 PSMC1 Zornitza Stark Mode of pathogenicity for gene: PSMC1 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mendeliome v1.218 PSMC1 Zornitza Stark commented on gene: PSMC1: Single family only, homozygous missense variant.
Mendeliome v1.218 WARS Seb Lunke Publications for gene: WARS were set to PMID: 28369220; 31321409; 31069783.
Mendeliome v1.217 DOHH Zornitza Stark Marked gene: DOHH as ready
Mendeliome v1.217 WARS Seb Lunke Phenotypes for gene: WARS were changed from Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); distal wasting; distal weakness; length-dependent motor axonal degeneration to Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder (MONDO:0700092), WARS-related
Mendeliome v1.215 WARS Seb Lunke Mode of inheritance for gene: WARS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.213 SLITRK2 Zornitza Stark Marked gene: SLITRK2 as ready
Mendeliome v1.213 KIF15 Krithika Murali reviewed gene: KIF15: Rating: AMBER; Mode of pathogenicity: None; Publications: 28150392; Phenotypes: ?Braddock-Carey syndrome 2 - MIM#619981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.213 WARS Anna Ritchie reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35815345, PMID: 35790048; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), WARS-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.212 PSMC1 Hazel Phillimore gene: PSMC1 was added
gene: PSMC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC1 were set to PMID: 35861243
Phenotypes for gene: PSMC1 were set to spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes
Mode of pathogenicity for gene: PSMC1 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: PSMC1 was set to AMBER
Added comment: Homozygosity mapping on one large consanguineous Bedouin kindred showed three affected children (out of the ten) to be homozygous for NM_002802.3:c.983T>C; p.(Ile328Thr).

Drosophila rescue experiments were carried out. Transgenic studies using drosophila with the silenced ortholog Rpt2 gene were rescued by the human wild-type PSMC1.

Three of the ten offspring of healthy consanguineous parents of Bedouin Israeli ancestry were affected with a similar phenotype of failure to thrive, developmental delay and severe intellectual disability, spastic tetraplegia with central hypotonia, chorea, as well as hearing loss. None of the three achieved verbal communication or ambulation (sitting / standing) at any age. They had mild dysmorphism of borderline dolichocephaly and microcephaly, prominent bushy eyebrows, flat midface, long nasal bridge and micrognathia. All three had micropenis with undescended testes. One of the affected (as a toddler) underwent thorough endocrinological analysis: testosterone and gonadotropin levels were low.
Sources: Literature
Mendeliome v1.212 KIF15 Krithika Murali gene: KIF15 was added
gene: KIF15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIF15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF15 were set to 28150392
Phenotypes for gene: KIF15 were set to ?Braddock-Carey syndrome 2 - MIM#619981
Review for gene: KIF15 was set to GREEN
Added comment: PMID 28150392 Sleiman et al 2017 report one individual with homozygous R501* variant (NMD-predicted) from a consanguineous family. The child had thrombocytopenia, PRS, microcephaly -3SD by age 6, dysmorphic facies, bilateral external auditory canal atresia and deafness, microphthalmia, clinodactyly, short stature. Variant absent from gnomAD. Parents confirmed to be carriers and unaffected siblings were carriers/homozygous wild-type.

No other SNVs reported in ClinVar. Variant is absent from gnomAD. Authors note phenotypic similarities with Braddock-Carey syndrome (21q22 contiguous deletion also involving RUNX1).
Sources: Literature
Mendeliome v1.212 BMP3 Seb Lunke Marked gene: BMP3 as ready
Mendeliome v1.211 BMP3 Seb Lunke gene: BMP3 was added
gene: BMP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP3 were set to 35089417
Phenotypes for gene: BMP3 were set to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
Review for gene: BMP3 was set to AMBER
Added comment: Single missense variant identified segregating with disease following WES screen in a family with coloboma and/or microphthalmia in BMP3. Two additional unrelated patients identified with different missense in BMP3. Pathogenicity however largely on in-silicos, with one of the 3 missense having 29 hets in gnomAD. Additional functional work in bmp3 -/- zebra fish and some supporting evidence but not conclusive
Sources: Literature
Mendeliome v1.210 C18orf32 Alison Yeung Marked gene: C18orf32 as ready
Mendeliome v1.209 ALG5 Zornitza Stark Marked gene: ALG5 as ready
Mendeliome v1.208 ALG5 Chern Lim gene: ALG5 was added
gene: ALG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALG5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALG5 were set to 35896117
Phenotypes for gene: ALG5 were set to Cystic renal disease MONDO:0002473, ALG5-related
Review for gene: ALG5 was set to GREEN
gene: ALG5 was marked as current diagnostic
Added comment: PMID:35896117:
- Five unrelated families, including 23 affected individuals with non-enlarged cystic kidneys and few or no liver cysts, 8 of them reached end-stage kidney disease from 62 to 91 years of age. Variant confirmed in all but one individual.
- Various variant types: frameshift, nonsense, two missense, splice.
- Functional studies showed haploinsufficiency is the disease mechanism.
Sources: Literature
Mendeliome v1.208 DOHH Daniel Flanagan gene: DOHH was added
gene: DOHH was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to PMID: 35858628
Phenotypes for gene: DOHH were set to Neurodevelopmental disorder, DOHH-related (MONDO#0700092)
Review for gene: DOHH was set to GREEN
Added comment: Bi-allelic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. Clinical features were developmental delay and/or intellectual disability (5/5), microcephaly (5/5), visual impairment (nystagmus (3/5), strabismus (3/5), and cortical visual impairment (1/5)) and congenital heart malformations (3/5 individuals).
Sources: Expert list
Mendeliome v1.208 SLITRK2 Paul De Fazio gene: SLITRK2 was added
gene: SLITRK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLITRK2 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: SLITRK2 were set to 35840571
Phenotypes for gene: SLITRK2 were set to Neurodevelopmental disorder, SLITRK2-related MONDO:0700092
Review for gene: SLITRK2 was set to GREEN
gene: SLITRK2 was marked as current diagnostic
Added comment: 6 missense variants and 1 nonsense variant (NOT NMD-predicted, single-exon gene) reported in 7 males and 1 female with neurodevelopmental disorders. Phenotypes included dev delay, mild to severe ID, delayed or absent speech, seizures and brain MRI anomalies (in some patients).

The nonsense variant was identified in two affected brothers but not in the mother, suggesting it was de novo in the maternal germline. The variant in the one affected female was de novo. All other variants in hemizygous males were inherited from an unaffected mother. In one case, the variant was also identified in the unaffected grandmother.

Functional studies showed some but not all variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Conditional knockout mice exhibited impaired long-term memory and abnormal gait.
Sources: Literature
Mendeliome v1.208 RFC1 Ain Roesley Phenotypes for gene: RFC1 were changed from Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome OMIM 614575 to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575
Mendeliome v1.206 C18orf32 Naomi Baker gene: C18orf32 was added
gene: C18orf32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C18orf32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C18orf32 were set to PMID:35107634
Phenotypes for gene: C18orf32 were set to Neurodevelopmental disorder (MONDO:0700092), C18orf32-related
Review for gene: C18orf32 was set to RED
Added comment: Two siblings reported as affected, although sequencing only performed in one sibling, with homozygous loss-of-function variant identified. Clinical presentation included developmental delay, recurrent lower respiratory tract infections, sparse rough hair, roving eye movements, hypotonia, bilateral ankle contractures and inverted nipples.
Sources: Literature
Mendeliome v1.205 RFC1 Ain Roesley reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35883251; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.204 ADGRL1 Elena Savva Marked gene: ADGRL1 as ready
Mendeliome v1.204 ADGRL1 Elena Savva gene: ADGRL1 was added
gene: ADGRL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ADGRL1 were set to PMID: 35907405
Phenotypes for gene: ADGRL1 were set to Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092)
Review for gene: ADGRL1 was set to GREEN
Added comment: PMID: 35907405 - 9 patients w/ ADHD (3/9), autism (4/9), mild-moderate ID (5/9) and epilepsy (2/9) and facial dysmorphism (7/9). Variants include missense (4) and PTCs (5), and were either de novo (7/9) or inherited from parents with learning difficulties/ID (2/9).

Functional studies on both PTCs and missense variants show significant reductions in calcium signalling and surface protein.

Het null mouse model shows neurological and developmental abnormalities, with hom null mice non-viable.
Sources: Literature
Mendeliome v1.202 EHHADH Zornitza Stark edited their review of gene: EHHADH: Added comment: https://clinmedjournals.org/articles/jcnrc/journal-of-clinical-nephrology-and-renal-care-jcnrc-3-027.pdf

Second case report, same variant, de novo. Also, experimental evidence. Assessed as MODERATE by ClinGen.; Changed rating: AMBER
Mendeliome v1.198 CWH43 Zornitza Stark Marked gene: CWH43 as ready
Mendeliome v1.196 ADGRA3 Zornitza Stark Marked gene: ADGRA3 as ready
Mendeliome v1.185 IKZF1 Zornitza Stark Phenotypes for gene: IKZF1 were changed from Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset; Immune dysregulation
Mendeliome v1.183 IKZF1 Zornitza Stark edited their review of gene: IKZF1: Added comment: PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.; Changed publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317, 35333544; Changed phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset, Immune dysregulation
Mendeliome v1.180 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Added comment: Iranian male with homozygous missense variant with recurrent infection, hypogammaglobulinaemia. Extends inheritance to AR. Supportive functional data.; Changed publications: 34920454, 34826259; Changed phenotypes: Immunodeficiency, MONDO:0021094, IKZF2-related, Immune dysregulation; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.180 TMEM63C Zornitza Stark Marked gene: TMEM63C as ready
Mendeliome v1.180 TMEM63C Zornitza Stark Phenotypes for gene: TMEM63C were changed from Hereditary spastic paraplegia, MONDO:0019064, TMEM63C-related to Spastic paraplegia 87, autosomal recessive, MIM# 619966
Mendeliome v1.179 TMEM63C Zornitza Stark reviewed gene: TMEM63C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 87, autosomal recessive, MIM# 619966; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.179 EIF2B1 Elena Savva reviewed gene: EIF2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31882561; Phenotypes: Leukoencephalopathy with vanishing white matter MIM#603896, permanent neonatal/early onset diabetes and transient liver dysfunction; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.179 ARFGEF1 Zornitza Stark Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Mendeliome v1.178 ARFGEF1 Zornitza Stark edited their review of gene: ARFGEF1: Changed phenotypes: Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Mendeliome v1.176 WASL Zornitza Stark Marked gene: WASL as ready
Mendeliome v1.176 WASL Zornitza Stark gene: WASL was added
gene: WASL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASL were set to 33571872
Phenotypes for gene: WASL were set to Parkinson's disease, MONDO:0005180, WASL-related
Review for gene: WASL was set to RED
Added comment: Single family reported, where bi-allelic variants segregated with PD in three affected individuals.
Sources: Literature
Mendeliome v1.173 PMM2 Zornitza Stark edited their review of gene: PMM2: Added comment: Association with HIPKD:
Cabezas et al (2017) reported co-occurrence of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD in 17 children from 11 unrelated families. Patients presented with hyperinsulinaemic hypoglycaemia in infancy and enlarged kidneys with multiple kidney cysts. Some progressed to ESKD and some had liver cysts. Whole-genome linkage analysis in 5 informative families identified a single significant locus on chromosome 16p13.2. Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, they found in all patients a promoter mutation (c.-167G>T) in PMM2, either homozygous or in trans with PMM2 coding mutations. They found deglycosylation in cultured pancreatic β cells altered insulin secretion. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2. They proposed that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. None of the patients exhibited the typical clinical or diagnostic features of CDG1A. Serum transferrin glycosylation was normal in 11 patients who had assessment.; Changed publications: 28108845, 28373276, 32595772; Changed phenotypes: Congenital disorder of glycosylation, type Ia (MIM#212065), Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease (HIPKD), MONDO:0020642, PMM2-related
Mendeliome v1.173 SLCO2A1 Zornitza Stark Phenotypes for gene: SLCO2A1 were changed from Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100; Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441 to Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100; Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441; Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related
Mendeliome v1.171 SLCO2A1 Zornitza Stark edited their review of gene: SLCO2A1: Added comment: PMID 29313109: Over 40 Japanese individuals reported with bi-allelic variants in this gene and multiple small intestinal ulcers of nonspecific histology. Some overlap with the hypertrophic osteoarthropathy also associated with bi-allelic variants in this gene. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO.; Changed publications: 23509104, 27134495, 33852188, 22331663, 27134495, 29313109; Changed phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441, Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related
Mendeliome v1.169 C20orf24 Zornitza Stark Marked gene: C20orf24 as ready
Mendeliome v1.169 C20orf24 Zornitza Stark gene: C20orf24 was added
gene: C20orf24 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C20orf24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C20orf24 were set to 35614220; 24194475
Phenotypes for gene: C20orf24 were set to Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2, MIM# 616994
Review for gene: C20orf24 was set to RED
Added comment: Bi-allelic LoF variant identified in patient originally reported in PMID 24194475.

HGNC approved name is RAB5IF.
Sources: Literature
Mendeliome v1.164 PPP1R13L Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Dilated cardiomyopathy, onset in infancy to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy
Mendeliome v1.163 CHD5 Elena Savva Phenotypes for gene: CHD5 were changed from Intellectual disability; Epilepsy to Parenti-Mignot neurodevelopmental syndrome MIM#619873
Mendeliome v1.162 CHD5 Elena Savva reviewed gene: CHD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33944996; Phenotypes: Parenti-Mignot neurodevelopmental syndrome MIM#619873; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.162 GINS3 Zornitza Stark Marked gene: GINS3 as ready
Mendeliome v1.161 GINS3 Zornitza Stark gene: GINS3 was added
gene: GINS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS3 were set to 35603789
Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome, MONDO:0016817, GINS3-related
Review for gene: GINS3 was set to GREEN
Added comment: 7 individuals from 5 families reported, presenting with prenatal and postnatal growth deficiency as well as other features. Three unique missense variants identified, two affecting p.Asp24. These variants are thought to be hypomorphic. Supportive mouse model.
Sources: Literature
Mendeliome v1.159 C9orf84 Zornitza Stark Marked gene: C9orf84 as ready
Mendeliome v1.158 C9orf84 Zornitza Stark changed review comment from: 8 families reported with bi-allelic variants in this gene and spermatogenic failure.
Sources: Literature; to: 8 families reported with bi-allelic variants in this gene and spermatogenic failure. A male germ cell-specific Shoc1 knockout mouse model recapitulates the phenotype (germline knockout: early lethality).

HGNC approved name is SHOC1.

Sources: Literature
Mendeliome v1.158 C9orf84 Zornitza Stark gene: C9orf84 was added
gene: C9orf84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C9orf84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C9orf84 were set to 32741963; 32900840; 35485979
Phenotypes for gene: C9orf84 were set to Spermatogenic failure 75, MIM# 619949
Review for gene: C9orf84 was set to GREEN
Added comment: 8 families reported with bi-allelic variants in this gene and spermatogenic failure.
Sources: Literature
Mendeliome v1.155 KMT2B Zornitza Stark edited their review of gene: KMT2B: Added comment: Nine individuals reported in PMID 33150406 with heterozygous variants in this gene and intellectual disability, speech delay, microcephaly, growth delay, feeding problems, and dysmorphic features, including epicanthic folds, posteriorly rotated ears, syndactyly/clinodactyly of toes, and fifth finger clinodactyly, normal MRIs and NO dystonia.; Changed publications: 27839873, 27992417, 33150406; Changed phenotypes: Dystonia 28, childhood-onset 617284, MONDO:0015004, Intellectual developmental disorder, autosomal dominant 68, MIM# 619934
Mendeliome v1.155 LMAN2L Zornitza Stark Phenotypes for gene: LMAN2L were changed from Mental retardation, autosomal recessive, 52; OMIM #616887 to Mental retardation, autosomal recessive, 52 OMIM #616887; Intellectual developmental disorder, autosomal dominant 69 , MIM# 617863
Mendeliome v1.154 LMAN2L Zornitza Stark edited their review of gene: LMAN2L: Changed phenotypes: Mental retardation, autosomal recessive, 52 OMIM #616887, Intellectual developmental disorder, autosomal dominant 69 , MIM# 617863
Mendeliome v1.154 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, Attention deficit-hyperactivity disorder 8 , MIM# 619957
Mendeliome v1.154 CDH2 Zornitza Stark Phenotypes for gene: CDH2 were changed from Intellectual disability; corpus callosum abnormalities; congenital abnormalities; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929 to Intellectual disability; corpus callosum abnormalities; congenital abnormalities; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929; Attention deficit-hyperactivity disorder 8 , MIM# 619957
Mendeliome v1.152 CDH2 Zornitza Stark edited their review of gene: CDH2: Added comment: PMID 34702855: three sibs with homozygous missense and strikingly severe ADHD. Mouse model of same variant recapitulated the phenotype. AMBER for bi-allelic association (segregation and functional data).; Changed publications: 31585109, 34702855; Changed phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities, Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MIM# 618929:Attention deficit-hyperactivity disorder 8 , MIM# 619957; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.151 KITLG Zornitza Stark Phenotypes for gene: KITLG were changed from Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697 to Deafness, autosomal dominant 69, unilateral or asymmetric, MIM# 616697; deafness; heterochromia iridis; hypopigmentation of the skin; hyperpigmentation of the skin; Waardenburg syndrome,MONDO:0018094, KITLG-related
Mendeliome v1.148 CLDN5 Zornitza Stark Marked gene: CLDN5 as ready
Mendeliome v1.147 CLDN5 Zornitza Stark gene: CLDN5 was added
gene: CLDN5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN5 were set to 35714222
Phenotypes for gene: CLDN5 were set to alternating hemiplegia, MONDO:0016210, CLDN5-related
Mode of pathogenicity for gene: CLDN5 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: CLDN5 was set to AMBER
Added comment: PMID: 35714222; Hashimoto, Y. et al. (2022): Two unrelated cases (early-onset) with alternating hemiplegia with microcephaly were shown to have the same de novo variant, NM_001363066.2:c.178G>A, p.(Gly60Arg).

One with Jewish / Tunisian ancestry: Onset was at 8 months, three episodes of febrile tonic-clonic 1 seizures of the four limbs, with eye rolling, loss of consciousness, transient left and right post-2 ictal hemiparesis and vomiting. The other with Asian / European ancestry: Onset was at 30 months with three iterative episodes of febrile and non-febrile hemiplegia and loss of 18 consciousness. The recurrent episodes alternatively involved the left-and 19 right-hand side, then generalised and were followed by post ictal hemiparesis.

CT scans of both showed brain calcifications and aberrant blood flow patterns. Transfected cell lines with this variant, c178G>A, showed higher chloride ion permeability and lower sodium ion permeability when compared to wildtype.
Sources: Literature
Mendeliome v1.143 HCK Zornitza Stark Marked gene: HCK as ready
Mendeliome v1.140 TBX21 Zornitza Stark changed review comment from: Single individual reported with disseminated disease following BCG vaccination, who subsequently developed severe persistent reactive airway disease and eosinophilia that responded to steroid treatment. Homozygous variant identified.

Association with asthma and nasal polyps pertains to promoter SNPs.; to: Single individual reported with disseminated disease following BCG vaccination, who subsequently developed severe persistent reactive airway disease and eosinophilia that responded to steroid treatment. Homozygous variant identified. Functional data.

Association with asthma and nasal polyps pertains to promoter SNPs.
Mendeliome v1.138 KITLG Dean Phelan reviewed gene: KITLG: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 35543077, 28504826, 19375057, 21368769; Phenotypes: deafness, heterochromia iridis, hypopigmentation of the skin, hyperpigmentation of the skin, Waardenburg syndrome,MONDO:0018094, KITLG-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.138 NFATC2 Zornitza Stark Marked gene: NFATC2 as ready
Mendeliome v1.137 NFATC2 Paul De Fazio gene: NFATC2 was added
gene: NFATC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC2 were set to 35789258
Phenotypes for gene: NFATC2 were set to Skeletal system disorder MONDO:0005172
Review for gene: NFATC2 was set to RED
gene: NFATC2 was marked as current diagnostic
Added comment: Patient born to consanguineous parents homozygous for a frameshift variant. No other (unaffected) members of the family were homozygous. Family history of recurrent childhood deaths.

After a healthy birth the patient developed painless decreased range of motion at 1.5yrs leading to difficulty with ambulation at 3yrs. Formal orthopedic assessment at age 15 years
demonstrated a neurodevelopmentally normal young man with marked bilateral fixed flexion contractures of knees, hips, and ankles. The main musculoskeletal findings were painless contractures of the large and small joints of the upper and lower limbs, osteochondromas, and osteopenia. Patient was diagnosed with B-cell lymphoma at age 18.

Patient CD8+ T-cells show impaired polyfunctionality, and the patient had an accumulation of non-functional memory CD4+ T-cells. TFH cell function was also impaired.
Sources: Literature
Mendeliome v1.137 PIK3C2B Zornitza Stark Marked gene: PIK3C2B as ready
Mendeliome v1.136 CCDC155 Zornitza Stark Marked gene: CCDC155 as ready
Mendeliome v1.136 CCDC155 Zornitza Stark Phenotypes for gene: CCDC155 were changed from Non-obstructive azoospermia; Premature ovarian insufficiency to Non-obstructive azoospermia; Premature ovarian insufficiency; Infertility disorder, MONDO:0005047, CCDC155-related
Mendeliome v1.134 PIK3C2B Krithika Murali gene: PIK3C2B was added
gene: PIK3C2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIK3C2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C2B were set to PMID:35786744
Phenotypes for gene: PIK3C2B were set to familial partial epilepsy - MONDO#0017704
Review for gene: PIK3C2B was set to AMBER
Added comment: No OMIM gene disease association.

Gozzelino et al.(2022) Brain - report enrichment of ultra-rare PIK3C2B variants in focal epilepsy cohorts, including one variant shown to be de novo (G1294Q). Segregation data not provided for all cases. The p.G1345S variant was inherited from an affected father. The p.K584* variant was inherited from an unaffected father suggesting incomplete penetrance. Functional studies supported a LoF mechanism and mouse model studies suggestive of mTORC1 pathway hyperactivation.
Sources: Literature
Mendeliome v1.134 CCDC155 Melanie Marty gene: CCDC155 was added
gene: CCDC155 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC155 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC155 were set to 35674372; 35708642; 29790874; 35587281
Phenotypes for gene: CCDC155 were set to Non-obstructive azoospermia; Premature ovarian insufficiency
Review for gene: CCDC155 was set to GREEN
Added comment: Current HGNC name is KASH5

Summary: 4 families reported with non-obstructive azoospermia or premature ovarian insufficiency. Functional studies have been performed and mouse models recapitulate the phenotype.

PMID: 35674372 CNV and frameshift variants in KASH5 were identified in a non-obstructive azoospermia affected patient and in his infertile sister by whole-exome sequencing and CNV array. Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis.

PMID: 35708642 Hom splice identified in KASH5 in 2 sisters with premature ovarian insufficiency. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes.

PMID: 29790874 2 brothers with non-obstructive azoospermia with hom missense in CCDC155

35587281 2 siblings with hom missense in CCDC155 non-obstructive azoospermia and premature ovarian insufficiency.
Sources: Literature
Mendeliome v1.134 SLC30A7 Alison Yeung Marked gene: SLC30A7 as ready
Mendeliome v1.130 SLC30A7 Naomi Baker gene: SLC30A7 was added
gene: SLC30A7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC30A7 were set to PMID: 35751429
Phenotypes for gene: SLC30A7 were set to Joubert syndrome (MONDO:0018772), SLC30A7-related
Review for gene: SLC30A7 was set to AMBER
Added comment: PMID: 35751429: Two individuals reported with de novo variants, one missense and one delins resulting in missense. The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. No functional studies reported.
Sources: Literature
Mendeliome v1.130 CHMP3 Zornitza Stark Marked gene: CHMP3 as ready
Mendeliome v1.129 PABPC1 Elena Savva Marked gene: PABPC1 as ready
Mendeliome v1.128 PABPC1 Elena Savva gene: PABPC1 was added
gene: PABPC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to PMID: 35511136
Phenotypes for gene: PABPC1 were set to Neurodevelopmental disorder, PABPC1-related (MONDO#0700092)
Review for gene: PABPC1 was set to GREEN
Added comment: PMID: 35511136 - 4 probands with an overlapping phenotype of DD, expressive speech delay, and autistic features and heterozygous de novo variants that cluster in the PABP domain of PABPC1.
Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. Wild-type Pabpc1 could rescue this disturbance, whereas 3 of the 4 variants did not.
Sources: Literature
Mendeliome v1.127 WNK3 Zornitza Stark Marked gene: WNK3 as ready
Mendeliome v1.126 CHMP3 Chern Lim gene: CHMP3 was added
gene: CHMP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHMP3 were set to PMID: 35710109
Phenotypes for gene: CHMP3 were set to Hereditary spastic paraplegia (MONDO:0019064), CHMP3-related
Review for gene: CHMP3 was set to AMBER
gene: CHMP3 was marked as current diagnostic
Added comment: PMID: 35710109
- Single large family with consanguinity, homozygous missense variant in 5 affected individuals with intellectual and progressive motor disabilities, seizures and spastic quadriplegia.
- Functional studies showed reduced CHMP3 protein in patient's fibroblasts, lenti-rescue study showed improved cellular phenotypes associated with impaired autophagy.
Sources: Literature
Mendeliome v1.126 WNK3 Lucy Spencer gene: WNK3 was added
gene: WNK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WNK3 were set to 35678782
Phenotypes for gene: WNK3 were set to Neurodevelopmental disorder, WNK3-related (MONDO#0700092)
Added comment: 6 maternally inherited hemizygous variants, 3 missense, 2 canonical splice, and a nonsense. Seen in 14 individuals from 6 families, all 14 are male who inherited hemizygous variants from their unaffected heterozygous mothers. The variants cosegregated with disease in 3 families with multiple affected individuals. All 14 patients have ID, 11 have speech delay, 10 have facial abnormalities, 5 have seizures, 6 with microcephaly and 7 with anomalies in brain imaging.
Sources: Literature
Mendeliome v1.126 WNT7B Zornitza Stark Marked gene: WNT7B as ready
Mendeliome v1.125 WNT7B Zornitza Stark gene: WNT7B was added
gene: WNT7B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNT7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT7B were set to 35790350
Phenotypes for gene: WNT7B were set to Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects syndrome; Multiple congenital anomalies/dysmorphic features syndrome MONDO:0043005, WNT7B-related
Review for gene: WNT7B was set to GREEN
Added comment: Three families reported with fetuses with multiple congenital anomalies and bi-allelic LoF variants. Two of the families had at the same variant. Supportive zebrafish model.
Sources: Literature
Mendeliome v1.123 TMEM63C Elena Savva gene: TMEM63C was added
gene: TMEM63C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to PMID: 35718349
Phenotypes for gene: TMEM63C were set to Hereditary spastic paraplegia, MONDO:0019064, TMEM63C-related
Review for gene: TMEM63C was set to GREEN
Added comment: PMID: 35718349 - Four NMD PTCs observed in at least 3 unrelated patients. Two segregated strongly in highly consanguineous families.
Common clinical details include mild ID, spastic paraplegia, hypereflexia, spasticity, delayed motor development. Single patient was microcephalic
Sources: Literature
Mendeliome v1.122 MAL Zornitza Stark Marked gene: MAL as ready
Mendeliome v1.121 MAL Zornitza Stark gene: MAL was added
gene: MAL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to Leukodystrophy MONDO:0019046, MAL-related
Review for gene: MAL was set to AMBER
Added comment: Single family with two affected siblings reported, with homozygous missense variant, some functional data.
Sources: Literature
Mendeliome v1.119 RELN Zornitza Stark edited their review of gene: RELN: Added comment: PMID 35769015: 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants had moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Additional 7 individuals from 4 families with bi-allelic variants.; Changed publications: 35769015
Mendeliome v1.119 TAF8 Zornitza Stark changed review comment from: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. This is likely to be a founder variant. One family with different compound heterozygous variants.
Sources: Literature; to: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. Unclear if this is a founder variant, families of different ethnicities. One family with different compound heterozygous variants.
Sources: Literature
Mendeliome v1.119 TAF8 Zornitza Stark Marked gene: TAF8 as ready
Mendeliome v1.118 TAF8 Zornitza Stark gene: TAF8 was added
gene: TAF8 was added to Mendeliome. Sources: Literature
founder tags were added to gene: TAF8.
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to 29648665; 35759269
Phenotypes for gene: TAF8 were set to Neurodevelopmental disorder, MONDO:0700092, TAF8-related
Review for gene: TAF8 was set to GREEN
Added comment: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. This is likely to be a founder variant. One family with different compound heterozygous variants.
Sources: Literature
Mendeliome v1.117 PNPT1 Zornitza Stark Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13 (MIM#614932); Deafness, autosomal recessive 70 (MIM#614934) to Combined oxidative phosphorylation deficiency 13 (MIM#614932); Deafness, autosomal recessive 70 (MIM#614934); Spinocerebellar ataxia 25, MIM# 608703
Mendeliome v1.114 PNPT1 Zornitza Stark edited their review of gene: PNPT1: Added comment: Three families reported with heterozygous variants and SCA25. Incomplete penetrance in one of the families. In the third family, the variant was inherited from an asymptomatic 80+ year old. Note bi-allelic variants in this gene cause a mitochondrial disorder. Exact mechanism through which mono-allelic variants cause SCA25 not elucidated: authors speculate abnormal accumulation of mitochondrial RNA with subsequent leakage into the cytosol that may trigger a type 1 interferon response leading to neuroinflammation with neuronal dysfunction or neuronal loss.; Changed rating: AMBER; Changed publications: 35411967; Changed phenotypes: Spinocerebellar ataxia 25, MIM# 608703; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.114 TTC25 Arina Puzriakova reviewed gene: TTC25: Rating: GREEN; Mode of pathogenicity: None; Publications: 27486780, 31765523, 33715250, 33746037, 34215651; Phenotypes: Ciliary dyskinesia, primary, 35, OMIM:617092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.113 RHOG Zornitza Stark Marked gene: RHOG as ready
Mendeliome v1.111 TNFSF13 Zornitza Stark Marked gene: TNFSF13 as ready
Mendeliome v1.111 TNFSF13 Zornitza Stark gene: TNFSF13 was added
gene: TNFSF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNFSF13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFSF13 were set to 32298700
Phenotypes for gene: TNFSF13 were set to Hypogammaglobulinaemia, MONDO:0015977, TNSF13-related
Review for gene: TNFSF13 was set to RED
Added comment: Single individual, consanguineous parents.
Sources: Literature
Mendeliome v1.110 POU2AF1 Zornitza Stark Marked gene: POU2AF1 as ready
Mendeliome v1.110 POU2AF1 Zornitza Stark gene: POU2AF1 was added
gene: POU2AF1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: POU2AF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POU2AF1 were set to 33571536
Phenotypes for gene: POU2AF1 were set to Agammaglobulinaemia, MONDO:0015977, POU2AF1-related
Review for gene: POU2AF1 was set to RED
Added comment: Single individual from consanguineous parents lacking immunoglobulins despite normal total B-cell numbers.
Sources: Expert Review
Mendeliome v1.109 CD28 Zornitza Stark Marked gene: CD28 as ready
Mendeliome v1.108 CD28 Zornitza Stark changed review comment from: Rare homozygous CD28 variant segregates with severe verrucosis in three relatives and supportive functional data.
Sources: Expert Review; to: Rare homozygous CD28 variant segregates with severe verrucosis in three relatives and supportive functional data. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1.
Sources: Expert Review
Mendeliome v1.108 CD28 Zornitza Stark gene: CD28 was added
gene: CD28 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CD28 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD28 were set to 34214472
Phenotypes for gene: CD28 were set to Hereditary predisposition to infections, MONDO:0015979, CD28-related; isolated susceptibility to cutaneous α- and γ-HPVs
Review for gene: CD28 was set to RED
Added comment: Rare homozygous CD28 variant segregates with severe verrucosis in three relatives and supportive functional data.
Sources: Expert Review
Mendeliome v1.106 IKZF3 Zornitza Stark edited their review of gene: IKZF3: Added comment: Additional multigenerational family where novel missense variant segregated with disease in 4 individuals.; Changed rating: GREEN; Changed publications: 34155405, 34694366
Mendeliome v1.106 COPG1 Zornitza Stark Marked gene: COPG1 as ready
Mendeliome v1.105 COPG1 Zornitza Stark gene: COPG1 was added
gene: COPG1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: COPG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPG1 were set to 33529166
Phenotypes for gene: COPG1 were set to Combined immunodeficiency MONDO:0015131, COPG1-related
Review for gene: COPG1 was set to RED
Added comment: Five Omani siblings, born to consanguineous parents, homozygous missense.

Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice.
Sources: Expert Review
Mendeliome v1.104 TSPAN7 Zornitza Stark edited their review of gene: TSPAN7: Added comment: Two families reported with LoF variants and ID: Abidi FE et al. 2002 Jun (PMID:12070254); Zemni R et al. 2000 Feb (PMID:10655063)

Assessed as MODERATE by ClinGen.; Changed rating: AMBER; Changed publications: 12070254, 10655063
Mendeliome v1.104 IFNAR2 Zornitza Stark Publications for gene: IFNAR2 were set to 26424569
Mendeliome v1.103 IFNAR2 Zornitza Stark Classified gene: IFNAR2 as Green List (high evidence)
Mendeliome v1.103 IFNAR2 Zornitza Stark Gene: ifnar2 has been classified as Green List (High Evidence).
Mendeliome v1.102 IFNAR2 Zornitza Stark edited their review of gene: IFNAR2: Added comment: Five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination; Changed rating: GREEN; Changed publications: 26424569, 35442417
Mendeliome v1.102 IFNAR1 Zornitza Stark Phenotypes for gene: IFNAR1 were changed from Severe disease caused by Yellow Fever vaccine and Measles vaccine to Immunodeficiency 106, susceptibility to viral infections, MIM# 619935; Severe disease caused by Yellow Fever vaccine and Measles vaccine
Mendeliome v1.101 IFNAR1 Zornitza Stark Publications for gene: IFNAR1 were set to 31270247
Mendeliome v1.100 IFNAR1 Zornitza Stark Classified gene: IFNAR1 as Green List (high evidence)
Mendeliome v1.100 IFNAR1 Zornitza Stark Gene: ifnar1 has been classified as Green List (High Evidence).
Mendeliome v1.99 IFNAR1 Zornitza Stark edited their review of gene: IFNAR1: Changed rating: GREEN
Mendeliome v1.99 IFNAR1 Zornitza Stark edited their review of gene: IFNAR1: Added comment: Seven children from five unrelated kindreds; Changed publications: 31270247, 35442418; Changed phenotypes: Immunodeficiency 106, susceptibility to viral infections, MIM# 619935, Severe disease caused by Yellow Fever vaccine and Measles vaccine
Mendeliome v1.96 NEK8 Zornitza Stark edited their review of gene: NEK8: Added comment: ESHG 2022: 12 families with paediatric renal cystic disease (enlarged kidneys, kidney cysts, ESKF <20yrs) -3 recurrent HTZ variants in NEK8 kinase domain (Arg45Trp, Ile150Met, Lys157Gln) -suspected dominant negative effect -patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8 (Note carriers of AR-NEK8 disease do not show renal manifestations, as variants are LOF); Changed phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174, Familial renal cystic disease MONDO:0019741, NEK8-related, dominant; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.89 DDR2 Zornitza Stark changed review comment from: Bi-allelic variants in this gene are associated with a severe perinatal skeletal dysplasia.

Mono-allelic variants cause Warburg-Cinotti syndrome, which is characterized by progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acroosteolysis. Four unrelated families reported with missense variants, which were activating.; to: Bi-allelic variants in this gene are associated with a severe perinatal skeletal dysplasia. LoF.

Mono-allelic variants cause Warburg-Cinotti syndrome, which is characterized by progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acroosteolysis. Four unrelated families reported with missense variants, which were activating. GoF.
Mendeliome v1.85 EPHA2 Elena Savva reviewed gene: EPHA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34638995, 19005574, 19649315, 19306328, 33671840; Phenotypes: Early-Onset Cataract, cataract 6 multiple types MONDO:0007288; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.82 GRIA1 Zornitza Stark edited their review of gene: GRIA1: Added comment: Single individual reported with bi-allelic LoF variant. RED/AMBER for bi-allelic variants.; Changed publications: 28628100, 23033978, 26350204, 24896178, 35675825; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.81 MSH5 Zornitza Stark Phenotypes for gene: MSH5 were changed from Premature ovarian failure 13, MIM#617442; Premature ovarian failure 13, MIM#617442 to Spermatogenic failure 74, MIM# 619937; Premature ovarian failure 13, MIM#617442
Mendeliome v1.80 MSH5 Zornitza Stark Phenotypes for gene: MSH5 were changed from Premature ovarian failure 13 MIM#617442 to Premature ovarian failure 13, MIM#617442; Premature ovarian failure 13, MIM#617442
Mendeliome v1.79 GCH1 Zornitza Stark Phenotypes for gene: GCH1 were changed from Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230 to Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230; Hereditary spastic paraplegia MONDO:0019064, GCH1-related
Mendeliome v1.77 GCH1 Zornitza Stark reviewed gene: GCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21935284, 24509643, 33713342; Phenotypes: Hereditary spastic paraplegia MONDO:0019064, GCH1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.75 KCNA5 Zornitza Stark edited their review of gene: KCNA5: Added comment: Multiple families reported. At least one with LoF variant, rest missense. The missense variants are present in the population, ranging from 2 to 40 individuals in gnomad, which raises doubt about their pathogenicity.; Changed rating: AMBER
Mendeliome v1.74 GATA1 Zornitza Stark edited their review of gene: GATA1: Added comment: Variants in GATA1 are associated with a number of haematological disorders, which probably represent a spectrum rather than distinct entities.; Changed phenotypes: Thrombocytopaenia, X-linked, with or without dyserythropoietic anaemia, MIM# 300367, Haemolytic anaemia due to elevated adenosine deaminase, MIM# 301083, Anemia, X-linked, with/without neutropenia and/or platelet abnormalities, MIM# 300835
Mendeliome v1.74 NR4A2 Zornitza Stark Phenotypes for gene: NR4A2 were changed from Intellectual disability; epilepsy to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, MIM# 619911
Mendeliome v1.73 NR4A2 Zornitza Stark edited their review of gene: NR4A2: Changed phenotypes: Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, MIM# 619911
Mendeliome v1.69 KCNJ1 Zornitza Stark reviewed gene: KCNJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8841184, 19096086, 7635463, 12086641, 9580661, 12122007; Phenotypes: Bartter syndrome, type 2, MIM#241200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.68 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from Chorioretinal atrophy, progressive bifocal, MIM# 600790; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761 to Chorioretinal atrophy, progressive bifocal, MIM# 600790; Pontocerebellar hypoplasia, type 17, MIM# 619909; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976
Mendeliome v1.66 PRDM13 Zornitza Stark edited their review of gene: PRDM13: Added comment: Note only single family reported with Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976 -- this likely lies on the same spectrum as Pontocerebellar hypoplasia, type 17, MIM# 619909 rather than being a distinct disorder.; Changed publications: 30710461, 34730112; Changed phenotypes: Retinal dystrophy, Chorioretinal atrophy, progressive bifocal, MIM# 600790, Pontocerebellar hypoplasia, type 17, MIM# 619909, Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 61976; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.65 RBFOX2 Chern Lim changed review comment from: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. Same cohort later included in PMID: 32368696, listed 4 de novo variants in this gene, in patients with left ventricular outflow tract obstruction (LVOTO) or conotruncal defects (CTDs).

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.; to: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.
Mendeliome v1.52 RRM1 Seb Lunke Marked gene: RRM1 as ready
Mendeliome v1.52 BUB1 Zornitza Stark Marked gene: BUB1 as ready
Mendeliome v1.52 RRM1 Seb Lunke Added comment: Comment on list classification: 3 families but only 2 Hom variants, not convinced they are definitely unrelated. 4th probed inconclusive.
Mendeliome v1.50 PAN2 Zornitza Stark Marked gene: PAN2 as ready
Mendeliome v1.49 RRM1 Daniel Flanagan gene: RRM1 was added
gene: RRM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RRM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRM1 were set to 35617047
Phenotypes for gene: RRM1 were set to Multiple mitochondrial DNA deletion syndrome (MONDO:0016797)
Review for gene: RRM1 was set to GREEN
Added comment: Homozygous missense were identified in 4 four probands (p.Arg381Cys or p.Arg381His) from three families, who presented with ptosis and ophthalmoplegia, plus other manifestations and multiple mtDNA deletions in muscle. Heterozygous carriers were unaffected. An additional proband was heterozygous for a different RRM1 missense (p.Asn427Lys), another variant not identified.
Sources: Expert list
Mendeliome v1.49 LMOD2 Seb Lunke Marked gene: LMOD2 as ready
Mendeliome v1.49 LMOD2 Seb Lunke Phenotypes for gene: LMOD2 were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Mendeliome v1.48 ATOH1 Zornitza Stark Marked gene: ATOH1 as ready
Mendeliome v1.47 PAN2 Naomi Baker gene: PAN2 was added
gene: PAN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to PMID:35304602; 29620724
Phenotypes for gene: PAN2 were set to Neurodevelopmental disorder, MONDO:0700092, PAN2-related
Review for gene: PAN2 was set to GREEN
Added comment: PMID:35304602 reports five individuals from 3 families with biallelic (homozygous) loss-of-function variants. Clinical presentation incudes mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck.

PMID:29620724 reports one individual with biallelic (homozygous) loss-of-function variant who presented with global developmental delay, mild hypotonia, craniosynostosis, severe early-onset scoliosis, imperforate anus, and double urinary collecting system.
Sources: Literature
Mendeliome v1.47 ATOH1 Zornitza Stark Phenotypes for gene: ATOH1 were changed from Pontocerebellar hypoplasia; developmental delay; hearing loss to Pontocerebellar hypoplasia MONDO:0020135, ATOH1-related
Mendeliome v1.46 PTPN13 Ain Roesley Marked gene: PTPN13 as ready
Mendeliome v1.45 PTPN13 Ain Roesley gene: PTPN13 was added
gene: PTPN13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN13 were set to 35643866
Phenotypes for gene: PTPN13 were set to bone marrow failure syndrome MONDO#0000159, PTPN13-related
Review for gene: PTPN13 was set to AMBER
gene: PTPN13 was marked as current diagnostic
Added comment: 2 families

Family A: 3 affecteds only 2 sequenced. Hom for a missense
3/3 Anaemia, 1x thrombocytopaenia, 1x severe neutropaenia, bone marrow with pure red cell aplasia
noted that the sibling who wasn't sequenced had normal bone marrow morphology

Family B: Chet for a missense and inframe del of 1 amino acid
Persistent hypogammaglobulinemia after transplant (at least 14 months after) with normal blood counts and Pre-B ALL with MLL rearrangement

In vitro studies of individual variants were LoF, including defective erythroid and megakaryocytic differentiation, consistent with anaemia and thrombocytopaenia reported in family A
Sources: Literature
Mendeliome v1.44 ATOH1 Chloe Stutterd gene: ATOH1 was added
gene: ATOH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATOH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATOH1 were set to 35518571
Phenotypes for gene: ATOH1 were set to Pontocerebellar hypoplasia; developmental delay; hearing loss
Penetrance for gene: ATOH1 were set to unknown
Review for gene: ATOH1 was set to AMBER
Added comment: Single report of novel homozygous missense variant in functional domain segregating with disease in two affected siblings with pontocerebellar hypoplasia, developmental delay and hearing loss. Similar phenotype previously reported in animal model with biallelic missense variant affecting same functional domain. Homology modelling predicts this missense variant affects binding capability of the bHLH domain to the DNA. Gene encodes a core transcription factor in developing cerebellum, brainstem, dorsal spinal cord and ear.
Sources: Literature
Mendeliome v1.44 BUB1 Paul De Fazio gene: BUB1 was added
gene: BUB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816; 19772675; 19117986; 23209306
Phenotypes for gene: BUB1 were set to Intellectual disability and microcephaly
Review for gene: BUB1 was set to GREEN
gene: BUB1 was marked as current diagnostic
Added comment: 2 unrelated patients with ID, microcephaly, short stature, dysmorphic features reported with biallelic variants:

P1 (3yo male): homozygous start-loss variant (2 hets and 0 hom in gnomAD). Functional testing showed a small amount of full-length protein was translated, and BUB1 recruitment to kinetochores was nearly undetectable.
P2 (16yo female): compound heterozygous for a canonical splice variant (1 het and no hom in gnomAD) and an NMD-predicted frameshift variant (absent from gnomAD). The splice variant was shown to result in an in-frame deletion of 54 amino acids in the kinase domain. P2 cells have reduced protein levels but essentially no kinase activity.

BUB1 patient cells have impaired mitotic fidelity.

Homozygous Bub1 disruption in mice is embryonic lethal (PMID:19772675). A hypomorphic mouse is viable with increased tumourigenesis with ageing and aneuploidy (PMID:19117986). A kinase-dead mouse does not show increased tumourigenesis but does have a high frequency of aneuploid cells (PMID:23209306)
Sources: Literature
Mendeliome v1.44 LMOD2 Melanie Marty gene: LMOD2 was added
gene: LMOD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LMOD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMOD2 were set to PMID: 31517052; PMID: 34888509; PMID: 35082396; PMID: 35188328; PMID: 26487682
Phenotypes for gene: LMOD2 were set to Dilated cardiomyopathy
Review for gene: LMOD2 was set to GREEN
Added comment: 4 unrelated families with early onset dilated cardiomyopathy, autosomal recessive inheritance, functional studies showing loss of protein and a mouse model reported.

PMID: 31517052 1 x neonate with DCM, homozygous nonsense variant identified.

PMID: 34888509 2 x neonatal deaths (from 1 family) related to dilated cardiomyopathy (DCM), compound heterozygous loss-of-function variants identified.

PMID:35082396 2 x siblings with DCM who died shortly after birth due to heart failure, homozygous canonical splice variant identified. Functional studies show loss of donor site and loss of protein.

PMID: 35188328 1 x child (9 months) with DCM, with homozygous frameshift variant. Functional studies showed absence of LMOD2 protein (western blot).

PMID: 26487682 Lmod2 null (knockout) mice present with short cardiac thin filaments and die at ~3 weeks due to dysfunctional, dilated hearts
Sources: Literature
Mendeliome v1.40 SEMA6B Dean Phelan commented on gene: SEMA6B: PMID: 35604360
- 14 heterozygous variants were observed in 16 unrelated individuals referred for intellectual disability. Majority of the variants 9/14 were PTCs in the last exon and predicted to escape NMD. Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.
Mendeliome v1.40 GIMAP6 Elena Savva Marked gene: GIMAP6 as ready
Mendeliome v1.38 HEATR3 Zornitza Stark Marked gene: HEATR3 as ready
Mendeliome v1.37 IREB2 Lucy Spencer reviewed gene: IREB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35602653; Phenotypes: Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.37 HEATR3 Zornitza Stark Phenotypes for gene: HEATR3 were changed from Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability to DiMONDO:0015253
Mendeliome v1.35 GIMAP6 Elena Savva gene: GIMAP6 was added
gene: GIMAP6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GIMAP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP6 were set to PMID: 35551368; 33328581
Phenotypes for gene: GIMAP6 were set to Autophagy, immune competence and inflammation
Review for gene: GIMAP6 was set to AMBER
Added comment: PMID: 35551368, PMID: 33328581
- K/O mice show autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)–containing lipids and die prematurely from microangiopathic glomerulosclerosis with immunodeficiency.
- 2 unrelated families (3 patients) w/ a homozygous missense (p.Gly153Val) and nonsense (p.Trp86*). All unaffected siblings were heterozygous.
Patient 1 (missense) presented with Coombs-positive hemolytic anemia, hepatosplenomegaly, Cranial MRI showed bilateral effusions, sulcal hyperintensity, and lateral parietal subcortical acute focal ischemic lesions.
Patient 2 (nonsense) presented with recurrent purulent otitis media and a chronic wet cough, persistent jaundice, recurrent chest and ear infections, lingular consolidation, mild bronchiectasis, bibasilar bronchial wall thickening, right peribronchial consolidation, right lower lobe bronchiectasis, bilateral axillary lymphadenopathy, and splenomegaly.
Patient 3 (nonsense) presented with suffered headaches, abdomen pain, mouth ulcers, and recurrent infections

- Functional studies show patient 1 (missense) with reduced protein expression on western blot, and patient 2/3 (nonsense) with no protein expression. T cells of Pt 1 were similar to mouse K/O model (elevated basal LC3-II, reduced autophagic flux).

gnomAD: 0 homozygous PTCs, but a very common canonical splice which is present in the non-canonical transcript
Sources: Literature
Mendeliome v1.34 HEATR3 Chern Lim gene: HEATR3 was added
gene: HEATR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to PMID: 35213692
Phenotypes for gene: HEATR3 were set to Bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability
Review for gene: HEATR3 was set to GREEN
gene: HEATR3 was marked as current diagnostic
Added comment: PMID: 35213692:
- 4 unrelated individuals with biallelic HEATR3 variants (missense and splice site variants), exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and mild intellectual disability.
- Functional analysis showed HEATR3 variants destabilised the protein, resulting in a reduction of nuclear uL18 and impaired ribosome biogenesis.
Sources: Literature
Mendeliome v1.34 TRIM47 Zornitza Stark Marked gene: TRIM47 as ready
Mendeliome v1.34 TRIM47 Zornitza Stark gene: TRIM47 was added
gene: TRIM47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM47 were set to 35511193
Phenotypes for gene: TRIM47 were set to Genetic cerebral small vessel disease MONDO:0018787
Review for gene: TRIM47 was set to RED
Added comment: GWAS data: Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. Observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology.
Sources: Literature
Mendeliome v1.33 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790; intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 to Chorioretinal atrophy, progressive bifocal, MIM# 600790; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761
Mendeliome v1.31 MESP1 Zornitza Stark Phenotypes for gene: MESP1 were changed from Congenital heart disease to Congenital heart disease MONDO:0005453
Mendeliome v1.29 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, MIM# 613477; hereditary motor neuropathy to Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; hereditary motor neuropathy
Mendeliome v1.28 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Added comment: Leveille et al (2019) - 2 patients with HSP with biallelic missense SPTAN1 variants Previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. Xie et al (2022) - 1 patient with complicated HSP and homozygous SPTAN1 mutation. Healthy parents and sister all carried the heterozygous mutation. Van de Vondel et al (2022) - 22 patients from 14 families with five novel heterozygous SPTAN1 variants. Presentations ranged from cerebellar ataxia, intellectual disability, epilepsy, and spastic paraplegia. A recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia. Through protein modeling they showed that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.; Changed publications: 20493457, 22258530, 32811770, 35150594, 34526651, 31515523; Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.18 TULP3 Zornitza Stark Phenotypes for gene: TULP3 were changed from progressive degenerative liver fibrosis with variable fibrocystic kidney disease; hypertrophic cardiomyopathy MONDO:0005045 to Hepatorenocardiac degenerative fibrosis, MIM# 619902
Mendeliome v1.17 TULP3 Zornitza Stark reviewed gene: TULP3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hepatorenocardiac degenerative fibrosis, MIM# 619902; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.15 IKBKG Zornitza Stark edited their review of gene: IKBKG: Added comment: X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature. 6 unrelated boys and a girl reported. All variants resulted in absence of the domain encoded by exon 5 (NEMOdelEx5).

Note variants in this gene are associated with immunodeficiency +/- ectodermal features and with IP.; Changed phenotypes: Ectodermal dysplasia and immunodeficiency 1, MIM# 300291, Immunodeficiency 33 , MIM#300636, Incontinentia pigmenti, MIM# 308300, Autoinflammatory disease, systemic, X-linked, MIM# 301081
Mendeliome v1.14 MYO9A Zornitza Stark edited their review of gene: MYO9A: Added comment: This gene-disease association has been reviewed as part of GenCC discordance resolution: note at least two of the variants reported have homozygotes with gnomad, which would be out of keeping for a severe paediatric disorder.; Changed rating: AMBER
Mendeliome v1.12 FAT2 Elena Savva reviewed gene: FAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33884300, 29053796; Phenotypes: Spinocerebellar ataxia 45, MIM#617769; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.11 COPB2 Zornitza Stark Phenotypes for gene: COPB2 were changed from Microcephaly 19, primary, autosomal recessive, MIM# 617800; Osteoporosis and developmental delay to Microcephaly 19, primary, autosomal recessive, MIM# 617800; Osteoporosis, childhood- or juvenile-onset, with developmental delay, MIM# 619884
Mendeliome v1.10 ATP13A3 Zornitza Stark Phenotypes for gene: ATP13A3 were changed from Pulmonary arterial hypertension to Primary pulmonary hypertension 5, MIM#265400
Mendeliome v1.9 ATP13A3 Zornitza Stark edited their review of gene: ATP13A3: Changed phenotypes: Primary pulmonary hypertension 5, MIM#265400
Mendeliome v1.9 RBFOX2 Zornitza Stark Marked gene: RBFOX2 as ready
Mendeliome v1.9 RBFOX2 Zornitza Stark Phenotypes for gene: RBFOX2 were changed from Hypoplastic left heart syndrome (HLHS) to Hypoplastic left heart syndrome (HLHS) MONDO:0004933
Mendeliome v1.7 PROSER1 Zornitza Stark Marked gene: PROSER1 as ready
Mendeliome v1.7 PROSER1 Zornitza Stark gene: PROSER1 was added
gene: PROSER1 was added to Mendeliome. Sources: Expert Review
founder tags were added to gene: PROSER1.
Mode of inheritance for gene: PROSER1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PROSER1 were set to 35229282
Phenotypes for gene: PROSER1 were set to Syndromic disease MONDO:0002254, PROSER1-related
Review for gene: PROSER1 was set to RED
Added comment: 4 children from 3 related families with developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, genitourinary malformations, and common facial features (arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing). WES revealed a homozygous frame-shift variant (p.Thr612Glnfs*22) in PROSER1. This encodes the proline and serine rich protein 1, part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation. No functional assays and 3 related families, likely founder effect.
Sources: Expert Review
Mendeliome v1.6 SPATA22 Zornitza Stark Marked gene: SPATA22 as ready
Mendeliome v1.5 SPATA22 Zornitza Stark gene: SPATA22 was added
gene: SPATA22 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SPATA22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA22 were set to 35285020
Phenotypes for gene: SPATA22 were set to Premature ovarian insufficiency and nonobstructive azoospermia; Genetic infertility MONDO:0017143
Review for gene: SPATA22 was set to AMBER
Added comment: 1 consanguineous family with two premature ovarian insufficiency (POI) and two nonobstructive azoospermia (NOA) patients. WES identified a homozygous variant in SPATA22 (c.400C>T:p.R134X). Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA. 2nd patient found with idiopathic POI and compound heterozygous variants in SPATA22 (c.900+1G>A and c.31C>T:p.R11X).
Sources: Expert Review
Mendeliome v1.3 RDH11 Zornitza Stark edited their review of gene: RDH11: Added comment: 2nd case reported: 1 Chinese patient with retinitis pigmentosa, juvenile cataracts, intellectual disability, and myopathy. Trio-based WES and whole genomic CNV detection found compound heterozygous variants in RDH11 (p.Leu313Pro and c.75-3C>A) with biparental inheritance. Variant c.75-3C>A was confirmed to be a splice-site mutation by cDNA sequencing. It caused exon 2 skipping, resulting in a frameshift mutation and premature translation termination (p.Lys26Serfs*38). They found mislocalization of RDH11 protein in muscle cells of the patient by using immunofluorescence staining. Retinol dehydrogenase 11 (RDH11) is an 11-cis-retinol dehydrogenase that has a well-characterized, albeit auxiliary role in the retinoid cycle. Diseases caused by mutations in the RDH11 gene are very rare, and only one affected family with eye and intelligence involvement has been reported.; Changed rating: AMBER; Changed publications: 24916380, 15634683, 30731079, 18326732, 34988992
Mendeliome v1.3 ETV2 Ain Roesley changed review comment from: 1 family with 4 fetus-es, cHet for a fs (NMD-predicted) and a missense

3/4 vertebral malformations
2/4 Tetralogy of Fallot
1/4 arterial septal defect
1/4 ventricular septal defect, aortic dilatation
1/4 pre-axial polydactyly
Sources: Literature; to: 1 family with 4 fetus-es all cHet for a fs (NMD-predicted) and a missense

3/4 vertebral malformations
2/4 Tetralogy of Fallot
1/4 arterial septal defect
1/4 ventricular septal defect, aortic dilatation
1/4 pre-axial polydactyly
Sources: Literature
Mendeliome v1.2 ZNF526 Zornitza Stark Phenotypes for gene: ZNF526 were changed from Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia to Dentici-Novelli neurodevelopmental syndrome, MIM# 619877
Mendeliome v1.1 POLR3F Zornitza Stark Phenotypes for gene: POLR3F were changed from Severe VZV infection to Immunodeficiency 101 (varicella zoster virus-specific), MIM# 619872
Mendeliome v1.0 POLR3F Zornitza Stark edited their review of gene: POLR3F: Changed phenotypes: Immunodeficiency 101 (varicella zoster virus-specific), MIM# 619872
Mendeliome v0.14798 GLRX3 Zornitza Stark Marked gene: GLRX3 as ready
Mendeliome v0.14797 DNM1L Zornitza Stark Marked gene: DNM1L as ready
Mendeliome v0.14797 DNM1L Zornitza Stark Phenotypes for gene: DNM1L were changed from to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR); Optic atrophy 5 - MIM#610708 (AD)
Mendeliome v0.14795 DNASE1L3 Zornitza Stark Marked gene: DNASE1L3 as ready
Mendeliome v0.14794 DNASE1 Zornitza Stark Marked gene: DNASE1 as ready
Mendeliome v0.14791 DNAJC6 Zornitza Stark Marked gene: DNAJC6 as ready
Mendeliome v0.14791 DNAJC6 Zornitza Stark Phenotypes for gene: DNAJC6 were changed from to Parkinson disease 19a, juvenile-onset - MIM#615528; Parkinson disease 19b, early-onset - MIM#615528
Mendeliome v0.14786 DNAJC5 Zornitza Stark Marked gene: DNAJC5 as ready
Mendeliome v0.14784 DNAJC3 Zornitza Stark Marked gene: DNAJC3 as ready
Mendeliome v0.14784 DNAJC3 Zornitza Stark Phenotypes for gene: DNAJC3 were changed from to Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus - MIM#616192
Mendeliome v0.14781 DNAJC21 Zornitza Stark Marked gene: DNAJC21 as ready
Mendeliome v0.14781 DNAJC21 Zornitza Stark Phenotypes for gene: DNAJC21 were changed from to Bone marrow failure syndrome 3 - MIM#617052
Mendeliome v0.14779 DNM2 Zornitza Stark Marked gene: DNM2 as ready
Mendeliome v0.14779 DNM2 Zornitza Stark Phenotypes for gene: DNM2 were changed from to Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674
Mendeliome v0.14775 DPY19L2 Zornitza Stark Marked gene: DPY19L2 as ready
Mendeliome v0.14774 AVPR2 Zornitza Stark Marked gene: AVPR2 as ready
Mendeliome v0.14773 AVP Zornitza Stark Marked gene: AVP as ready
Mendeliome v0.14772 DRAM2 Zornitza Stark Marked gene: DRAM2 as ready
Mendeliome v0.14767 DRD2 Zornitza Stark Marked gene: DRD2 as ready
Mendeliome v0.14767 ATP6V1E1 Zornitza Stark Marked gene: ATP6V1E1 as ready
Mendeliome v0.14764 DRD3 Zornitza Stark Marked gene: DRD3 as ready
Mendeliome v0.14763 DRD3 Zornitza Stark Phenotypes for gene: DRD3 were changed from to {Essential tremor, hereditary, 1} - MIM#190300; {Schizophrenia, susceptibility to} - MIM#181500
Mendeliome v0.14760 ATP2A1 Zornitza Stark Marked gene: ATP2A1 as ready
Mendeliome v0.14758 DSC3 Zornitza Stark Marked gene: DSC3 as ready
Mendeliome v0.14755 ADD1 Zornitza Stark Marked gene: ADD1 as ready
Mendeliome v0.14753 DSCAM Zornitza Stark Marked gene: DSCAM as ready
Mendeliome v0.14748 DSE Zornitza Stark Marked gene: DSE as ready
Mendeliome v0.14745 DSG4 Zornitza Stark Marked gene: DSG4 as ready
Mendeliome v0.14742 DSPP Zornitza Stark Marked gene: DSPP as ready
Mendeliome v0.14740 DUOX2 Zornitza Stark Marked gene: DUOX2 as ready
Mendeliome v0.14738 GDNF Elena Savva Marked gene: GDNF as ready
Mendeliome v0.14738 DUOXA2 Zornitza Stark Marked gene: DUOXA2 as ready
Mendeliome v0.14736 ENPP1 Zornitza Stark Marked gene: ENPP1 as ready
Mendeliome v0.14736 EPOR Zornitza Stark Marked gene: EPOR as ready
Mendeliome v0.14736 EPRS Zornitza Stark Marked gene: EPRS as ready
Mendeliome v0.14736 EPS8 Zornitza Stark Marked gene: EPS8 as ready
Mendeliome v0.14736 EPS8 Zornitza Stark Phenotypes for gene: EPS8 were changed from to Autosomal recessive nonsyndromic hearing loss 102 MONDO:0014428
Mendeliome v0.14733 ETFB Zornitza Stark Marked gene: ETFB as ready
Mendeliome v0.14732 EXT1 Zornitza Stark Marked gene: EXT1 as ready
Mendeliome v0.14732 EXT1 Zornitza Stark Phenotypes for gene: EXT1 were changed from to hereditary multiple osteochondromas MONDO:0005508; exostoses, multiple, type 1 MONDO:0007585
Mendeliome v0.14731 EYA4 Zornitza Stark Marked gene: EYA4 as ready
Mendeliome v0.14731 EYS Zornitza Stark Marked gene: EYS as ready
Mendeliome v0.14728 FXR1 Zornitza Stark Marked gene: FXR1 as ready
Mendeliome v0.14728 ETV2 Ain Roesley Marked gene: ETV2 as ready
Mendeliome v0.14728 ETV2 Ain Roesley gene: ETV2 was added
gene: ETV2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ETV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ETV2 were set to 33359164
Phenotypes for gene: ETV2 were set to multiple fetal anomalies; congenital heart disease MONDO:000545, ETV2-related; vertebral malformations
Review for gene: ETV2 was set to RED
gene: ETV2 was marked as current diagnostic
Added comment: 1 family with 4 fetus-es, cHet for a fs (NMD-predicted) and a missense

3/4 vertebral malformations
2/4 Tetralogy of Fallot
1/4 arterial septal defect
1/4 ventricular septal defect, aortic dilatation
1/4 pre-axial polydactyly
Sources: Literature
Mendeliome v0.14727 GABRB2 Zornitza Stark Marked gene: GABRB2 as ready
Mendeliome v0.14726 GALNT2 Zornitza Stark Marked gene: GALNT2 as ready
Mendeliome v0.14725 GALNT3 Zornitza Stark Marked gene: GALNT3 as ready
Mendeliome v0.14722 GALT Zornitza Stark Marked gene: GALT as ready
Mendeliome v0.14719 GAMT Zornitza Stark Marked gene: GAMT as ready
Mendeliome v0.14716 GAN Zornitza Stark Marked gene: GAN as ready
Mendeliome v0.14713 GBA2 Zornitza Stark Marked gene: GBA2 as ready
Mendeliome v0.14713 GBA2 Zornitza Stark Phenotypes for gene: GBA2 were changed from to Spastic paraplegia 46, autosomal recessive, MIM# 614409; MONDO:0013737
Mendeliome v0.14710 GCDH Zornitza Stark Marked gene: GCDH as ready
Mendeliome v0.14710 GCDH Zornitza Stark Phenotypes for gene: GCDH were changed from to Glutaric aciduria, type I MIM#231670; Organic acidurias
Mendeliome v0.14707 GCH1 Zornitza Stark Marked gene: GCH1 as ready
Mendeliome v0.14704 GCK Zornitza Stark Marked gene: GCK as ready
Mendeliome v0.14704 GCK Zornitza Stark Phenotypes for gene: GCK were changed from to Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853); Diabetes mellitus, permanent neonatal 1, AR (MIM#606176); Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485); MODY, type II, AD (MIM#125851)
Mendeliome v0.14701 GCNT2 Zornitza Stark Marked gene: GCNT2 as ready
Mendeliome v0.14700 GCNT2 Zornitza Stark Phenotypes for gene: GCNT2 were changed from to Cataract 13 with adult i phenotype, OMIM # 116700
Mendeliome v0.14697 GDAP1 Zornitza Stark Marked gene: GDAP1 as ready
Mendeliome v0.14697 GDAP1 Zornitza Stark Phenotypes for gene: GDAP1 were changed from to Charcot-Marie-Tooth disease, axonal, type 2K 607831, MIM# Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, MIM# 607706; Charcot-Marie-Tooth disease, recessive intermediate, A, MIM# 608340; Charcot-Marie-Tooth disease, type 4A, MIM# 214400
Mendeliome v0.14695 GATAD1 Elena Savva Phenotypes for gene: GATAD1 were changed from to ?Cardiomyopathy, dilated, 2B MIM#614672
Mendeliome v0.14694 GATAD1 Elena Savva Marked gene: GATAD1 as ready
Mendeliome v0.14693 FBXW4 Elena Savva Marked gene: FBXW4 as ready
Mendeliome v0.14692 AURKC Elena Savva Marked gene: AURKC as ready
Mendeliome v0.14691 ATPAF2 Elena Savva Marked gene: ATPAF2 as ready
Mendeliome v0.14691 ATP2C2 Elena Savva Marked gene: ATP2C2 as ready
Mendeliome v0.14691 AHSG Elena Savva Marked gene: AHSG as ready
Mendeliome v0.14689 GDF2 Zornitza Stark Marked gene: GDF2 as ready
Mendeliome v0.14689 GDF2 Zornitza Stark Phenotypes for gene: GDF2 were changed from to Telangiectasia, hereditary hemorrhagic, type 5 OMIM # 615506; pulmonary arteriovenous malformations
Mendeliome v0.14686 GDF9 Zornitza Stark Marked gene: GDF9 as ready
Mendeliome v0.14686 GDF9 Zornitza Stark Phenotypes for gene: GDF9 were changed from to Premature ovarian failure 14, OMIM# 618014
Mendeliome v0.14683 GEMIN4 Zornitza Stark Marked gene: GEMIN4 as ready
Mendeliome v0.14683 GEMIN4 Zornitza Stark Phenotypes for gene: GEMIN4 were changed from to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, MIM# 617913
Mendeliome v0.14680 GFM2 Zornitza Stark Marked gene: GFM2 as ready
Mendeliome v0.14677 GIF Zornitza Stark Marked gene: GIF as ready
Mendeliome v0.14672 SLC26A1 Elena Savva Marked gene: SLC26A1 as ready
Mendeliome v0.14670 PRKAG3 Elena Savva Marked gene: PRKAG3 as ready
Mendeliome v0.14670 GINS1 Zornitza Stark Marked gene: GINS1 as ready
Mendeliome v0.14667 U2AF2 Elena Savva Marked gene: U2AF2 as ready
Mendeliome v0.14667 TDP1 Elena Savva Marked gene: TDP1 as ready
Mendeliome v0.14666 TIA1 Elena Savva Marked gene: TIA1 as ready
Mendeliome v0.14666 PLD3 Elena Savva Marked gene: PLD3 as ready
Mendeliome v0.14666 RBM7 Elena Savva Marked gene: RBM7 as ready
Mendeliome v0.14666 MFAP5 Elena Savva Marked gene: MFAP5 as ready
Mendeliome v0.14666 MMGT1 Elena Savva Marked gene: MMGT1 as ready
Mendeliome v0.14666 FRA12A Elena Savva Marked STR: FRA12A as ready
Mendeliome v0.14666 GIGYF2 Elena Savva Marked gene: GIGYF2 as ready
Mendeliome v0.14666 FRA12A Elena Savva Phenotypes for STR: FRA12A were changed from Mental retardation, FRA12A type MIM#136630 to Intellectual developmental disorder, autosomal dominant, FRA12A type MIM#136630
Mendeliome v0.14665 MEPE Elena Savva Marked gene: MEPE as ready
Mendeliome v0.14665 LRIF1 Elena Savva Marked gene: LRIF1 as ready
Mendeliome v0.14665 GIGYF2 Elena Savva Phenotypes for gene: GIGYF2 were changed from to {Parkinson disease 11} MIM#607688
Mendeliome v0.14663 DMGDH Elena Savva Marked gene: DMGDH as ready
Mendeliome v0.14663 DMGDH Elena Savva Phenotypes for gene: DMGDH were changed from to Dimethylglycine dehydrogenase deficiency MIM#605850; Disorders and variants of other enzymes that oxidise xenobiotics
Mendeliome v0.14662 DCAF8 Elena Savva Marked gene: DCAF8 as ready
Mendeliome v0.14662 CCT5 Elena Savva Marked gene: CCT5 as ready
Mendeliome v0.14662 ATG5 Elena Savva Marked gene: ATG5 as ready
Mendeliome v0.14662 USP8 Elena Savva Marked gene: USP8 as ready
Mendeliome v0.14662 LRP5 Krithika Murali reviewed gene: LRP5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Exudative vitreoretinopathy 4 - MIM#601813 (AD, AR), Hyperostosis, endosteal - MIM#144750 (AD), Osteopetrosis, autosomal dominant 1 - MIM#607634(AD), Osteoporosis-pseudoglioma syndrome - MIM#259770 (AR), Osteosclerosis - #144750 (AD), Polycystic liver disease 4 with or without kidney cysts - MIM#617875 (AD), van Buchem disease, type 2 - MIM#607636; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14660 LYRM7 Krithika Murali reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex III deficiency, nuclear type 8 - MIM#615838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14659 MSX1 Elena Savva Marked gene: MSX1 as ready
Mendeliome v0.14657 GJA1 Zornitza Stark Marked gene: GJA1 as ready
Mendeliome v0.14654 GJA5 Zornitza Stark Marked gene: GJA5 as ready
Mendeliome v0.14651 LRP2 Chirag Patel commented on gene: LRP2: Donnai-Barrow syndrome (DBS) was first described as a distinct disorder characterized by diaphragmatic hernia, exomphalos, absent corpus callosum, myopia, agenesis of the corpus callosum and proteinuria, and sensorineural deafness.

Kantarci et al. (2007) identified biallelic LRP2 mutations in 6 families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome.
Mendeliome v0.14651 LRP2 Chirag Patel reviewed gene: LRP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 17632512; Phenotypes: Donnai-Barrow syndrome, MIM#222448; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14651 ATPAF2 Krithika Murali reviewed gene: ATPAF2: Rating: RED; Mode of pathogenicity: None; Publications: 14757859; Phenotypes: ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 - MIM#604273; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14650 ADD1 Chirag Patel gene: ADD1 was added
gene: ADD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ADD1 were set to PMID: 34906466
Phenotypes for gene: ADD1 were set to Intellectual disability, corpus callosum dysgenesis, and ventriculomegaly; no OMIM #
Review for gene: ADD1 was set to GREEN
Added comment: 4 unrelated individuals affected by ID and/or complete or partial agenesis of corpus callosum, and enlarged lateral ventricles. WES found loss-of-function variants - 1 recessive missense variant and 3 de novo variants. The recessive variant is associated with ACC and enlarged lateral ventricles, and the de novo variants were associated with complete or partial agenesis of corpus callosum, mild ID and attention deficit. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. Three adducin genes (ADD1, ADD2, and ADD3) encode cytoskeleton proteins that are critical for osmotic rigidity and cell shape. ADD1, ADD2, and ADD3 form heterodimers (ADD1/ADD2, ADD1/ADD3), which further form heterotetramers. Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown
Sources: Literature
Mendeliome v0.14647 ATPAF2 Chirag Patel reviewed gene: ATPAF2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 14757859; Phenotypes: ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, OMIM# 604273; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14647 GJA5 Chirag Patel commented on gene: GJA5: Gollob et al. (2006) presented evidence that tissue-specific mutations in the GJA5 gene may predispose the atria to fibrillation. They identified a heterozygous missense mutation in blood and cardiac tissue in patient with AF. They also found 3 heterozygous missense mutations in cardiac tissue only in 3 other patients, indicating a somatic source of the genetic defects

Yang et al. (2010) identified a heterozygous nonsense mutationin a 64-year-old female patient who was diagnosed with paroxysmal AF at 32 years of age. The mutation was detected in 6 additional affected family members, but was not found in 6 unaffected family members or in 200 ethnically matched controls.

Yang et al. (2010) identified 3 heterozygous missense mutations in 3 probands with AF. The mutations segregated with disease in all 3 families and were not found in 200 ethnically matched controls.

Sun et al. (2013) identified a heterozygous missense mutation in a 42-year-old woman who had been diagnosed with AF at age 40 years. The mutation was also detected in her father, who had been diagnosed with lone AF at 41 years of age, but it was not found in unaffected family members, in 200 controls, or in the dbSNP database. Functional analysis demonstrated that the I75F mutant is unable to form functional gap junction channels and also impairs coupling when expressed with wildtype CX40 or CX43.
Mendeliome v0.14647 GEMIN4 Chirag Patel reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25558065, 30237576, 27878435; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, MIM# 617913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14647 GJB2 Zornitza Stark Marked gene: GJB2 as ready
Mendeliome v0.14647 GJB2 Zornitza Stark Phenotypes for gene: GJB2 were changed from to Bart-Pumphrey syndrome, MIM#149200; Deafness, autosomal dominant 3A, MIM#601544; Deafness, autosomal recessive 1A, MIM#220290; Hystrix-like ichthyosis with deafness, MIM#602540; Keratitis-ichthyosis-deafness syndrome, MIM#148210; Keratoderma, palmoplantar, with deafness, MIM#148350; Vohwinkel syndrome, MIM# 124500
Mendeliome v0.14644 GJB3 Zornitza Stark Marked gene: GJB3 as ready
Mendeliome v0.14644 GJB3 Zornitza Stark Phenotypes for gene: GJB3 were changed from to Erythrokeratodermia variabilis et progressiva 1, MIM# 133200
Mendeliome v0.14642 GJB2 Chirag Patel reviewed gene: GJB2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 11179004, 9529365, 14985372, 19941053, 11354642; Phenotypes: Bart-Pumphrey syndrome, MIM#149200, Deafness, autosomal dominant 3A, MIM#601544, Deafness, autosomal recessive 1A, MIM#220290, Hystrix-like ichthyosis with deafness, MIM#602540, Keratitis-ichthyosis-deafness syndrome, MIM#148210, Keratoderma, palmoplantar, with deafness, MIM#148350, Vohwinkel syndrome, MIM# 124500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14640 GJB3 Zornitza Stark reviewed gene: GJB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843209, 10594760, 10798362, 12019212; Phenotypes: Erythrokeratodermia variabilis et progressiva 1, MIM# 133200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14640 GJB3 Chirag Patel reviewed gene: GJB3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 9843209, 10798362, 10594760, 17446259, 9843210; Phenotypes: Erythrokeratodermia variabilis et progressiva 1, OMIM #133200, Deafness, autosomal dominant 2B, OMIM # 612644; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14640 GNB5 Chirag Patel reviewed gene: GNB5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27523599, 27677260, 28697420, 29368331; Phenotypes: Intellectual developmental disorder with cardiac arrhythmia, OMIM #617173, Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, OMIM # 617182, Early infantile epileptic encephalopathy (EIEE); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14640 GJB4 Zornitza Stark Marked gene: GJB4 as ready
Mendeliome v0.14640 GJB4 Zornitza Stark Phenotypes for gene: GJB4 were changed from to Erythrokeratodermia variabilis et progressiva 2, MIM# 617524
Mendeliome v0.14637 GJB4 Zornitza Stark reviewed gene: GJB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11017804, 12648223, 19291775; Phenotypes: Erythrokeratodermia variabilis et progressiva 2, MIM# 617524; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14637 GJB6 Zornitza Stark Marked gene: GJB6 as ready
Mendeliome v0.14634 GK Zornitza Stark Marked gene: GK as ready
Mendeliome v0.14631 GLCCI1 Zornitza Stark Marked gene: GLCCI1 as ready
Mendeliome v0.14628 GLE1 Zornitza Stark Marked gene: GLE1 as ready
Mendeliome v0.14625 GLIS3 Zornitza Stark Marked gene: GLIS3 as ready
Mendeliome v0.14622 GLUL Zornitza Stark Marked gene: GLUL as ready
Mendeliome v0.14619 GLYCTK Zornitza Stark Marked gene: GLYCTK as ready
Mendeliome v0.14616 GMPPA Zornitza Stark Marked gene: GMPPA as ready
Mendeliome v0.14616 GMPPA Zornitza Stark Phenotypes for gene: GMPPA were changed from to Alacrima, achalasia, and mental retardation syndrome, MIM# 615510
Mendeliome v0.14613 GMPPA Zornitza Stark reviewed gene: GMPPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24035193, 28574218; Phenotypes: Alacrima, achalasia, and mental retardation syndrome, MIM# 615510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14613 GMPPB Zornitza Stark Marked gene: GMPPB as ready
Mendeliome v0.14613 GMPPB Zornitza Stark Phenotypes for gene: GMPPB were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352
Mendeliome v0.14611 GMPPB Zornitza Stark reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14611 GNAS Zornitza Stark Marked gene: GNAS as ready
Mendeliome v0.14611 GNAS Zornitza Stark Phenotypes for gene: GNAS were changed from to Osseous heteroplasia, progressive (166350) AD; Pituitary adenoma 3, multiple types, somatic (617686); Pseudohypoparathyroidism Ia (103580) AD; Pseudohypoparathyroidism Ib (603233) AD; Pseudohypoparathyroidism Ic (612462) AD; Pseudopseudohypoparathyroidism (612463)
Mendeliome v0.14609 GNAS Zornitza Stark reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Osseous heteroplasia, progressive (166350) AD, Pituitary adenoma 3, multiple types, somatic (617686), Pseudohypoparathyroidism Ia (103580) AD, Pseudohypoparathyroidism Ib (603233) AD, Pseudohypoparathyroidism Ic (612462) AD, Pseudopseudohypoparathyroidism (612463); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14609 GNAT1 Zornitza Stark Marked gene: GNAT1 as ready
Mendeliome v0.14609 GNAT1 Zornitza Stark Phenotypes for gene: GNAT1 were changed from to Night blindness, congenital stationary, autosomal dominant 3, MIM# 610444; Night blindness, congenital stationary, type 1G, MIM# 616389
Mendeliome v0.14606 GNAT1 Zornitza Stark reviewed gene: GNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8673138, 17584859, 22190596, 26472407, 11095744, 11095744, 30051303; Phenotypes: Night blindness, congenital stationary, autosomal dominant 3, MIM# 610444, Night blindness, congenital stationary, type 1G, MIM# 616389; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14606 GNB3 Zornitza Stark Marked gene: GNB3 as ready
Mendeliome v0.14606 GNB3 Zornitza Stark Phenotypes for gene: GNB3 were changed from to Night blindness, congenital stationary, type 1H, MIM# 617024
Mendeliome v0.14603 GNB3 Zornitza Stark reviewed gene: GNB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27063057, 17065478; Phenotypes: Night blindness, congenital stationary, type 1H, MIM# 617024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14603 GNMT Zornitza Stark Marked gene: GNMT as ready
Mendeliome v0.14600 GOSR2 Zornitza Stark Marked gene: GOSR2 as ready
Mendeliome v0.14597 GOT1 Zornitza Stark Marked gene: GOT1 as ready
Mendeliome v0.14597 GOT1 Zornitza Stark Phenotypes for gene: GOT1 were changed from to Aspartate aminotransferase, serum level of, QTL1, MIM# 614419
Mendeliome v0.14595 GOT1 Zornitza Stark reviewed gene: GOT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Aspartate aminotransferase, serum level of, QTL1, MIM# 614419; Mode of inheritance: None
Mendeliome v0.14595 GPC4 Zornitza Stark Marked gene: GPC4 as ready
Mendeliome v0.14592 GPNMB Krithika Murali reviewed gene: GPNMB: Rating: GREEN; Mode of pathogenicity: None; Publications: 31226264, 29336782, 31260093, 34551863, 33687658; Phenotypes: Amyloidosis, primary localized cutaneous, 3 - MIM#617920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14592 GDF2 Chirag Patel reviewed gene: GDF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23972370, 27081547, 32573726, 32992168, 34611981, 33834622, 32669404, 26056270, 23972370; Phenotypes: Telangiectasia, hereditary hemorrhagic, type 5 OMIM # 615506, pulmonary arteriovenous malformations; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14592 GCNT2 Chirag Patel reviewed gene: GCNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15161861, 27936067, 12424189, 28224043; Phenotypes: Cataract 13 with adult i phenotype, OMIM # 116700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14592 GCK Chirag Patel reviewed gene: GCK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19790256; Phenotypes: Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853), Diabetes mellitus, permanent neonatal 1, AR (MIM#606176), Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485), MODY, type II, AD (MIM#125851); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14591 GDF9 Chirag Patel reviewed gene: GDF9: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29044499, 8849725, 33036707; Phenotypes: Premature ovarian failure 14, OMIM# 618014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14589 GIGYF2 Chirag Patel reviewed gene: GIGYF2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 18358451; Phenotypes: {Parkinson disease 11} , OMIM # 607688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14589 HEY2 Zornitza Stark Marked gene: HEY2 as ready
Mendeliome v0.14589 HEY2 Zornitza Stark Phenotypes for gene: HEY2 were changed from congenital heart defects and thoracic aortic aneurysms to congenital heart disease MONDO:0005453; thoracic aortic aneurysms
Mendeliome v0.14588 IL18BP Zornitza Stark Marked gene: IL18BP as ready
Mendeliome v0.14588 ITPKB Zornitza Stark Marked gene: ITPKB as ready
Mendeliome v0.14587 MUC7 Zornitza Stark Marked gene: MUC7 as ready
Mendeliome v0.14585 MYF6 Zornitza Stark Marked gene: MYF6 as ready
Mendeliome v0.14585 MYF6 Zornitza Stark Phenotypes for gene: MYF6 were changed from to Centronuclear myopathy, MONDO:0018947
Mendeliome v0.14582 PDCD6IP Zornitza Stark Marked gene: PDCD6IP as ready
Mendeliome v0.14580 POU5F1 Zornitza Stark Marked gene: POU5F1 as ready
Mendeliome v0.14580 GBA2 Chirag Patel reviewed gene: GBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23332916, 23332917, 29524657; Phenotypes: Spastic paraplegia 46, autosomal recessive, MIM# 614409, MONDO:0013737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14579 SGK3 Zornitza Stark Marked gene: SGK3 as ready
Mendeliome v0.14579 GATAD1 Chirag Patel reviewed gene: GATAD1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 21965549; Phenotypes: ?Cardiomyopathy, dilated, 2B, OMIM # 614672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14579 DMPK Zornitza Stark Marked gene: DMPK as ready
Mendeliome v0.14579 NOP56 Zornitza Stark Marked gene: NOP56 as ready
Mendeliome v0.14579 GPD1 Zornitza Stark Marked gene: GPD1 as ready
Mendeliome v0.14576 GPHN Zornitza Stark Marked gene: GPHN as ready
Mendeliome v0.14575 GPNMB Zornitza Stark Marked gene: GPNMB as ready
Mendeliome v0.14575 GPNMB Zornitza Stark Phenotypes for gene: GPNMB were changed from to Amyloidosis, primary localized cutaneous, 3, MIM# 617920
Mendeliome v0.14572 GPNMB Zornitza Stark reviewed gene: GPNMB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29336782; Phenotypes: Amyloidosis, primary localized cutaneous, 3, MIM# 617920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14572 GREM1 Zornitza Stark Marked gene: GREM1 as ready
Mendeliome v0.14568 MRAP Zornitza Stark Marked gene: MRAP as ready
Mendeliome v0.14565 MPZL2 Zornitza Stark Marked gene: MPZL2 as ready
Mendeliome v0.14562 MPZ Zornitza Stark Marked gene: MPZ as ready
Mendeliome v0.14562 MPZ Zornitza Stark Phenotypes for gene: MPZ were changed from to Charcot Marie Tooth disease, dominant intermediate D, 60779; Neuropathy, congenital hypomyelinating, 605253; Charcot Marie Tooth disease, type 2J, 607736; Dejerine Sottas disease, 145900; Charcot Marie Tooth disease, type 1B, 118200; Charcot Marie Tooth disease, type 2I, 607677; HMSN
Mendeliome v0.14559 MPV17 Zornitza Stark Marked gene: MPV17 as ready
Mendeliome v0.14559 MPV17 Zornitza Stark Phenotypes for gene: MPV17 were changed from to Charcot-Marie-Tooth disease, axonal, type 2EE, MIM# 618400
Mendeliome v0.14556 MPO Zornitza Stark Marked gene: MPO as ready
Mendeliome v0.14553 MPC1 Zornitza Stark Marked gene: MPC1 as ready
Mendeliome v0.14553 MPC1 Zornitza Stark Phenotypes for gene: MPC1 were changed from to Mitochondrial pyruvate carrier deficiency, MIM# 614741
Mendeliome v0.14550 MPC1 Zornitza Stark reviewed gene: MPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22628558, 34873722; Phenotypes: Mitochondrial pyruvate carrier deficiency, MIM# 614741; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14550 MOG Zornitza Stark Marked gene: MOG as ready
Mendeliome v0.14550 MOG Zornitza Stark Phenotypes for gene: MOG were changed from to Narcolepsy 7 , MIM# 614250
Mendeliome v0.14546 MOG Zornitza Stark reviewed gene: MOG: Rating: RED; Mode of pathogenicity: None; Publications: 21907016; Phenotypes: Narcolepsy 7 , MIM# 614250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14546 MOCS3 Zornitza Stark Marked gene: MOCS3 as ready
Mendeliome v0.14542 MOCS1 Zornitza Stark Marked gene: MOCS1 as ready
Mendeliome v0.14541 MNX1 Zornitza Stark Marked gene: MNX1 as ready
Mendeliome v0.14541 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from to Currarino syndrome, MIM# 176450
Mendeliome v0.14538 MMP2 Zornitza Stark Marked gene: MMP2 as ready
Mendeliome v0.14538 MMP2 Zornitza Stark Phenotypes for gene: MMP2 were changed from to Multicentric osteolysis, nodulosis, and arthropathy, MIM# 259600
Mendeliome v0.14535 MMP2 Zornitza Stark reviewed gene: MMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11431697, 15691365, 17059372, 17400654; Phenotypes: Multicentric osteolysis, nodulosis, and arthropathy, MIM# 259600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14533 ATP6V1A Elena Savva Marked gene: ATP6V1A as ready
Mendeliome v0.14532 ATP6AP2 Elena Savva Phenotypes for gene: ATP6AP2 were changed from ?Parkinsonism with spasticity, X-linked MIM#300911; Congenital disorder of glycosylation, type IIr MIM#301045; Intellectual developmental disorder, X-linked, syndromic, Hedera type MIM#300423 to ?Parkinsonism with spasticity, X-linked MIM#300911; Congenital disorder of glycosylation, type IIr MIM#301045; Intellectual developmental disorder, X-linked, syndromic, Hedera type MIM#300423
Mendeliome v0.14531 ATP6AP2 Elena Savva Marked gene: ATP6AP2 as ready
Mendeliome v0.14531 ATP6AP2 Elena Savva Phenotypes for gene: ATP6AP2 were changed from to ?Parkinsonism with spasticity, X-linked MIM#300911; Congenital disorder of glycosylation, type IIr MIM#301045; Intellectual developmental disorder, X-linked, syndromic, Hedera type MIM#300423
Mendeliome v0.14530 ATP6AP2 Elena Savva reviewed gene: ATP6AP2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 23595882; Phenotypes: ?Parkinsonism with spasticity, X-linked MIM#300911, Congenital disorder of glycosylation, type IIr MIM#301045, Intellectual developmental disorder, X-linked, syndromic, Hedera type MIM#300423; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14530 MMADHC Zornitza Stark Marked gene: MMADHC as ready
Mendeliome v0.14530 MMADHC Zornitza Stark Phenotypes for gene: MMADHC were changed from to Homocystinuria, cblD type, variant 1 MIM#277410; Methylmalonic aciduria and homocystinuria, cblD type MIM#277410; Methylmalonic aciduria, cblD type, variant 2 MIM#277410; Disorders of cobalamin absorption, transport and metabolism
Mendeliome v0.14527 MMACHC Zornitza Stark Marked gene: MMACHC as ready
Mendeliome v0.14524 MMAB Zornitza Stark Marked gene: MMAB as ready
Mendeliome v0.14522 MMAA Zornitza Stark Marked gene: MMAA as ready
Mendeliome v0.14520 MLPH Zornitza Stark Marked gene: MLPH as ready
Mendeliome v0.14517 MITF Zornitza Stark Marked gene: MITF as ready
Mendeliome v0.14517 MITF Zornitza Stark Phenotypes for gene: MITF were changed from to COMMAD syndrome, MIM# 617306; Tietz albinism-deafness syndrome, MIM# 103500; Waardenburg syndrome, type 2A, MIM# 193510
Mendeliome v0.14514 MITF Zornitza Stark reviewed gene: MITF: Rating: GREEN; Mode of pathogenicity: None; Publications: 27889061, 32541011; Phenotypes: COMMAD syndrome, MIM# 617306, Tietz albinism-deafness syndrome, MIM# 103500, Waardenburg syndrome, type 2A, MIM# 193510; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14514 MIR936 Zornitza Stark Marked gene: MIR936 as ready
Mendeliome v0.14513 MIR184 Zornitza Stark Marked gene: MIR184 as ready
Mendeliome v0.14510 MIR183 Zornitza Stark Marked gene: MIR183 as ready
Mendeliome v0.14506 ATP2C1 Elena Savva Marked gene: ATP2C1 as ready
Mendeliome v0.14505 ATP6V0A1 Elena Savva Marked gene: ATP6V0A1 as ready
Mendeliome v0.14505 MIR182 Zornitza Stark Marked gene: MIR182 as ready
Mendeliome v0.14504 MIP Zornitza Stark Marked gene: MIP as ready
Mendeliome v0.14504 MIP Zornitza Stark Phenotypes for gene: MIP were changed from to Cataract 15, multiple types, MIM# 615274
Mendeliome v0.14501 MIP Zornitza Stark reviewed gene: MIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 10802646, 16564824, 33530927, 30214549; Phenotypes: Cataract 15, multiple types, MIM# 615274; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14501 MIF Zornitza Stark Marked gene: MIF as ready
Mendeliome v0.14500 MIF Zornitza Stark Phenotypes for gene: MIF were changed from to {Rheumatoid arthritis, systemic juvenile, susceptibility to}, MIM# 604302
Mendeliome v0.14498 MIF Zornitza Stark reviewed gene: MIF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Rheumatoid arthritis, systemic juvenile, susceptibility to}, MIM# 604302; Mode of inheritance: None
Mendeliome v0.14498 MGME1 Zornitza Stark Marked gene: MGME1 as ready
Mendeliome v0.14495 MFN2 Zornitza Stark Marked gene: MFN2 as ready
Mendeliome v0.14494 MFF Zornitza Stark Marked gene: MFF as ready
Mendeliome v0.14491 METTL23 Zornitza Stark Marked gene: METTL23 as ready
Mendeliome v0.14488 MET Zornitza Stark Marked gene: MET as ready
Mendeliome v0.14488 MET Zornitza Stark Phenotypes for gene: MET were changed from to Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074; Papillary renal cell carcinoma MONDO:0017884
Mendeliome v0.14486 MET Zornitza Stark edited their review of gene: MET: Changed phenotypes: Renal cell carcinoma, papillary, 1, familial and somatic, MIM# 605074, Papillary renal cell carcinoma MONDO:0017884
Mendeliome v0.14486 MET Zornitza Stark reviewed gene: MET: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Papillary renal cell carcinoma MONDO:0017884; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14486 ATG16L1 Elena Savva Marked gene: ATG16L1 as ready
Mendeliome v0.14486 MERTK Zornitza Stark Marked gene: MERTK as ready
Mendeliome v0.14483 MEIS1 Zornitza Stark Marked gene: MEIS1 as ready
Mendeliome v0.14482 ATP1A1 Elena Savva Phenotypes for gene: ATP1A1 were changed from Charcot-Marie-Tooth disease, axonal, type 2DD MIM#618036; Hypomagnesemia, seizures, and mental retardation 2 MIM#618314 to Charcot-Marie-Tooth disease, axonal, type 2DD MIM#618036; Hypomagnesemia, seizures, and mental retardation 2 MIM#618314
Mendeliome v0.14481 ATP2A2 Elena Savva Marked gene: ATP2A2 as ready
Mendeliome v0.14479 ATL3 Elena Savva Phenotypes for gene: ATL3 were changed from Neuropathy, hereditary sensory, type IF, MIM# 615632 to Neuropathy, hereditary sensory, type IF, MIM# 615632
Mendeliome v0.14478 ATP2A2 Elena Savva Phenotypes for gene: ATP2A2 were changed from to Acrokeratosis verruciformis MIM#101900; Darier disease MIM#124200
Mendeliome v0.14476 ATP1A1 Elena Savva Phenotypes for gene: ATP1A1 were changed from to Charcot-Marie-Tooth disease, axonal, type 2DD MIM#618036; Hypomagnesemia, seizures, and mental retardation 2 MIM#618314
Mendeliome v0.14475 ATP1A1 Elena Savva Marked gene: ATP1A1 as ready
Mendeliome v0.14475 ATL3 Elena Savva Phenotypes for gene: ATL3 were changed from to Neuropathy, hereditary sensory, type IF, MIM# 615632
Mendeliome v0.14474 ATL3 Elena Savva Marked gene: ATL3 as ready
Mendeliome v0.14474 ATP2A2 Elena Savva reviewed gene: ATP2A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24336169; Phenotypes: Acrokeratosis verruciformis MIM#101900, Darier disease MIM#124200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14472 ATF1 Elena Savva Marked gene: ATF1 as ready
Mendeliome v0.14471 MEIOB Zornitza Stark Marked gene: MEIOB as ready
Mendeliome v0.14471 ASPN Elena Savva Marked gene: ASPN as ready
Mendeliome v0.14471 MEGF8 Zornitza Stark Marked gene: MEGF8 as ready
Mendeliome v0.14471 MEGF8 Zornitza Stark Phenotypes for gene: MEGF8 were changed from to Carpenter syndrome, MIM#614976
Mendeliome v0.14468 MEGF8 Zornitza Stark reviewed gene: MEGF8: Rating: GREEN; Mode of pathogenicity: None; Publications: 23063620; Phenotypes: Carpenter syndrome, MIM#614976; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14468 MEFV Zornitza Stark Marked gene: MEFV as ready
Mendeliome v0.14465 MED23 Zornitza Stark Marked gene: MED23 as ready
Mendeliome v0.14462 MED13 Zornitza Stark Marked gene: MED13 as ready
Mendeliome v0.14459 MECP2 Zornitza Stark Marked gene: MECP2 as ready
Mendeliome v0.14456 MCM9 Zornitza Stark Marked gene: MCM9 as ready
Mendeliome v0.14456 MCM9 Zornitza Stark Phenotypes for gene: MCM9 were changed from to Ovarian dysgenesis 4, MIM# 616185
Mendeliome v0.14453 MCM9 Zornitza Stark reviewed gene: MCM9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25480036, 26771056, 33538981, 33095795; Phenotypes: Ovarian dysgenesis 4, MIM# 616185; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14453 MCM8 Zornitza Stark Marked gene: MCM8 as ready
Mendeliome v0.14453 ASPN Elena Savva Phenotypes for gene: ASPN were changed from {Lumbar disc degeneration} MIM#603932; {Osteoarthritis susceptibility 3} MIM#607850 to {Lumbar disc degeneration} MIM#603932; {Osteoarthritis susceptibility 3} MIM#607850
Mendeliome v0.14453 ASPN Elena Savva Phenotypes for gene: ASPN were changed from to {Lumbar disc degeneration} MIM#603932; {Osteoarthritis susceptibility 3} MIM#607850
Mendeliome v0.14451 ARV1 Elena Savva Marked gene: ARV1 as ready
Mendeliome v0.14451 ARV1 Elena Savva Gene: arv1 has been classified as Green List (High Evidence).
Mendeliome v0.14450 ARV1 Elena Savva Phenotypes for gene: ARV1 were changed from to DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 38 MIM#61720; Dilated cardiomyopathy
Mendeliome v0.14449 ARV1 Elena Savva Publications for gene: ARV1 were set to
Mendeliome v0.14449 ARV1 Elena Savva Mode of inheritance for gene: ARV1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14448 MCM8 Zornitza Stark Phenotypes for gene: MCM8 were changed from to Premature ovarian failure 10, MIM# 612885
Mendeliome v0.14445 MCM8 Zornitza Stark reviewed gene: MCM8: Rating: GREEN; Mode of pathogenicity: None; Publications: 25437880, 25873734; Phenotypes: Premature ovarian failure 10, MIM# 612885; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14445 MCM6 Zornitza Stark Marked gene: MCM6 as ready
Mendeliome v0.14442 OAS1 Zornitza Stark Phenotypes for gene: OAS1 were changed from Autoinflammatory immunodeficiency; infantile-onset pulmonary alveolar proteinosis; hypogammaglobulinaemia to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042
Mendeliome v0.14441 OAS1 Zornitza Stark edited their review of gene: OAS1: Changed phenotypes: Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042
Mendeliome v0.14441 MCEE Zornitza Stark Marked gene: MCEE as ready
Mendeliome v0.14438 MCCC2 Zornitza Stark Marked gene: MCCC2 as ready
Mendeliome v0.14438 MCCC2 Zornitza Stark Phenotypes for gene: MCCC2 were changed from to 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210; Organic acidurias
Mendeliome v0.14435 MCCC2 Zornitza Stark reviewed gene: MCCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14435 MCCC1 Zornitza Stark Marked gene: MCCC1 as ready
Mendeliome v0.14435 MCCC1 Zornitza Stark Phenotypes for gene: MCCC1 were changed from to 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200; Organic acidurias
Mendeliome v0.14432 MCCC1 Zornitza Stark reviewed gene: MCCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14432 MC3R Zornitza Stark Marked gene: MC3R as ready
Mendeliome v0.14429 MC2R Zornitza Stark Marked gene: MC2R as ready
Mendeliome v0.14426 MBL2 Zornitza Stark Marked gene: MBL2 as ready
Mendeliome v0.14422 MATR3 Zornitza Stark Marked gene: MATR3 as ready
Mendeliome v0.14419 MAP3K1 Zornitza Stark Marked gene: MAP3K1 as ready
Mendeliome v0.14416 MAK Zornitza Stark Marked gene: MAK as ready
Mendeliome v0.14413 MAGT1 Zornitza Stark Marked gene: MAGT1 as ready
Mendeliome v0.14413 MAGT1 Zornitza Stark Phenotypes for gene: MAGT1 were changed from to Congenital disorder of glycosylation, type Icc (MIM# 301031); Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853)
Mendeliome v0.14410 MAGT1 Zornitza Stark reviewed gene: MAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31036665, 31714901; Phenotypes: Congenital disorder of glycosylation, type Icc (MIM# 301031), Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14410 GREM1 Krithika Murali reviewed gene: GREM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 22561515, 26493165, 21128281, 29804199; Phenotypes: hereditary mixed polyposis syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14410 MNX1 Abhijit Kulkarni reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571425, 33836786 , 11528505; Phenotypes: Currarino syndrome, MIM# 176450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14410 MAGI2 Zornitza Stark Marked gene: MAGI2 as ready
Mendeliome v0.14407 MYO3A Zornitza Stark Marked gene: MYO3A as ready
Mendeliome v0.14407 OPHN1 Zornitza Stark Marked gene: OPHN1 as ready
Mendeliome v0.14407 OPHN1 Zornitza Stark Phenotypes for gene: OPHN1 were changed from to Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, MIM#300486
Mendeliome v0.14404 OPHN1 Zornitza Stark commented on gene: OPHN1: OPHN1 variants cause cerebellar hypoplasia and distinctive facial appearance, macrocephaly is a feature. At least 8 families reported.
Mendeliome v0.14404 PAH Zornitza Stark Marked gene: PAH as ready
Mendeliome v0.14401 PCDH12 Zornitza Stark Marked gene: PCDH12 as ready
Mendeliome v0.14398 PEPD Zornitza Stark Marked gene: PEPD as ready
Mendeliome v0.14395 PEX10 Zornitza Stark Marked gene: PEX10 as ready
Mendeliome v0.14392 PCK1 Zornitza Stark Marked gene: PCK1 as ready
Mendeliome v0.14392 PCK1 Zornitza Stark Phenotypes for gene: PCK1 were changed from to Phosphoenolpyruvate carboxykinase deficiency, cytosolic MIM#261680; Disorders of gluconeogenesis
Mendeliome v0.14389 QDPR Zornitza Stark Marked gene: QDPR as ready
Mendeliome v0.14389 REEP1 Zornitza Stark Marked gene: REEP1 as ready
Mendeliome v0.14389 REEP1 Zornitza Stark Phenotypes for gene: REEP1 were changed from to Neuronopathy, distal hereditary motor, type VB MIM#614751; Spastic paraplegia 31, autosomal dominant MIM#610250; Charcot-Marie-Tooth; severe congenital distal SMA with diaphragmatic paralysis; congenital axonal neuropathy and diaphragmatic palsy
Mendeliome v0.14386 RLBP1 Zornitza Stark Marked gene: RLBP1 as ready
Mendeliome v0.14383 RMND1 Zornitza Stark Marked gene: RMND1 as ready
Mendeliome v0.14381 RNASEH1 Zornitza Stark Marked gene: RNASEH1 as ready
Mendeliome v0.14379 RBFOX2 Chern Lim edited their review of gene: RBFOX2: Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. Same cohort later included in PMID: 32368696, listed 4 de novo variants in this gene, in patients with left ventricular outflow tract obstruction (LVOTO) or conotruncal defects (CTDs).

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.; Changed publications: PMID: 26785492, 27670201, 27485310, 25205790, 35137168, 26785492
Mendeliome v0.14378 RNASEH2A Zornitza Stark Marked gene: RNASEH2A as ready
Mendeliome v0.14378 RNASEH2A Zornitza Stark Phenotypes for gene: RNASEH2A were changed from to Aicardi-Goutieres syndrome 4 MIM#610333
Mendeliome v0.14375 RNF139 Zornitza Stark Marked gene: RNF139 as ready
Mendeliome v0.14375 RNF139 Zornitza Stark Phenotypes for gene: RNF139 were changed from to Renal cell carcinoma MIM#144700
Mendeliome v0.14371 RP1 Zornitza Stark Marked gene: RP1 as ready
Mendeliome v0.14368 RP2 Zornitza Stark Marked gene: RP2 as ready
Mendeliome v0.14365 RP9 Zornitza Stark Marked gene: RP9 as ready
Mendeliome v0.14360 RYR1 Zornitza Stark Marked gene: RYR1 as ready
Mendeliome v0.14360 RYR1 Zornitza Stark Phenotypes for gene: RYR1 were changed from to {Malignant hyperthermia susceptibility 1} MIM#145600; Central core disease, MIM# 117000; King-Denborough syndrome , MIM#619542; Minicore myopathy with external ophthalmoplegia , MIM#255320; Neuromuscular disease, congenital, with uniform type 1 fiber, MIM# 117000
Mendeliome v0.14357 RYR1 Zornitza Stark reviewed gene: RYR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Central core disease, MIM# 117000, King-Denborough syndrome , MIM#619542, Minicore myopathy with external ophthalmoplegia , MIM#255320, Neuromuscular disease, congenital, with uniform type 1 fiber, MIM# 117000; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14357 SACS Zornitza Stark Marked gene: SACS as ready
Mendeliome v0.14357 SACS Zornitza Stark Phenotypes for gene: SACS were changed from to Spastic ataxia, Charlevoix-Saguenay type MIM#270550
Mendeliome v0.14355 SCN11A Zornitza Stark Marked gene: SCN11A as ready
Mendeliome v0.14355 SCN11A Zornitza Stark Phenotypes for gene: SCN11A were changed from to Neuropathy, hereditary sensory and autonomic, type VII, MIM# 615548; Episodic pain syndrome, familial, 3, MIM# 615552
Mendeliome v0.14352 SCN11A Zornitza Stark edited their review of gene: SCN11A: Changed phenotypes: Neuropathy, hereditary sensory and autonomic, type VII, MIM# 615548, Episodic pain syndrome, familial, 3, MIM# 615552
Mendeliome v0.14352 TMC8 Zornitza Stark Marked gene: TMC8 as ready
Mendeliome v0.14345 RBFOX2 Chern Lim gene: RBFOX2 was added
gene: RBFOX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX2 were set to PMID: 26785492; 27670201; 27485310; 25205790; 35137168
Phenotypes for gene: RBFOX2 were set to Hypoplastic left heart syndrome (HLHS)
Review for gene: RBFOX2 was set to AMBER
gene: RBFOX2 was marked as current diagnostic
Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS).
No further patient-specific clinical or variant info were available.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.
Sources: Literature
Mendeliome v0.14345 GRIA4 Ain Roesley Marked gene: GRIA4 as ready
Mendeliome v0.14344 GRID2 Ain Roesley Marked gene: GRID2 as ready
Mendeliome v0.14344 GRID2 Ain Roesley Phenotypes for gene: GRID2 were changed from to Spinocerebellar ataxia, autosomal recessive 18 MIM#616204
Mendeliome v0.14343 GRID2 Ain Roesley reviewed gene: GRID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622959, 32170608; Phenotypes: Spinocerebellar ataxia, autosomal recessive 18 MIM#616204; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14343 GRIN2D Ain Roesley Marked gene: GRIN2D as ready
Mendeliome v0.14341 ARV1 Abhijit Kulkarni reviewed gene: ARV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35227294, 27270415, 25558065; Phenotypes: DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 38 ( MIM:61720) Dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14341 UGT1A1 Zornitza Stark Marked gene: UGT1A1 as ready
Mendeliome v0.14341 UGT1A1 Zornitza Stark Phenotypes for gene: UGT1A1 were changed from to Bilirubin UDP-glucuronosyltransferase 1 deficiency (Disorders of bile acid metabolism and transport); Crigler-Najjar syndrome, type I 218800; Crigler-Najjar syndrome, type II 606785
Mendeliome v0.14339 UNC13D Zornitza Stark Marked gene: UNC13D as ready
Mendeliome v0.14339 UNG Zornitza Stark Marked gene: UNG as ready
Mendeliome v0.14337 UQCC2 Zornitza Stark Marked gene: UQCC2 as ready
Mendeliome v0.14337 UQCC2 Zornitza Stark Phenotypes for gene: UQCC2 were changed from to Mitochondrial complex III deficiency, nuclear type 7 - MIM#615824
Mendeliome v0.14334 UQCRB Zornitza Stark Marked gene: UQCRB as ready
Mendeliome v0.14334 UQCRB Zornitza Stark Phenotypes for gene: UQCRB were changed from to Mitochondrial complex III deficiency, nuclear type 3, MIM# 615158
Mendeliome v0.14331 UROD Zornitza Stark Marked gene: UROD as ready
Mendeliome v0.14331 UROD Zornitza Stark Phenotypes for gene: UROD were changed from to Porphyria cutanea tarda; Porphyria, hepatoerythropoietic (MIM#176100)
Mendeliome v0.14328 MAGED2 Zornitza Stark Marked gene: MAGED2 as ready
Mendeliome v0.14328 MAGED2 Zornitza Stark Phenotypes for gene: MAGED2 were changed from to Bartter syndrome, type 5, antenatal, transient, MIM# 300971
Mendeliome v0.14325 MAGED2 Zornitza Stark reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27120771; Phenotypes: Bartter syndrome, type 5, antenatal, transient, MIM# 300971; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14325 MRPS2 Zornitza Stark Marked gene: MRPS2 as ready
Mendeliome v0.14322 MSH3 Zornitza Stark Marked gene: MSH3 as ready
Mendeliome v0.14319 MSRB3 Zornitza Stark Marked gene: MSRB3 as ready
Mendeliome v0.14316 MTAP Zornitza Stark Marked gene: MTAP as ready
Mendeliome v0.14316 MTAP Zornitza Stark Phenotypes for gene: MTAP were changed from to Diaphyseal medullary stenosis with malignant fibrous histiocytoma, MIM# 112250
Mendeliome v0.14312 MTAP Zornitza Stark reviewed gene: MTAP: Rating: AMBER; Mode of pathogenicity: None; Publications: 22464254; Phenotypes: Diaphyseal medullary stenosis with malignant fibrous histiocytoma, MIM# 112250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14312 MTFMT Zornitza Stark Marked gene: MTFMT as ready
Mendeliome v0.14312 MTFMT Zornitza Stark Phenotypes for gene: MTFMT were changed from to Combined oxidative phosphorylation deficiency 15, MIM# 614947; Mitochondrial complex I deficiency, nuclear type 27, MIM# 618248
Mendeliome v0.14309 MTFMT Zornitza Stark reviewed gene: MTFMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907147, 23499752, 24461907, 22499348; Phenotypes: Combined oxidative phosphorylation deficiency 15, MIM# 614947, Mitochondrial complex I deficiency, nuclear type 27, MIM# 618248; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14309 MTHFD1 Zornitza Stark Marked gene: MTHFD1 as ready
Mendeliome v0.14305 MTHFR Zornitza Stark Marked gene: MTHFR as ready
Mendeliome v0.14302 MTM1 Zornitza Stark Marked gene: MTM1 as ready
Mendeliome v0.14302 MTM1 Zornitza Stark Phenotypes for gene: MTM1 were changed from to Myopathy, centronuclear, X-linked, MIM# 310400
Mendeliome v0.14299 MTM1 Zornitza Stark reviewed gene: MTM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10790201; Phenotypes: Myopathy, centronuclear, X-linked, MIM# 310400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.14299 MTO1 Zornitza Stark Marked gene: MTO1 as ready
Mendeliome v0.14295 MTOR Zornitza Stark Marked gene: MTOR as ready
Mendeliome v0.14291 DNAJC6 Krithika Murali reviewed gene: DNAJC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22563501, 23211418, 26528954; Phenotypes: Parkinson disease 19a, juvenile-onset - MIM#615528, Parkinson disease 19b, early-onset - MIM#615528; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14291 DNAJC3 Krithika Murali changed review comment from: Well-established association with monogenic diabetes with growth restriction, hypothyroidism, neuropathy, sensorineural hearing loss and cerebellar ataxia also reported affected individuals (PMID 33486469 Lytrvi et al 2021 report 2 additional families and summarise the phenotypic features of 4 previously reported families).; to: Well-established association with monogenic diabetes. Growth restriction, hypothyroidism, neuropathy, sensorineural hearing loss and cerebellar ataxia also reported in affected individuals (PMID 33486469 Lytrvi et al 2021 report 2 additional families and summarise the phenotypic features of 4 previously reported families).
Mendeliome v0.14291 DNAJC3 Krithika Murali reviewed gene: DNAJC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33486469, 34630333, 34654017, 32738013; Phenotypes: ?Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus - MIM#616192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14291 DNAJC21 Krithika Murali reviewed gene: DNAJC21: Rating: GREEN; Mode of pathogenicity: None; Publications: 29700810, 28062395, 27346687; Phenotypes: Bone marrow failure syndrome 3 - MIM#617052; Mode of inheritance: None
Mendeliome v0.14291 DNM1L Krithika Murali reviewed gene: DNM1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR), Optic atrophy 5 - MIM#610708 (AD); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14291 DRD3 Krithika Murali reviewed gene: DRD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Essential tremor, hereditary, 1} - MIM#190300, {Schizophrenia, susceptibility to} - MIM#181500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14291 DSCAM Krithika Murali edited their review of gene: DSCAM: Added comment: No OMIM gene disease association. Variants predominantly identified from large cohort studies with limited phenotypic information. Associations with ID, ASD, Hirschsprung disease reported. One homozygous splice site variant reported with no parental phenotypes provided.

PMID 34253863 Lim et al 2021 - 12 yo proband with severe autism spectrum disorder diagnosed age 3, de novo heterozygous c.2051 del p.(L684X) variant identified (absent from gnomAD). Skin fibroblast human iPSC cells generated from proband and healthy controls. Forebrain-like induced neuronal cells showed reduced mRNA expression for NMDA-R subunits.

PMID 28600779 Monies et al 2017 - Homozygous splice site variant identified in proband from consanguineous Saudi family. Proband had growth restriction, microcephaly, developmental delay. Parental phenotype not provided.

PMID 30095639 and PMID 23671607 - report association between DSCAM polymorphisms and Hirschsprung disease in Chinese and European populations.

PMID 27824329 Wang et al 2016 - 2 denovo mutations in mixed ID/ASD cohort of 1,045; including comparison of previously published cases 6 LOF out of 4,998 cases.

PMID 28191889 2 denovo LOF in 13,407 mixed ID/ASD cases plus 4 previosly published cases our ot 6158; conclude denovo LOF enriched in cases vs controls

PMID 21904980; mouse model – het LOF mice show hydrocephalus, decreased motor function and impaired motor learning ability,

Evidence for missense lacking currently; Changed publications: 34253863, 32807774, 28600779, 21904980, 28191889, 27824329, 30095639, 23671607
Mendeliome v0.14291 MTTP Zornitza Stark Marked gene: MTTP as ready
Mendeliome v0.14288 MUT Zornitza Stark Marked gene: MUT as ready
Mendeliome v0.14285 MVK Zornitza Stark Marked gene: MVK as ready
Mendeliome v0.14282 MXI1 Zornitza Stark Marked gene: MXI1 as ready
Mendeliome v0.14281 MYD88 Zornitza Stark Marked gene: MYD88 as ready
Mendeliome v0.14278 MYH14 Zornitza Stark Marked gene: MYH14 as ready
Mendeliome v0.14278 MYH14 Zornitza Stark Phenotypes for gene: MYH14 were changed from to Deafness, autosomal dominant 4A, MIM# 600652; Peripheral neuropathy, myopathy, hoarseness, and hearing loss 614369
Mendeliome v0.14275 MYH14 Zornitza Stark reviewed gene: MYH14: Rating: GREEN; Mode of pathogenicity: None; Publications: 15015131, 25719458, 31045651, 28221712, 34681017, 21480433, 31653586, 31631044, 31231018; Phenotypes: Deafness, autosomal dominant 4A, MIM# 600652, Peripheral neuropathy, myopathy, hoarseness, and hearing loss 614369; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14275 MYH3 Zornitza Stark Marked gene: MYH3 as ready
Mendeliome v0.14275 MYH3 Zornitza Stark Phenotypes for gene: MYH3 were changed from to Arthrogryposis, distal, type 2A (Freeman-Sheldon) 193700; Arthrogryposis, distal, type 2B3 (Sheldon-Hall) 618436; Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A 178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B 618469
Mendeliome v0.14272 MYH3 Zornitza Stark reviewed gene: MYH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25957469, 26544689, 21531865, 18695058; Phenotypes: Arthrogryposis, distal, type 2A (Freeman-Sheldon) 193700, Arthrogryposis, distal, type 2B3 (Sheldon-Hall) 618436, Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A 178110, Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B 618469; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14272 MYO1E Zornitza Stark Marked gene: MYO1E as ready
Mendeliome v0.14269 WNT1 Zornitza Stark Marked gene: WNT1 as ready
Mendeliome v0.14266 WNK4 Zornitza Stark Marked gene: WNK4 as ready
Mendeliome v0.14263 WNK1 Zornitza Stark Marked gene: WNK1 as ready
Mendeliome v0.14263 WNK1 Zornitza Stark Phenotypes for gene: WNK1 were changed from to Neuropathy, hereditary sensory and autonomic, type II, MIM# 201300; MONDO:0024309; Pseudohypoaldosteronism, type IIC, MIM# 614492
Mendeliome v0.14260 WNK1 Zornitza Stark changed review comment from: Well established gene-disease association.

Note mono-allelic variants are associated with pseudohypoaldosteronism; to: Well established gene-disease associations.
Mendeliome v0.14260 WNK1 Zornitza Stark edited their review of gene: WNK1: Changed phenotypes: Neuropathy, hereditary sensory and autonomic, type II, MIM# 201300, MONDO:0024309, Pseudohypoaldosteronism, type IIC, MIM# 614492; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14260 WDR4 Zornitza Stark Marked gene: WDR4 as ready
Mendeliome v0.14256 WDR36 Zornitza Stark changed review comment from: Multiple individuals reported.

However, note one of the earliest reported variants p.Asp658Gly is present in >1,000 individuals in gnomad, and another, p.Ala449Thr is present in >2000.; to: Multiple individuals reported. Adult-onset.

However, note one of the earliest reported variants p.Asp658Gly is present in >1,000 individuals in gnomad, and another, p.Ala449Thr is present in >2000.
Mendeliome v0.14256 WDR36 Zornitza Stark changed review comment from: Multiple individuals reported.

However, note one of the earliest reported variants p.Asp658Gly is present in >1,000 individuals in gnomad.; to: Multiple individuals reported.

However, note one of the earliest reported variants p.Asp658Gly is present in >1,000 individuals in gnomad, and another, p.Ala449Thr is present in >2000.
Mendeliome v0.14256 WDR36 Zornitza Stark Marked gene: WDR36 as ready
Mendeliome v0.14253 WASHC5 Zornitza Stark Marked gene: WASHC5 as ready
Mendeliome v0.14253 WASHC5 Zornitza Stark Phenotypes for gene: WASHC5 were changed from to Ritscher-Schinzel syndrome 1, MIM# 220210; Spastic paraplegia 8, autosomal dominant, MIM# 603563
Mendeliome v0.14250 WASHC5 Zornitza Stark reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 17160902, 23455931, 30778698, 24065355, 33456446; Phenotypes: Ritscher-Schinzel syndrome 1, MIM# 220210, Spastic paraplegia 8, autosomal dominant, MIM# 603563; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14250 WASF1 Zornitza Stark Marked gene: WASF1 as ready
Mendeliome v0.14250 WASF1 Zornitza Stark Phenotypes for gene: WASF1 were changed from to Neurodevelopmental disorder with absent language and variable seizures , MIM#618707
Mendeliome v0.14247 WASF1 Zornitza Stark reviewed gene: WASF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961568, 34845217, 34478686, 34356165; Phenotypes: Neurodevelopmental disorder with absent language and variable seizures , MIM#618707; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14247 WAC Zornitza Stark Marked gene: WAC as ready
Mendeliome v0.14244 FXYD2 Bryony Thompson Marked gene: FXYD2 as ready
Mendeliome v0.14239 RIPPLY2 Zornitza Stark Marked gene: RIPPLY2 as ready
Mendeliome v0.14236 FXN Bryony Thompson Marked gene: FXN as ready
Mendeliome v0.14236 MYOC Zornitza Stark Marked gene: MYOC as ready
Mendeliome v0.14236 MYOC Zornitza Stark Phenotypes for gene: MYOC were changed from to Glaucoma 1A, primary open angle, MIM# 137750
Mendeliome v0.14233 MYOC Zornitza Stark reviewed gene: MYOC: Rating: GREEN; Mode of pathogenicity: None; Publications: 9005853, 9535666, 15108121; Phenotypes: Glaucoma 1A, primary open angle, MIM# 137750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14232 MYOCD Zornitza Stark changed review comment from: Congenital megabladder (MGBL) is characterized by a massively dilated bladder with disrupted smooth muscle in the bladder wall. MGBL is a sex-limited trait with 95% male predominance, likely the result of differences in urethra and bladder development and length differences in urethra between males and females.

Seven affected males from three families. Five females and one male with the variant were unaffected, suggesting incomplete penetrance.

Additional family in PMID 35005812 as part of a large prenatal renal cohort.; to: Congenital megabladder (MGBL) is characterized by a massively dilated bladder with disrupted smooth muscle in the bladder wall. MGBL is a sex-limited trait with 95% male predominance, likely the result of differences in urethra and bladder development and length differences in urethra between males and females.

Seven affected males from three families. Five females and one male with the variant were unaffected, suggesting incomplete penetrance.

Additional family in PMID 35005812 as part of a large prenatal renal cohort.

Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease).

Mouse models.
Mendeliome v0.14232 MYOCD Zornitza Stark Marked gene: MYOCD as ready
Mendeliome v0.14229 MYOT Zornitza Stark Marked gene: MYOT as ready
Mendeliome v0.14229 MYOT Zornitza Stark Phenotypes for gene: MYOT were changed from to Myopathy, myofibrillar, 3, MIM# 609200; Myopathy, spheroid body, MIM# 182920
Mendeliome v0.14226 MYOT Zornitza Stark reviewed gene: MYOT: Rating: GREEN; Mode of pathogenicity: None; Publications: 10958653, 15111675, 16380616, 33250842, 32509353, 29924655; Phenotypes: Myopathy, myofibrillar, 3, MIM# 609200, Myopathy, spheroid body, MIM# 182920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14223 FXN Bryony Thompson edited their review of gene: FXN: Added comment: Well-established gene-disease association. 96% of cases are caused by biallelic intronic GAA triplet repeat expansion and 4% are attributable to biallelic single nucleotide variants and small indels. Loss of function is the mechanism of disease.; Changed rating: GREEN; Changed publications: 20301458, 26704351; Changed phenotypes: Friedreich ataxia MONDO:0100339; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Set current diagnostic: yes
Mendeliome v0.14223 RNF139 Belinda Chong reviewed gene: RNF139: Rating: RED; Mode of pathogenicity: None; Publications: 9689122; Phenotypes: Renal cell carcinoma MIM#144700; Mode of inheritance: Other
Mendeliome v0.14223 FUT8 Bryony Thompson Marked gene: FUT8 as ready
Mendeliome v0.14220 FUT1 Bryony Thompson Marked gene: FUT1 as ready
Mendeliome v0.14219 FUT1 Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants produce the Bombay blood group, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene.
Mendeliome v0.14217 FUT1 Bryony Thompson Added comment: Comment on list classification: Biallelic loss of function variants cause Bombay phenotype, which is a recessive H-deficient red blood cell phenotype. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion. No evidence for Mendelian disease associated with this gene.
Mendeliome v0.14215 FSHR Bryony Thompson Marked gene: FSHR as ready
Mendeliome v0.14215 FTO Bryony Thompson Marked gene: FTO as ready
Mendeliome v0.14214 FTO Bryony Thompson Phenotypes for gene: FTO were changed from to Growth retardation, developmental delay, facial dysmorphism MIM#612938
Mendeliome v0.14212 FTO Bryony Thompson reviewed gene: FTO: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234441, 19559399, 26378117, 26697951, 26378117, 26740239; Phenotypes: Growth retardation, developmental delay, facial dysmorphism MIM#612938; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14212 RIMS1 Zornitza Stark Marked gene: RIMS1 as ready
Mendeliome v0.14209 RHEB Zornitza Stark Marked gene: RHEB as ready
Mendeliome v0.14209 FSHR Bryony Thompson Phenotypes for gene: FSHR were changed from to Ovarian dysgenesis 1 MONDO:0024463; Ovarian hyperstimulation syndrome MONDO:0011972
Mendeliome v0.14203 FSHR Bryony Thompson reviewed gene: FSHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 16630814, 7553856, 9020851, 9769327, 20087398, 9854118, 12930928, 12930927, 17721928, 26911863; Phenotypes: Ovarian dysgenesis 1 MONDO:0024463, Ovarian hyperstimulation syndrome MONDO:0011972; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14203 RHCE Zornitza Stark Marked gene: RHCE as ready
Mendeliome v0.14200 RGS9BP Zornitza Stark Marked gene: RGS9BP as ready
Mendeliome v0.14197 RGS9 Zornitza Stark Marked gene: RGS9 as ready
Mendeliome v0.14194 RFX6 Zornitza Stark Marked gene: RFX6 as ready
Mendeliome v0.14191 FXYD6 Bryony Thompson Marked gene: FXYD6 as ready
Mendeliome v0.14188 FZD2 Bryony Thompson Marked gene: FZD2 as ready
Mendeliome v0.14186 FBP2 Zornitza Stark Marked gene: FBP2 as ready
Mendeliome v0.14185 FBP2 Zornitza Stark gene: FBP2 was added
gene: FBP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBP2 were set to 33977262
Phenotypes for gene: FBP2 were set to Leukodystrophy, childhood-onset, remitting, MIM# 619864
Review for gene: FBP2 was set to AMBER
Added comment: 8 individuals from 3 generations in a single family reported with a variant in this gene. The children presented with episode of regression and leukodystrophy in early childhood, from which they made a slow recovery. The adults had a broad range of neurobehavioural phenotypes but also had leukodystrophy on imaging. Some functional data presented (in vitro).
Sources: Expert list
Mendeliome v0.14181 MOV10L1 Zornitza Stark Marked gene: MOV10L1 as ready
Mendeliome v0.14178 RFC2 Zornitza Stark Marked gene: RFC2 as ready
Mendeliome v0.14177 REST Zornitza Stark Marked gene: REST as ready
Mendeliome v0.14174 REEP6 Zornitza Stark Marked gene: REEP6 as ready
Mendeliome v0.14171 RCBTB1 Zornitza Stark Marked gene: RCBTB1 as ready
Mendeliome v0.14171 RCBTB1 Zornitza Stark Phenotypes for gene: RCBTB1 were changed from to Retinal dystrophy with or without extraocular anomalies, MIM# 617175
Mendeliome v0.14168 RCBTB1 Zornitza Stark reviewed gene: RCBTB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27486781, 35057699, 33624564, 33104391; Phenotypes: Retinal dystrophy with or without extraocular anomalies, MIM# 617175; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14167 FSHB Bryony Thompson Marked gene: FSHB as ready
Mendeliome v0.14164 FRZB Bryony Thompson Marked gene: FRZB as ready
Mendeliome v0.14164 FRZB Bryony Thompson Phenotypes for gene: FRZB were changed from to {Osteoarthritis susceptibility 1} MIM#165720
Mendeliome v0.14163 FRRS1L Bryony Thompson Marked gene: FRRS1L as ready
Mendeliome v0.14158 FRZB Bryony Thompson reviewed gene: FRZB: Rating: RED; Mode of pathogenicity: None; Publications: 15210948; Phenotypes: {Osteoarthritis susceptibility 1} MIM#165720; Mode of inheritance: Unknown
Mendeliome v0.14158 FOXN1 Bryony Thompson Marked gene: FOXN1 as ready
Mendeliome v0.14158 RBPJ Zornitza Stark Marked gene: RBPJ as ready
Mendeliome v0.14152 FOXI1 Bryony Thompson Marked gene: FOXI1 as ready
Mendeliome v0.14152 FOXI1 Bryony Thompson Phenotypes for gene: FOXI1 were changed from to autosomal recessive distal renal tubular acidosis MONDO:0018440
Mendeliome v0.14149 FOXI1 Bryony Thompson reviewed gene: FOXI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843211, 12642503, 29242249, 17503324, 30268946, 27997596, 22285650, 23965030, 24860705, 32447495, 19204907; Phenotypes: autosomal recessive distal renal tubular acidosis MONDO:0018440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14149 FOXD3 Bryony Thompson Marked gene: FOXD3 as ready
Mendeliome v0.14146 FMR1 Bryony Thompson Marked gene: FMR1 as ready
Mendeliome v0.14145 RBP3 Zornitza Stark Marked gene: RBP3 as ready
Mendeliome v0.14142 RBM28 Zornitza Stark Marked gene: RBM28 as ready
Mendeliome v0.14138 RASGRP2 Zornitza Stark Marked gene: RASGRP2 as ready
Mendeliome v0.14135 SCN2A Zornitza Stark Marked gene: SCN2A as ready
Mendeliome v0.14131 SCN9A Zornitza Stark Marked gene: SCN9A as ready
Mendeliome v0.14131 SCN9A Zornitza Stark Phenotypes for gene: SCN9A were changed from to Erythermalgia, primary, MIM# 133020; Insensitivity to pain, congenital, MIM# 243000; Neuropathy, hereditary sensory and autonomic, type IID, MIM# 243000; Paroxysmal extreme pain disorder, MIM# 167400; Small fiber neuropathy,MIM# 133020
Mendeliome v0.14129 SLC22A5 Zornitza Stark Marked gene: SLC22A5 as ready
Mendeliome v0.14129 SLC22A5 Zornitza Stark Phenotypes for gene: SLC22A5 were changed from to Carnitine deficiency, systemic primary, MIM# 212140, MONDO:0008919
Mendeliome v0.14126 SLC22A12 Zornitza Stark Marked gene: SLC22A12 as ready
Mendeliome v0.14123 SLC1A2 Zornitza Stark Marked gene: SLC1A2 as ready
Mendeliome v0.14119 SLC1A1 Zornitza Stark Marked gene: SLC1A1 as ready
Mendeliome v0.14119 SLC1A1 Zornitza Stark Phenotypes for gene: SLC1A1 were changed from to Dicarboxylic aminoaciduria, MIM# 222730
Mendeliome v0.14115 SLC1A1 Zornitza Stark reviewed gene: SLC1A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21123949; Phenotypes: Dicarboxylic aminoaciduria, MIM# 222730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14115 SLC19A3 Zornitza Stark Marked gene: SLC19A3 as ready
Mendeliome v0.14112 SLC17A8 Zornitza Stark Marked gene: SLC17A8 as ready
Mendeliome v0.14109 SLC17A3 Zornitza Stark Marked gene: SLC17A3 as ready
Mendeliome v0.14105 SLC16A1 Zornitza Stark Marked gene: SLC16A1 as ready
Mendeliome v0.14105 SLC16A1 Zornitza Stark Phenotypes for gene: SLC16A1 were changed from to Erythrocyte lactate transporter defect, MIM# 245340; Hyperinsulinemic hypoglycaemia, familial, 7, MIM# 610021; Monocarboxylate transporter 1 deficiency, MIM# 616095
Mendeliome v0.14102 SLC16A1 Zornitza Stark reviewed gene: SLC16A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25390740, 32170320; Phenotypes: Erythrocyte lactate transporter defect, MIM# 245340, Hyperinsulinemic hypoglycaemia, familial, 7, MIM# 610021, Monocarboxylate transporter 1 deficiency, MIM# 616095; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14102 SLC11A2 Zornitza Stark Marked gene: SLC11A2 as ready
Mendeliome v0.14099 SH2D1A Zornitza Stark Marked gene: SH2D1A as ready
Mendeliome v0.14096 SGCG Zornitza Stark Marked gene: SGCG as ready
Mendeliome v0.14096 SGCG Zornitza Stark Phenotypes for gene: SGCG were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 5 MIM#253700; autosomal recessive limb-girdle muscular dystrophy MONDO:0015152
Mendeliome v0.14092 FLVCR1 Bryony Thompson Marked gene: FLVCR1 as ready
Mendeliome v0.14091 FLNC Bryony Thompson Marked gene: FLNC as ready
Mendeliome v0.14088 FLNC Bryony Thompson Phenotypes for gene: FLNC were changed from to Myofibrillar myopathy MONDO:0018943; Dilated cardiomyopathy MONDO:0005021; distal myopathy with posterior leg and anterior hand involvement MONDO:0013550
Mendeliome v0.14085 FLNC Bryony Thompson reviewed gene: FLNC: Rating: GREEN; Mode of pathogenicity: None; Publications: 15929027, 32112656; Phenotypes: Myofibrillar myopathy MONDO:0018943, Dilated cardiomyopathy MONDO:0005021, distal myopathy with posterior leg and anterior hand involvement MONDO:0013550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.14085 FLNB Bryony Thompson edited their review of gene: FLNB: Changed phenotypes: spondylocarpotarsal synostosis syndrome MONDO:0010094, filamin-related bone disorder MONDO:0019690
Mendeliome v0.14085 FLNB Bryony Thompson Phenotypes for gene: FLNB were changed from spondylocarpotarsal synostosis syndrome MONDO:0010094; osteochondrodysplasia MONDO:0005516 to spondylocarpotarsal synostosis syndrome MONDO:0010094; filamin-related bone disorder MONDO:0019690
Mendeliome v0.14084 FLNB Bryony Thompson Marked gene: FLNB as ready
Mendeliome v0.14084 FLNB Bryony Thompson Phenotypes for gene: FLNB were changed from to spondylocarpotarsal synostosis syndrome MONDO:0010094; osteochondrodysplasia MONDO:0005516
Mendeliome v0.14081 FLNB Bryony Thompson reviewed gene: FLNB: Rating: GREEN; Mode of pathogenicity: None; Publications: 14991055, 17360453, 20301736, 29566257, 16801345, 22190451; Phenotypes: spondylocarpotarsal synostosis syndrome MONDO:0010094, osteochondrodysplasia MONDO:0005516; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14081 FLI1 Bryony Thompson Marked gene: FLI1 as ready
Mendeliome v0.14078 FLG Bryony Thompson Marked gene: FLG as ready
Mendeliome v0.14078 ASS1 Elena Savva Marked gene: ASS1 as ready
Mendeliome v0.14078 FLG Bryony Thompson Phenotypes for gene: FLG were changed from to Ichthyosis vulgaris MONDO:0024304
Mendeliome v0.14074 ASTN1 Elena Savva Marked gene: ASTN1 as ready
Mendeliome v0.14072 FLG Bryony Thompson reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16444271, 19349982, 34608691; Phenotypes: Ichthyosis vulgaris MONDO:0024304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14070 FKTN Bryony Thompson Marked gene: FKTN as ready
Mendeliome v0.14070 FKTN Bryony Thompson Phenotypes for gene: FKTN were changed from to Muscular dystrophy-dystroglycanopathy MONDO:0018276
Mendeliome v0.14067 FKTN Bryony Thompson reviewed gene: FKTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 9690476, 19017726, 20301385, 28680109; Phenotypes: Muscular dystrophy-dystroglycanopathy MONDO:0018276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14067 GSN Zornitza Stark Marked gene: GSN as ready
Mendeliome v0.14064 GSN Zornitza Stark changed review comment from: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported.

Multiple families with same founder variant.; to: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported.

Multiple families with same founder variant, p.Asp187Asn, though other variants also reported.
Mendeliome v0.14064 GSS Zornitza Stark Marked gene: GSS as ready
Mendeliome v0.14061 GTF3C3 Zornitza Stark Marked gene: GTF3C3 as ready
Mendeliome v0.14058 GUCA1A Zornitza Stark Marked gene: GUCA1A as ready
Mendeliome v0.14054 ASB10 Elena Savva Marked gene: ASB10 as ready
Mendeliome v0.14053 FKRP Bryony Thompson Marked gene: FKRP as ready
Mendeliome v0.14053 FKRP Bryony Thompson Phenotypes for gene: FKRP were changed from to Muscular dystrophy-dystroglycanopathy MONDO:0018276
Mendeliome v0.14050 ART4 Elena Savva Phenotypes for gene: ART4 were changed from {Macular degeneration, age-related, 8} MIM#613778 to {Macular degeneration, age-related, 8} MIM#613778
Mendeliome v0.14050 ART4 Elena Savva Mode of inheritance for gene: ART4 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14049 FKRP Bryony Thompson reviewed gene: FKRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 11592034, 11741828, 14647208, 19299310, 19155270; Phenotypes: Muscular dystrophy-dystroglycanopathy MONDO:0018276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14049 ART4 Elena Savva Phenotypes for gene: ART4 were changed from to {Macular degeneration, age-related, 8} MIM#613778
Mendeliome v0.14048 ART4 Elena Savva Mode of inheritance for gene: ART4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14048 ART4 Elena Savva Marked gene: ART4 as ready
Mendeliome v0.14048 ART4 Elena Savva Gene: art4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.14048 ART4 Elena Savva Publications for gene: ART4 were set to
Mendeliome v0.14048 ART4 Elena Savva Classified gene: ART4 as Amber List (moderate evidence)
Mendeliome v0.14048 ART4 Elena Savva Gene: art4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.14047 ART4 Elena Savva reviewed gene: ART4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33675039, 33206405; Phenotypes: {Macular degeneration, age-related, 8} MIM#613778; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14047 FHL1 Bryony Thompson Marked gene: FHL1 as ready
Mendeliome v0.14047 FHL1 Bryony Thompson Phenotypes for gene: FHL1 were changed from to Reducing body myopathy MONDO:0019948; X-linked Emery-Dreifuss muscular dystrophy MONDO:0010680
Mendeliome v0.14045 ASPA Elena Savva Marked gene: ASPA as ready
Mendeliome v0.14044 ARMS2 Elena Savva Phenotypes for gene: ARMS2 were changed from {Macular degeneration, age-related, 8} MIM#613778 to {Macular degeneration, age-related, 8} MIM#613778
Mendeliome v0.14041 ASH1L Elena Savva Phenotypes for gene: ASH1L were changed from Mental retardation, autosomal dominant 52, MIM#617796 to Mental retardation, autosomal dominant 52, MIM#617796
Mendeliome v0.14040 ARMS2 Elena Savva Phenotypes for gene: ARMS2 were changed from to {Macular degeneration, age-related, 8} MIM#613778
Mendeliome v0.14040 ARMS2 Elena Savva Classified gene: ARMS2 as Red List (low evidence)
Mendeliome v0.14040 ARMS2 Elena Savva Gene: arms2 has been classified as Red List (Low Evidence).
Mendeliome v0.14039 ARMS2 Elena Savva Marked gene: ARMS2 as ready
Mendeliome v0.14039 ARMS2 Elena Savva Gene: arms2 has been classified as Green List (High Evidence).
Mendeliome v0.14039 FHL1 Bryony Thompson reviewed gene: FHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19716112, 20186852, 20301609, 18179901, 25274776, 34366191, 18274675, 19181672; Phenotypes: Reducing body myopathy MONDO:0019948, X-linked Emery-Dreifuss muscular dystrophy MONDO:0010680; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.14039 ASH1L Elena Savva Phenotypes for gene: ASH1L were changed from to Mental retardation, autosomal dominant 52, MIM#617796
Mendeliome v0.14038 ASH1L Elena Savva Marked gene: ASH1L as ready
Mendeliome v0.14037 ARMS2 Elena Savva reviewed gene: ARMS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Macular degeneration, age-related, 8} MIM#613778; Mode of inheritance: Unknown
Mendeliome v0.14037 ARL2BP Elena Savva Publications for gene: ARL2BP were set to PMID: 23849777; 27790702; 29718757
Mendeliome v0.14036 ARL2BP Elena Savva Publications for gene: ARL2BP were set to
Mendeliome v0.14035 ARL2BP Elena Savva Marked gene: ARL2BP as ready
Mendeliome v0.14035 ARL2BP Elena Savva Gene: arl2bp has been classified as Green List (High Evidence).
Mendeliome v0.14035 ARL2BP Elena Savva Phenotypes for gene: ARL2BP were changed from to Retinitis pigmentosa with or without situs inversus MIM#615434
Mendeliome v0.14035 ARL2BP Elena Savva Mode of inheritance for gene: ARL2BP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14034 ARL2BP Elena Savva reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa with or without situs inversus MIM#615434; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14034 FH Bryony Thompson Marked gene: FH as ready
Mendeliome v0.14034 FH Bryony Thompson Phenotypes for gene: FH were changed from to hereditary leiomyomatosis and renal cell cancer MONDO:0007888; fumaric aciduria MONDO:0011730
Mendeliome v0.14031 FH Bryony Thompson changed review comment from: Well established gene-disease associations. Loss of function is the mechanism of disease. Monoallelic variants associated with decreased fumarate hydratase enzyme activity cause FH tumour predisposition syndrome (also known as HLRCC; PMID: 11865300, 28300276). FH deficiency (also known as fumarase deficiency or fumaric aciduria) caused by biallelic variants results in severe neonatal and early infantile encephalopathy (PMID: 8200987, 20549362, 31746132). FH encodes for both mitochondrial and cytosolic FH enzyme isoforms, which catalyze hydration of fumarate to malate.; to: Well established gene-disease associations. Loss of function is the mechanism of disease. Monoallelic variants associated with decreased fumarate hydratase enzyme activity cause FH tumour predisposition syndrome (also known as HLRCC; PMID: 11865300, 28300276, 20301430). FH deficiency (also known as fumarase deficiency or fumaric aciduria) caused by biallelic variants results in severe neonatal and early infantile encephalopathy (PMID: 8200987, 20549362, 31746132, 20301679). FH encodes for both mitochondrial and cytosolic FH enzyme isoforms, which catalyze hydration of fumarate to malate.
Mendeliome v0.14031 FH Bryony Thompson reviewed gene: FH: Rating: GREEN; Mode of pathogenicity: None; Publications: 11865300, 28300276, 8200987, 20549362, 31746132; Phenotypes: hereditary leiomyomatosis and renal cell cancer MONDO:0007888, fumaric aciduria MONDO:0011730; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.14031 ARID1B Elena Savva Phenotypes for gene: ARID1B were changed from to Coffin-Siris syndrome 1 MIM#135900
Mendeliome v0.14030 ARID1B Elena Savva Marked gene: ARID1B as ready
Mendeliome v0.14030 ARID1B Elena Savva Gene: arid1b has been classified as Green List (High Evidence).
Mendeliome v0.14030 ARID1B Elena Savva Mode of inheritance for gene: ARID1B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14029 ARID1B Elena Savva reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coffin-Siris syndrome 1 MIM#135900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14029 FGG Bryony Thompson Marked gene: FGG as ready
Mendeliome v0.14027 ARHGDIA Elena Savva Phenotypes for gene: ARHGDIA were changed from Nephrotic syndrome, type 8 MIM#615244 to Nephrotic syndrome, type 8 MIM#615244
Mendeliome v0.14026 ARHGDIA Elena Savva Publications for gene: ARHGDIA were set to PMID: 23867502; 35060086
Mendeliome v0.14026 ARHGDIA Elena Savva Mode of inheritance for gene: ARHGDIA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14025 ARHGEF18 Elena Savva Marked gene: ARHGEF18 as ready
Mendeliome v0.14025 ARHGEF18 Elena Savva Gene: arhgef18 has been classified as Green List (High Evidence).
Mendeliome v0.14024 FGFR3 Bryony Thompson Phenotypes for gene: FGFR3 were changed from achondroplasia MONDO:0007037; Thanatophoric dysplasia type 1 MONDO:0008546; Thanatophoric dysplasia type 2 MONDO:0008547; hypochondroplasia MONDO:0007793; Muenke syndrome MONDO:0011274; FGFR3-related chondrodysplasia MONDO:0019685; severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658; camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504; Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833 to achondroplasia MONDO:0007037; Thanatophoric dysplasia type 1 MONDO:0008546; Thanatophoric dysplasia type 2 MONDO:0008547; hypochondroplasia MONDO:0007793; Muenke syndrome MONDO:0011274; FGFR3-related chondrodysplasia MONDO:0019685; severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658; Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833; camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504
Mendeliome v0.14020 FGFR3 Bryony Thompson changed review comment from: FGFR3 has many well-established gene-disease associations with various skeletal dysplasia phenotypes. Gain-of-function is the main mechanism of disease for these disorders, except camptodactyly-tall stature-scoliosis-hearing loss syndrome where bialellic loss-of-function is the expected mechanism of disease. Specific monoallelic variants cause different phenotypes: >99% achondroplasia is caused by variants leading to the missense change p.Gly380Arg; Cysteine substitutions and stop-loss protein elongation variants are highly specific for Thanatophoric dysplasia (TD) type 1; p.Lys650Glu is associated with TD type 2; p.Ala391Glu causes Crouzon syndrome with acanthosis nigricans; and p.Pro250Arg causes Muenke syndrome.; to: FGFR3 has many well-established gene-disease associations with various skeletal dysplasia phenotypes. Gain-of-function is the main mechanism of disease for these disorders, except camptodactyly-tall stature-scoliosis-hearing loss syndrome (CATSHL syndrome, see separate curation below). Specific monoallelic variants cause different phenotypes: >99% achondroplasia is caused by variants leading to the missense change p.Gly380Arg; Cysteine substitutions and stop-loss protein elongation variants are highly specific for Thanatophoric dysplasia (TD) type 1; p.Lys650Glu is associated with TD type 2; p.Ala391Glu causes Crouzon syndrome with acanthosis nigricans; and p.Pro250Arg causes Muenke syndrome.
Moderate evidence for CATSHL syndrome, AD & AR: PMID: 8630492, 17033969, 27139183, 24864036, 32641982 - 2 apparently unrelated families segregating the same missense, p.Arg621His. One consanguineous family with 2 affected brothers with homozygous p.Thr546Lys. Heterozygous individuals in the family were unaffected. No functional assays were conducted for either missense to demonstrate loss of function. Null mouse and zebrafish models are similar to the human CATSHL syndrome phenotype.
Mendeliome v0.14020 GUCA1B Zornitza Stark changed review comment from: Single founder variant identified in several Japanese individuals.; to: Single founder variant identified in several Japanese individuals.

No other P/LP variants in ClinVar.
Mendeliome v0.14020 GUCA1B Zornitza Stark Marked gene: GUCA1B as ready
Mendeliome v0.14016 FGFR3 Bryony Thompson edited their review of gene: FGFR3: Changed mode of pathogenicity: Other; Changed publications: 8630492, 32641982, 27139183, 24864036, 17033969, 20301331, 20301540, 20301650, 20301628; Changed phenotypes: achondroplasia MONDO:0007037, Thanatophoric dysplasia type 1 MONDO:0008546, Thanatophoric dysplasia type 2 MONDO:0008547, hypochondroplasia MONDO:0007793, Muenke syndrome MONDO:0011274, FGFR3-related chondrodysplasia MONDO:0019685, severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658, Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833, camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.14016 GUCY1A3 Zornitza Stark Marked gene: GUCY1A3 as ready
Mendeliome v0.14013 GYG1 Zornitza Stark Marked gene: GYG1 as ready
Mendeliome v0.14010 GUCY2D Zornitza Stark Marked gene: GUCY2D as ready
Mendeliome v0.14010 GUCY2D Zornitza Stark Phenotypes for gene: GUCY2D were changed from to Cone-rod dystrophy 6, MIM# 601777; Leber congenital amaurosis 1, MIM# 204000; Night blindness, congenital stationary, type 1I, MIM# 618555
Mendeliome v0.14007 GUCY2D Zornitza Stark reviewed gene: GUCY2D: Rating: GREEN; Mode of pathogenicity: None; Publications: 35314386, 35205358; Phenotypes: Cone-rod dystrophy 6, MIM# 601777, Leber congenital amaurosis 1, MIM# 204000, Night blindness, congenital stationary, type 1I, MIM# 618555; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.14007 HPRT1 Zornitza Stark Marked gene: HPRT1 as ready
Mendeliome v0.14006 ARHGEF18 Elena Savva Phenotypes for gene: ARHGEF18 were changed from to Retinitis pigmentosa 78 MIM#617433
Mendeliome v0.14005 ARHGEF18 Elena Savva Publications for gene: ARHGEF18 were set to
Mendeliome v0.14005 ARHGEF18 Elena Savva Mode of inheritance for gene: ARHGEF18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14004 ARHGEF18 Elena Savva reviewed gene: ARHGEF18: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28132693; Phenotypes: Retinitis pigmentosa 78 MIM#617433; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14004 ARHGDIA Elena Savva Publications for gene: ARHGDIA were set to
Mendeliome v0.14004 ARHGDIA Elena Savva Phenotypes for gene: ARHGDIA were changed from to Nephrotic syndrome, type 8 MIM#615244
Mendeliome v0.14004 ARHGDIA Elena Savva Mode of inheritance for gene: ARHGDIA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14003 ARHGDIA Elena Savva Marked gene: ARHGDIA as ready
Mendeliome v0.14003 ARHGDIA Elena Savva Gene: arhgdia has been classified as Green List (High Evidence).
Mendeliome v0.14003 ARHGDIA Elena Savva reviewed gene: ARHGDIA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23867502, 35060086; Phenotypes: Nephrotic syndrome, type 8 MIM#615244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14003 ARHGAP31 Elena Savva Marked gene: ARHGAP31 as ready
Mendeliome v0.14003 ARHGAP31 Elena Savva Gene: arhgap31 has been classified as Green List (High Evidence).
Mendeliome v0.14003 ARHGAP31 Elena Savva Phenotypes for gene: ARHGAP31 were changed from to Adams-Oliver syndrome 1, MIM#100300
Mendeliome v0.14002 ARHGAP31 Elena Savva Publications for gene: ARHGAP31 were set to
Mendeliome v0.14001 ARHGAP31 Elena Savva Mode of inheritance for gene: ARHGAP31 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14000 ARHGAP31 Elena Savva reviewed gene: ARHGAP31: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33655927, 29924900; Phenotypes: Adams-Oliver syndrome 1, MIM#100300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.14000 ANXA5 Elena Savva Marked gene: ANXA5 as ready
Mendeliome v0.13997 AR Elena Savva Marked gene: AR as ready
Mendeliome v0.13997 AR Elena Savva Gene: ar has been classified as Green List (High Evidence).
Mendeliome v0.13997 GYPA Zornitza Stark Marked gene: GYPA as ready
Mendeliome v0.13994 GYPB Zornitza Stark Marked gene: GYPB as ready
Mendeliome v0.13991 HAAO Zornitza Stark reviewed gene: HAAO: Rating: GREEN; Mode of pathogenicity: None; Publications: 33942433; Phenotypes: Vertebral, cardiac, renal, and limb defects syndrome 1 MIM#617660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13991 LZTS1 Alison Yeung Marked gene: LZTS1 as ready
Mendeliome v0.13991 LZTS1 Alison Yeung Phenotypes for gene: LZTS1 were changed from to Esophageal squamous cell carcinoma, somatic, MIM# 133239
Mendeliome v0.13989 LZTS1 Alison Yeung reviewed gene: LZTS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Esophageal squamous cell carcinoma, somatic, MIM# 133239; Mode of inheritance: Unknown
Mendeliome v0.13989 LYZ Alison Yeung Marked gene: LYZ as ready
Mendeliome v0.13986 LYST Alison Yeung Marked gene: LYST as ready
Mendeliome v0.13984 LYRM7 Alison Yeung Marked gene: LYRM7 as ready
Mendeliome v0.13984 LYRM7 Alison Yeung Phenotypes for gene: LYRM7 were changed from to Mitochondrial complex III deficiency, nuclear type 8, MIM#615838
Mendeliome v0.13982 LYN Alison Yeung Marked gene: LYN as ready
Mendeliome v0.13982 LYN Alison Yeung Added comment: Comment when marking as ready: No human disease association published. Mouse models suggest role in auto inflammatory pathways.
Mendeliome v0.13981 LTC4S Alison Yeung Marked gene: LTC4S as ready
Mendeliome v0.13978 LTA Alison Yeung Marked gene: LTA as ready
Mendeliome v0.13978 LTA Alison Yeung Added comment: Comment when marking as ready: Not associated with Mendelian disease
Mendeliome v0.13978 LTA Alison Yeung Phenotypes for gene: LTA were changed from to Myocardial infarction, susceptibility to, MIM# 608446
Mendeliome v0.13975 LTA Alison Yeung reviewed gene: LTA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myocardial infarction, susceptibility to, MIM# 608446; Mode of inheritance: Other
Mendeliome v0.13975 LRP6 Alison Yeung Marked gene: LRP6 as ready
Mendeliome v0.13973 LRP5 Alison Yeung Marked gene: LRP5 as ready
Mendeliome v0.13971 LRP2 Alison Yeung Marked gene: LRP2 as ready
Mendeliome v0.13971 LRP2 Alison Yeung Phenotypes for gene: LRP2 were changed from to Donnai-Barrow syndrome, MIM# 222448
Mendeliome v0.13970 LRIG2 Alison Yeung Marked gene: LRIG2 as ready
Mendeliome v0.13967 FGFR3 Bryony Thompson Marked gene: FGFR3 as ready
Mendeliome v0.13967 FGFR3 Bryony Thompson Phenotypes for gene: FGFR3 were changed from to achondroplasia MONDO:0007037; Thanatophoric dysplasia type 1 MONDO:0008546; Thanatophoric dysplasia type 2 MONDO:0008547; hypochondroplasia MONDO:0007793; Muenke syndrome MONDO:0011274; FGFR3-related chondrodysplasia MONDO:0019685; severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658; camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504; Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833
Mendeliome v0.13964 FGFR3 Bryony Thompson reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26740388, 20301331, 20301540, 20301650, 20301628, 24864036, 17033969; Phenotypes: achondroplasia MONDO:0007037, Thanatophoric dysplasia type 1 MONDO:0008546, Thanatophoric dysplasia type 2 MONDO:0008547, hypochondroplasia MONDO:0007793, Muenke syndrome MONDO:0011274, FGFR3-related chondrodysplasia MONDO:0019685, severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658, camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504, Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13964 DNAJB6 Ain Roesley Marked gene: DNAJB6 as ready
Mendeliome v0.13964 DNAJB6 Ain Roesley Phenotypes for gene: DNAJB6 were changed from to Muscular dystrophy, limb-girdle, autosomal dominant 1 MIM#603511
Mendeliome v0.13962 DNAJB6 Ain Roesley reviewed gene: DNAJB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 26847086, 26338452, 24170373; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 1 MIM#603511; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13962 DNAH1 Ain Roesley Phenotypes for gene: DNAH1 were changed from Spermatogenic failure 18 MIM#617576 to primary ciliary dyskinesia,37 MIM#617577; Spermatogenic failure 18 MIM#617576
Mendeliome v0.13961 DNAH1 Ain Roesley Marked gene: DNAH1 as ready
Mendeliome v0.13958 DNAH1 Ain Roesley reviewed gene: DNAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31507630, 31765523, 25927852, 24360805, 33577779; Phenotypes: primary ciliary dyskinesia,37 MIM#617577, Spermatogenic failure 18 MIM#617576; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13958 DNA2 Ain Roesley Marked gene: DNA2 as ready
Mendeliome v0.13956 DMP1 Ain Roesley Marked gene: DMP1 as ready
Mendeliome v0.13954 AQP3 Elena Savva Marked gene: AQP3 as ready
Mendeliome v0.13954 DMD Ain Roesley Marked gene: DMD as ready
Mendeliome v0.13954 DMD Ain Roesley Phenotypes for gene: DMD were changed from to Becker muscular dystrophy MIM@300376 XLR; Cardiomyopathy, dilated, 3B MIM#302045 XL; Duchenne muscular dystrophy MIM#310200
Mendeliome v0.13952 DMD Ain Roesley reviewed gene: DMD: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301298; Phenotypes: Becker muscular dystrophy MIM@300376 XLR, Cardiomyopathy, dilated, 3B MIM#302045 XL, Duchenne muscular dystrophy MIM#310200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.13952 DLX3 Ain Roesley Marked gene: DLX3 as ready
Mendeliome v0.13951 DLAT Ain Roesley Marked gene: DLAT as ready
Mendeliome v0.13949 DISC1 Ain Roesley Marked gene: DISC1 as ready
Mendeliome v0.13948 LPL Alison Yeung Marked gene: LPL as ready
Mendeliome v0.13946 DHTKD1 Ain Roesley Marked gene: DHTKD1 as ready
Mendeliome v0.13946 DHTKD1 Ain Roesley Added comment: Comment when marking as ready: green for AR, amber for AD
Mendeliome v0.13945 DHTKD1 Ain Roesley Phenotypes for gene: DHTKD1 were changed from to Alpha-aminoadipic and alpha-ketoadipic aciduria MIM#204750, AR; Charcot-Marie-Tooth disease, axonal, type 2Q, MIM#615025
Mendeliome v0.13943 LPAR6 Alison Yeung Marked gene: LPAR6 as ready
Mendeliome v0.13943 LPAR6 Alison Yeung Gene: lpar6 has been classified as Green List (High Evidence).
Mendeliome v0.13943 LPAR6 Alison Yeung Phenotypes for gene: LPAR6 were changed from to Woolly hair, autosomal recessive 1, with or without hypotrichosis, MIM# 609239
Mendeliome v0.13942 LPAR6 Alison Yeung Mode of inheritance for gene: LPAR6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13941 LPAR6 Alison Yeung reviewed gene: LPAR6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Woolly hair, autosomal recessive 1, with or without hypotrichosis, MIM# 609239; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13941 DHH Ain Roesley Marked gene: DHH as ready
Mendeliome v0.13941 DHH Ain Roesley Phenotypes for gene: DHH were changed from 46XY partial gonadal dysgenesis, with minifascicular neuropathy, MIM# 607080 to 46XY gonadal dysgenesis with minifascicular neuropathy MIM#607080; 46XY sex reversal 7 MIM#233420
Mendeliome v0.13940 LOXL1 Alison Yeung Marked gene: LOXL1 as ready
Mendeliome v0.13937 LMF1 Alison Yeung Marked gene: LMF1 as ready
Mendeliome v0.13935 LMBRD1 Alison Yeung Marked gene: LMBRD1 as ready
Mendeliome v0.13932 LMBR1 Alison Yeung Marked gene: LMBR1 as ready
Mendeliome v0.13930 SLC22A5 Manny Jacobs reviewed gene: SLC22A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916797, 10072434, 10051646, 10425211, 10480371, 10679939, 9837751, 23379544, 31399326; Phenotypes: Carnitine deficiency, systemic primary, MIM# 212140, MONDO:0008919; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13930 CYP27B1 Ain Roesley Marked gene: CYP27B1 as ready
Mendeliome v0.13928 CYP51A1 Ain Roesley Marked gene: CYP51A1 as ready
Mendeliome v0.13928 CYP51A1 Ain Roesley Phenotypes for gene: CYP51A1 were changed from to congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome MONDO#0033853
Mendeliome v0.13926 CYP4V2 Ain Roesley Marked gene: CYP4V2 as ready
Mendeliome v0.13924 CYP2R1 Ain Roesley Marked gene: CYP2R1 as ready
Mendeliome v0.13922 CYP2D6 Ain Roesley Marked gene: CYP2D6 as ready
Mendeliome v0.13919 CYP2C19 Ain Roesley changed review comment from: Voriconazole: Improved time to target concentration with genotype directed dosing (PMID 26616742), reduced underexposure (PMID: 31549389) (PMID 31549386)

(PMID:27981572)
Voriconazole, moderate strength.
Poor metabolizer: "Higher dose-adjusted trough concentrations of voriconazole and
may increase probability of adverse events."
Ultrarapid metabolizer: "probability of attainment of therapeutic voriconazole concentrations is small with standard dosing."; to: Pharmacogenomics gene

Voriconazole: Improved time to target concentration with genotype directed dosing (PMID 26616742), reduced underexposure (PMID: 31549389) (PMID 31549386)

(PMID:27981572)
Voriconazole, moderate strength.
Poor metabolizer: "Higher dose-adjusted trough concentrations of voriconazole and
may increase probability of adverse events."
Ultrarapid metabolizer: "probability of attainment of therapeutic voriconazole concentrations is small with standard dosing."
Mendeliome v0.13919 DGUOK Zornitza Stark Marked gene: DGUOK as ready
Mendeliome v0.13916 DGKE Zornitza Stark Marked gene: DGKE as ready
Mendeliome v0.13913 DES Zornitza Stark Marked gene: DES as ready
Mendeliome v0.13913 DES Zornitza Stark Phenotypes for gene: DES were changed from to Cardiomyopathy, dilated, 1I, MIM# 604765; Myopathy, myofibrillar, 1 , MIM#601419; Arrhythmogenic right ventricular cardiomyopathy
Mendeliome v0.13911 DES Zornitza Stark reviewed gene: DES: Rating: GREEN; Mode of pathogenicity: None; Publications: 20718792, 19879535, 20423733, 24200904, 22395865, 29212896, 23168288, 20829228, 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 33947203; Phenotypes: Cardiomyopathy, dilated, 1I, MIM# 604765, Myopathy, myofibrillar, 1 , MIM#601419, Arrhythmogenic right ventricular cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13911 DEPDC5 Zornitza Stark Marked gene: DEPDC5 as ready
Mendeliome v0.13911 DEPDC5 Zornitza Stark Phenotypes for gene: DEPDC5 were changed from to Epilepsy, familial focal, with variable foci 1, MIM#604364
Mendeliome v0.13908 DEPDC5 Zornitza Stark reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31444548, 23542697, 23542701; Phenotypes: Epilepsy, familial focal, with variable foci 1 MIM#604364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13908 DECR1 Zornitza Stark Marked gene: DECR1 as ready
Mendeliome v0.13907 DDIT3 Zornitza Stark Marked gene: DDIT3 as ready
Mendeliome v0.13906 DDHD2 Zornitza Stark Marked gene: DDHD2 as ready
Mendeliome v0.13906 DDHD2 Zornitza Stark Phenotypes for gene: DDHD2 were changed from to Spastic paraplegia 54, autosomal recessive, MIM# 615033
Mendeliome v0.13903 DDHD2 Zornitza Stark reviewed gene: DDHD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23486545, 24482476, 23176823, 31302745; Phenotypes: Spastic paraplegia 54, autosomal recessive, MIM# 615033; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13903 DDC Zornitza Stark Marked gene: DDC as ready
Mendeliome v0.13903 DDC Zornitza Stark Phenotypes for gene: DDC were changed from to Aromatic L-amino acid decarboxylase deficiency, MIM# 608643
Mendeliome v0.13900 DDC Zornitza Stark reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 20505134, 30952622; Phenotypes: Aromatic L-amino acid decarboxylase deficiency, MIM# 608643; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13900 DDB2 Zornitza Stark Marked gene: DDB2 as ready
Mendeliome v0.13895 DCTN1 Zornitza Stark Marked gene: DCTN1 as ready
Mendeliome v0.13895 DCTN1 Zornitza Stark Phenotypes for gene: DCTN1 were changed from to Neuronopathy, distal hereditary motor, type VIIB, MIM# 607641; MONDO:0011879; Perry syndrome, MIM# 168605
Mendeliome v0.13892 DCTN1 Zornitza Stark edited their review of gene: DCTN1: Changed phenotypes: Neuronopathy, distal hereditary motor, type VIIB, MIM# 607641, MONDO:0011879, Perry syndrome, MIM# 168605
Mendeliome v0.13892 AQP5 Elena Savva Phenotypes for gene: AQP5 were changed from Palmoplantar keratoderma, Bothnian type MIM#600231 to Palmoplantar keratoderma, Bothnian type MIM#600231
Mendeliome v0.13892 AQP5 Elena Savva Phenotypes for gene: AQP5 were changed from to Palmoplantar keratoderma, Bothnian type MIM#600231
Mendeliome v0.13891 AQP5 Elena Savva Marked gene: AQP5 as ready
Mendeliome v0.13890 AQP5 Elena Savva reviewed gene: AQP5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35014096, 23830519; Phenotypes: Palmoplantar keratoderma, Bothnian type MIM#600231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13890 AR Elena Savva Phenotypes for gene: AR were changed from to Hypospadias 1, X-linked MIM#30063; Androgen insensitivity MIM#300068; Androgen insensitivity, partial, with or without breast cancer MIM#312300; Spinal and bulbar muscular atrophy of Kennedy MIM#313200
Mendeliome v0.13890 AR Elena Savva Publications for gene: AR were set to
Mendeliome v0.13889 AR Elena Savva Mode of inheritance for gene: AR was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.13888 AR Elena Savva reviewed gene: AR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22334387; Phenotypes: Hypospadias 1, X-linked MIM#30063, Androgen insensitivity MIM#300068, Androgen insensitivity, partial, with or without breast cancer MIM#312300, Spinal and bulbar muscular atrophy of Kennedy MIM#313200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.13888 DCLRE1C Zornitza Stark Marked gene: DCLRE1C as ready
Mendeliome v0.13885 ARCN1 Elena Savva Marked gene: ARCN1 as ready
Mendeliome v0.13885 ARCN1 Elena Savva Gene: arcn1 has been classified as Green List (High Evidence).
Mendeliome v0.13884 DCHS1 Zornitza Stark Marked gene: DCHS1 as ready
Mendeliome v0.13879 APPL1 Elena Savva Marked gene: APPL1 as ready
Mendeliome v0.13879 AQP1 Elena Savva Phenotypes for gene: AQP1 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension
Mendeliome v0.13878 APRT Elena Savva Marked gene: APRT as ready
Mendeliome v0.13878 AQP1 Elena Savva Phenotypes for gene: AQP1 were changed from to Pulmonary arterial hypertension
Mendeliome v0.13877 AQP1 Elena Savva Marked gene: AQP1 as ready
Mendeliome v0.13875 AQP1 Elena Savva reviewed gene: AQP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:22683574, 29650961; Phenotypes: Pulmonary arterial hypertension; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13873 APOC4-APOC2 Elena Savva Marked gene: APOC4-APOC2 as ready
Mendeliome v0.13870 APOC2 Elena Savva Marked gene: APOC2 as ready
Mendeliome v0.13868 APOC3 Elena Savva Marked gene: APOC3 as ready
Mendeliome v0.13864 ACTL6B Zornitza Stark edited their review of gene: ACTL6B: Changed phenotypes: Epileptic encephalopathy, early infantile, 76, MIM# 618468, Intellectual developmental disorder with severe speech and ambulation defects, MIM# 618470; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13862 MAPKAPK5 Zornitza Stark Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic to Neurocardiofaciodigital syndrome, MIM# 619869
Mendeliome v0.13861 MAPKAPK5 Zornitza Stark edited their review of gene: MAPKAPK5: Changed phenotypes: Neurocardiofaciodigital syndrome, MIM# 619869
Mendeliome v0.13860 DCAF17 Zornitza Stark Marked gene: DCAF17 as ready
Mendeliome v0.13857 CYP2C19 Ain Roesley Marked gene: CYP2C19 as ready
Mendeliome v0.13856 CYP2B6 Ain Roesley Marked gene: CYP2B6 as ready
Mendeliome v0.13854 DAZ4 Zornitza Stark Marked gene: DAZ4 as ready
Mendeliome v0.13853 DAZ3 Zornitza Stark Marked gene: DAZ3 as ready
Mendeliome v0.13852 CYP2A6 Ain Roesley Marked gene: CYP2A6 as ready
Mendeliome v0.13852 CYP2A6 Ain Roesley Phenotypes for gene: CYP2A6 were changed from to Coumarin resistance MIM#122700
Mendeliome v0.13851 CYP2A6 Ain Roesley reviewed gene: CYP2A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Coumarin resistance MIM#122700; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13851 DAZ2 Zornitza Stark Marked gene: DAZ2 as ready
Mendeliome v0.13850 DAZ1 Zornitza Stark Marked gene: DAZ1 as ready
Mendeliome v0.13848 CYP27A1 Ain Roesley Marked gene: CYP27A1 as ready
Mendeliome v0.13846 DARS2 Zornitza Stark Marked gene: DARS2 as ready
Mendeliome v0.13846 DARS2 Zornitza Stark Gene: dars2 has been classified as Green List (High Evidence).
Mendeliome v0.13846 DARS2 Zornitza Stark Phenotypes for gene: DARS2 were changed from to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105
Mendeliome v0.13845 CYP26C1 Ain Roesley Marked gene: CYP26C1 as ready
Mendeliome v0.13845 DARS2 Zornitza Stark Publications for gene: DARS2 were set to
Mendeliome v0.13844 DARS2 Zornitza Stark Mode of inheritance for gene: DARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13843 DARS2 Zornitza Stark changed review comment from: Slowly progressive disorder with variable age of onset, multiple families reported.; to: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (Scheper et al., 2007). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline.
Mendeliome v0.13842 DARS2 Zornitza Stark reviewed gene: DARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17384640, 15002045, 16788019; Phenotypes: Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13842 D2HGDH Zornitza Stark Marked gene: D2HGDH as ready
Mendeliome v0.13842 D2HGDH Zornitza Stark Phenotypes for gene: D2HGDH were changed from to D-2-hydroxyglutaric aciduria MIM#600721
Mendeliome v0.13839 D2HGDH Zornitza Stark reviewed gene: D2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 25778941, 31349060, 15609246, 20020533; Phenotypes: D-2-hydroxyglutaric aciduria MIM#600721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13839 CYP7B1 Zornitza Stark Marked gene: CYP7B1 as ready
Mendeliome v0.13839 CYP7B1 Zornitza Stark Phenotypes for gene: CYP7B1 were changed from to Bile acid synthesis defect, congenital, 3 MIM#613812; Spastic paraplegia 5A, autosomal recessive MIM#270800; Disorders of bile acid biosynthesis
Mendeliome v0.13836 CYP1A2 Ain Roesley Marked gene: CYP1A2 as ready
Mendeliome v0.13835 KLF4 Zornitza Stark Marked gene: KLF4 as ready
Mendeliome v0.13834 CYP19A1 Ain Roesley Marked gene: CYP19A1 as ready
Mendeliome v0.13834 CYP19A1 Ain Roesley Phenotypes for gene: CYP19A1 were changed from to Aromatase deficiency (MIM#613546), AR; Aromatase excess syndrome (MIM#139300), AD
Mendeliome v0.13832 CYP19A1 Ain Roesley reviewed gene: CYP19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17164303, 25264451; Phenotypes: Aromatase deficiency (MIM#613546), AR, Aromatase excess syndrome (MIM#139300), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13832 CYCS Ain Roesley Marked gene: CYCS as ready
Mendeliome v0.13828 CYC1 Ain Roesley Marked gene: CYC1 as ready
Mendeliome v0.13828 CYC1 Ain Roesley Phenotypes for gene: CYC1 were changed from to Mitochondrial complex III deficiency, nuclear type 6 MIM#615453
Mendeliome v0.13826 CYC1 Ain Roesley reviewed gene: CYC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23910460, 34252606; Phenotypes: Mitochondrial complex III deficiency, nuclear type 6 MIM#615453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13825 HNRNPA2B1 Zornitza Stark Phenotypes for gene: HNRNPA2B1 were changed from Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422 to oculopharyngeal muscular dystrophy, MONDO:0008116; Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422
Mendeliome v0.13820 KCNH5 Zornitza Stark Marked gene: KCNH5 as ready
Mendeliome v0.13820 CREB1 Zornitza Stark Phenotypes for gene: CREB1 were changed from corpus callosum agenesis; thyroid follicular hypoplasia to Agenesis of corpus callosum, MONDO:0009022
Mendeliome v0.13819 SLC16A12 Zornitza Stark Marked gene: SLC16A12 as ready
Mendeliome v0.13819 SLC16A12 Zornitza Stark Phenotypes for gene: SLC16A12 were changed from to Cataract 47, juvenile, with microcornea, MIM# 612018
Mendeliome v0.13816 SLC14A1 Zornitza Stark Marked gene: SLC14A1 as ready
Mendeliome v0.13812 SLC12A5 Zornitza Stark Marked gene: SLC12A5 as ready
Mendeliome v0.13809 CORIN Zornitza Stark Marked gene: CORIN as ready
Mendeliome v0.13809 DUSP6 Zornitza Stark Marked gene: DUSP6 as ready
Mendeliome v0.13805 DYRK1B Zornitza Stark Marked gene: DYRK1B as ready
Mendeliome v0.13798 KLF4 Elena Savva gene: KLF4 was added
gene: KLF4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KLF4 were set to PMID: 35168889; 10431239
Phenotypes for gene: KLF4 were set to Hereditary palmoplantar keratoderma MONDO:0019272, KFL4-related
Review for gene: KLF4 was set to GREEN
Added comment: PMID: 35168889 - 3 patients from 2 unrelated families with palmoplantar keratoderma. Two variants found, fs and a missense.
Functional studies on patient skin biopsy shows "slightly but significantly decreased" protein expression in both children.
Gene was shown to bind the DSG1 promoter and regulate expression. Transfected cells showed reduced DSG1 expression.

PMID: 10431239 - mouse K/O died shortly after birth due to loss of skin barrier function

gnomAD: single het fs in the population
Sources: Literature
Mendeliome v0.13797 CTR9 Zornitza Stark Marked gene: CTR9 as ready
Mendeliome v0.13797 HNRNPA2B1 Naomi Baker reviewed gene: HNRNPA2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:35484142; Phenotypes: oculopharyngeal muscular dystrophy, MONDO:0008116; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13796 P3H2 Daniel Flanagan reviewed gene: P3H2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35499085; Phenotypes: Myopia, high, with cataract and vitreoretinal degeneration (MIM# 614292); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13796 CDH4 Ain Roesley Marked gene: CDH4 as ready
Mendeliome v0.13796 DNAH14 Zornitza Stark Marked gene: DNAH14 as ready
Mendeliome v0.13796 CDH4 Ain Roesley gene: CDH4 was added
gene: CDH4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDH4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH4 were set to 35034853
Phenotypes for gene: CDH4 were set to coloboma MONDO#0001476, CDH4-related
Review for gene: CDH4 was set to RED
gene: CDH4 was marked as current diagnostic
Added comment: 1x family with AD coloboma

Also presented with ID and post natal microcephaly

zebrafish KO model
Sources: Literature
Mendeliome v0.13793 CD164 Alison Yeung Marked gene: CD164 as ready
Mendeliome v0.13792 CD164 Alison Yeung gene: CD164 was added
gene: CD164 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CD164 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CD164 were set to 26197441; 35254497; 26197441
Phenotypes for gene: CD164 were set to Deafness, autosomal dominant 66, MIM# 616969
Review for gene: CD164 was set to GREEN
Added comment: p.(Arg192Ter), a truncating variant that results in loss of 6 amino acids, was detected in two families (one Polish and one Korean) with hearing loss. Four affected (heterozygous) and two unaffected (neg) were tested, however 14 members had been diagnosed with HL in a large multi generational family (gene panel 237 genes). The second family (WES) had two affected heterozygous and no unaffected were tested. This same variant had previously been reported in a Danish family (12 affected heterozygous and 13 unaffected negative, but one younger member unaffected are heterozygous) with hearing loss (PMID: 26197441), for which functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments. The YHTL motif, deleted by the c.574C>T nonsense mutation, is a canonical sorting motif
known to be recognized by specific adaptor proteins in the cytosol, leading to subcellular trafficking of the transmembrane protein to endosomes and lysosomes.
Sources: Literature
Mendeliome v0.13791 CTR9 Dean Phelan gene: CTR9 was added
gene: CTR9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTR9 were set to PMID: 35499524
Phenotypes for gene: CTR9 were set to Neurodevelopmental disorder (MONDO:0700092), CTR9 related; Intellectual disability (MONDO:0001071); hypotonia (HP:0001252); joint hyperlaxity (HP:0001388); speech delay; coordination problems; tremor (HP:0001337); autism spectrum disorder (MONDO:0005258)
Review for gene: CTR9 was set to GREEN
Added comment: PMID: 35499524 - Thirteen individuals with variables degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. Eleven of the variants were shown to be de novo.
Sources: Literature
Mendeliome v0.13791 TULP3 Zornitza Stark Marked gene: TULP3 as ready
Mendeliome v0.13789 DNAH14 Chern Lim gene: DNAH14 was added
gene: DNAH14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to PMID: 35438214
Phenotypes for gene: DNAH14 were set to Neurodevelopmental disorder, DNAH14-related (MONDO#0700092)
Review for gene: DNAH14 was set to GREEN
gene: DNAH14 was marked as current diagnostic
Added comment: PMID: 35438214:
- Three previously unreported patients with compound heterozygous DNAH14 variants, including one nonsense, one frameshift, and four missense variants. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia.
Sources: Literature
Mendeliome v0.13789 ANK3 Ain Roesley Phenotypes for gene: ANK3 were changed from Mental retardation, autosomal recessive, 37 615493; Intellectual disability, autosomal dominant; coloboma MONDO#0001476, ANK3-related to Mental retardation, autosomal recessive, 37 615493; Intellectual disability, autosomal dominant; coloboma MONDO#0001476, ANK3-related
Mendeliome v0.13788 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790; intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770 to Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790; intellectual disability, MONDO:0001071, PRDM13-associated; ataxia with cerebellar hypoplasia, MONDO:0016054, PRDM13-associated; congenital hypogonadotropic hypogonadism, MONDO:0015770
Mendeliome v0.13788 ANK3 Ain Roesley Phenotypes for gene: ANK3 were changed from Mental retardation, autosomal recessive, 37 615493; Intellectual disability, autosomal dominant to Mental retardation, autosomal recessive, 37 615493; Intellectual disability, autosomal dominant; coloboma MONDO#0001476, ANK3-related
Mendeliome v0.13787 TULP3 Anna Ritchie gene: TULP3 was added
gene: TULP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TULP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TULP3 were set to PMID: 35397207
Phenotypes for gene: TULP3 were set to progressive degenerative liver fibrosis with variable fibrocystic kidney disease; hypertrophic cardiomyopathy MONDO:0005045
Review for gene: TULP3 was set to GREEN
Added comment: 15 individuals from eight unrelated families with bi-allelic variants in TULP3 were detected. The affected individuals reported are mostly adults, in the 3rd through 7th decades of life, and presented with progressive degenerative liver fibrosis with variable fibrocystic kidney disease and hypertrophic cardiomyopathy.

The human phenotype was ecapitulated in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals
Sources: Literature
Mendeliome v0.13786 DROSHA Zornitza Stark Marked gene: DROSHA as ready
Mendeliome v0.13784 PRDM13 Dean Phelan reviewed gene: PRDM13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35390279; Phenotypes: Pontocerebellar hypoplasia (MONDO:0020135), PRDM13 related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13784 DROSHA Lucy Spencer gene: DROSHA was added
gene: DROSHA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Neurodevelopmental disorder (MONDO#0700092), DROSHA-related
Review for gene: DROSHA was set to AMBER
Added comment: 2 individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly, and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. Both variants are missense, absent from gnomad. Both individuals noted to have Rett-like features.

Functional studies in patient fibroblasts showed one of the missense altered the expression of mature miRNA. Fruit fly models with homozygous LOF variants die during larval stages. introduction of the missense seen in the patients was able to partially rescue this phenotype suggesting LOF is not the mechanism.
Sources: Literature
Mendeliome v0.13784 KCNH5 Elena Savva gene: KCNH5 was added
gene: KCNH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNH5 were set to https://www.medrxiv.org/content/10.1101/2022.04.26.22274147v1
Phenotypes for gene: KCNH5 were set to Neurodevelopmental disorders
Mode of pathogenicity for gene: KCNH5 was set to Other
Review for gene: KCNH5 was set to GREEN
Added comment: Happ (2022), preprint: Screen of 893 patients with DEE found 17 patients with missense variants (16/17 de novo, 1/17 inherited). GOF mechanism suggested.
Patient phenotypes included focal/generalized seizures, Cognitive outcome for the ten individuals >5 years ranged from normal (3/10) to mild (3/10), moderate (2/10), severe (1/10) and profound (1/10) intellectual disability (ID)

p.Arg327His (7 probands), p.Arg333His (4 probands) were recurring
Sources: Literature
Mendeliome v0.13783 PPFIBP1 Zornitza Stark Marked gene: PPFIBP1 as ready
Mendeliome v0.13783 STX1A Ain Roesley Marked gene: STX1A as ready
Mendeliome v0.13782 STX1A Ain Roesley changed review comment from: Preprint:
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature; to: Preprint: https://www.medrxiv.org/content/10.1101/2022.04.20.22274073v1
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature
Mendeliome v0.13781 PPFIBP1 Zornitza Stark gene: PPFIBP1 was added
gene: PPFIBP1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: PPFIBP1 was set to GREEN
Added comment: 16 individuals from 10 unrelated families reported with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Drosophila model.
Sources: Expert Review
Mendeliome v0.13778 STX1A Ain Roesley gene: STX1A was added
gene: STX1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STX1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Review for gene: STX1A was set to GREEN
gene: STX1A was marked as current diagnostic
Added comment: Preprint:
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature
Mendeliome v0.13777 HYDIN Zornitza Stark Marked gene: HYDIN as ready
Mendeliome v0.13777 HYDIN Zornitza Stark Phenotypes for gene: HYDIN were changed from to Ciliary dyskinesia, primary, 5 (MIM#608647)
Mendeliome v0.13774 HYDIN Zornitza Stark reviewed gene: HYDIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 23022101, 23849777, 28441829, 31116566; Phenotypes: Ciliary dyskinesia, primary, 5 (MIM#608647); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13774 HTRA2 Zornitza Stark Marked gene: HTRA2 as ready
Mendeliome v0.13771 HTR1A Zornitza Stark Marked gene: HTR1A as ready
Mendeliome v0.13767 HSPD1 Zornitza Stark Marked gene: HSPD1 as ready
Mendeliome v0.13767 HSPD1 Zornitza Stark Phenotypes for gene: HSPD1 were changed from to Leukodystrophy, hypomyelinating, 4, MIM# 612233; Spastic paraplegia 13, autosomal dominant, MIM# 605280
Mendeliome v0.13764 HSPD1 Zornitza Stark reviewed gene: HSPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18571143, 27405012, 32532876, 28377887, 27405012, 11898127, 17420924; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM# 612233, Spastic paraplegia 13, autosomal dominant, MIM# 605280; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13764 HSD3B7 Zornitza Stark Marked gene: HSD3B7 as ready
Mendeliome v0.13761 HSD3B2 Zornitza Stark Marked gene: HSD3B2 as ready
Mendeliome v0.13758 CPN1 Ain Roesley changed review comment from: only 1 probed reported thus far; to: only 1 proband reported thus far
Mendeliome v0.13758 CUBN Ain Roesley Marked gene: CUBN as ready
Mendeliome v0.13758 CUBN Ain Roesley Phenotypes for gene: CUBN were changed from to Imerslund-Grasbeck syndrome 1 MIM#261100 AR; [Proteinuria, chronic benign] MIM#618884
Mendeliome v0.13755 CUBN Ain Roesley reviewed gene: CUBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 31613795, 21903995, 31497480; Phenotypes: Imerslund-Grasbeck syndrome 1 MIM#261100 AR, [Proteinuria, chronic benign] MIM#618884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13755 CTSF Ain Roesley Marked gene: CTSF as ready
Mendeliome v0.13753 CTSC Ain Roesley Marked gene: CTSC as ready
Mendeliome v0.13750 CTNS Ain Roesley Marked gene: CTNS as ready
Mendeliome v0.13750 CTNS Ain Roesley Phenotypes for gene: CTNS were changed from to Cystinosis, atypical nephropathic MIM#219800; Cystinosis, late-onset juvenile or adolescent nephropathic MIM#219900; Cystinosis, nephropathic MIM#219800; Cystinosis, ocular nonnephropathic MIM#219750
Mendeliome v0.13747 CTNS Ain Roesley reviewed gene: CTNS: Rating: ; Mode of pathogenicity: None; Publications: 20301574, 9537412, 31068690; Phenotypes: Cystinosis, atypical nephropathic MIM#219800, Cystinosis, late-onset juvenile or adolescent nephropathic MIM#219900, Cystinosis, nephropathic MIM#219800, Cystinosis, ocular nonnephropathic MIM#219750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13747 CTNNA1 Ain Roesley Marked gene: CTNNA1 as ready
Mendeliome v0.13747 CTNNA1 Ain Roesley Phenotypes for gene: CTNNA1 were changed from to Macular dystrophy, butterfly-shaped pigmentary, 2, MIM# 608970; Familial exudative vitreoretinopathy MONDO#0019516, CTNNA1-related
Mendeliome v0.13745 CTNNA1 Ain Roesley reviewed gene: CTNNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26691986, 33497368; Phenotypes: Macular dystrophy, butterfly-shaped pigmentary, 2, MIM# 608970, Familial exudative vitreoretinopathy MONDO#0019516, CTNNA1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13745 CTHRC1 Ain Roesley Marked gene: CTHRC1 as ready
Mendeliome v0.13745 CTHRC1 Ain Roesley Phenotypes for gene: CTHRC1 were changed from to Barrett esophagus/esophageal adenocarcinoma MIM#614266
Mendeliome v0.13743 CTHRC1 Ain Roesley reviewed gene: CTHRC1: Rating: RED; Mode of pathogenicity: None; Publications: 21791690; Phenotypes: Barrett esophagus/esophageal adenocarcinoma MIM#614266; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13743 CSRP3 Ain Roesley Marked gene: CSRP3 as ready
Mendeliome v0.13743 CSRP3 Ain Roesley Phenotypes for gene: CSRP3 were changed from to hypertrophic cardiomyopathy12 MIM#612124; dilated cardiomyopathy 1M MIM#607482
Mendeliome v0.13741 CSRP3 Ain Roesley reviewed gene: CSRP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18505755, 30681346, 12507422, 14567970, 19412328; Phenotypes: hypertrophic cardiomyopathy12 MIM#612124, dilated cardiomyopathy 1M MIM#607482; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13741 CRYGS Ain Roesley Marked gene: CRYGS as ready
Mendeliome v0.13741 CRYGS Ain Roesley Phenotypes for gene: CRYGS were changed from to Cataract 20, multiple types MIM#116100
Mendeliome v0.13739 CRYGS Ain Roesley reviewed gene: CRYGS: Rating: GREEN; Mode of pathogenicity: None; Publications: 34014271, 16141006, 18587492, 19262743; Phenotypes: Cataract 20, multiple types MIM#116100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13739 CRYGB Ain Roesley Marked gene: CRYGB as ready
Mendeliome v0.13739 CRYGB Ain Roesley Phenotypes for gene: CRYGB were changed from to Cataract 39, multiple types, autosomal dominant MIM#615188
Mendeliome v0.13737 CRYGB Ain Roesley reviewed gene: CRYGB: Rating: RED; Mode of pathogenicity: None; Publications: 23288985; Phenotypes: Cataract 39, multiple types, autosomal dominant MIM#615188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13737 CRYAB Ain Roesley Marked gene: CRYAB as ready
Mendeliome v0.13737 CRYAB Ain Roesley Phenotypes for gene: CRYAB were changed from to Cataract 16, multiple types MIM#613763 AD, AR; Myopathy, myofibrillar, 2 MIM#608810 AD; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related MIM#613869 AR
Mendeliome v0.13735 CRYAB Ain Roesley reviewed gene: CRYAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 31215171, 21337604, 21130652, 32420686, 33272090; Phenotypes: Cataract 16, multiple types MIM#613763 AD, AR, Myopathy, myofibrillar, 2 MIM#608810 AD, Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related MIM#613869 AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13735 CRX Ain Roesley Marked gene: CRX as ready
Mendeliome v0.13732 CREB1 Ain Roesley Marked gene: CREB1 as ready
Mendeliome v0.13732 CREB1 Ain Roesley Phenotypes for gene: CREB1 were changed from to corpus callosum agenesis; thyroid follicular hypoplasia
Mendeliome v0.13729 CREB1 Ain Roesley reviewed gene: CREB1: Rating: RED; Mode of pathogenicity: None; Publications: 22267179; Phenotypes: corpus callosum agenesis, thyroid follicular hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13729 SLC16A12 Samantha Ayres reviewed gene: SLC16A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 20181839, 21778275, 18304496, 29088427, 34126080; Phenotypes: Cataract 47, juvenile, with microcornea, MIM# 612018; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13729 CRBN Ain Roesley Marked gene: CRBN as ready
Mendeliome v0.13727 CRB1 Ain Roesley Marked gene: CRB1 as ready
Mendeliome v0.13727 CRB1 Ain Roesley Phenotypes for gene: CRB1 were changed from to Leber congenital amaurosis 8 MIM#613835; Pigmented paravenous chorioretinal atrophy MIM#172870; Retinitis pigmentosa-12 MIM#600105
Mendeliome v0.13725 CRB1 Ain Roesley reviewed gene: CRB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30285347, 32922261, 31884620, 15459956; Phenotypes: Leber congenital amaurosis 8 MIM#613835, Pigmented paravenous chorioretinal atrophy MIM#172870, Retinitis pigmentosa-12 MIM#600105; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13725 CPT1A Ain Roesley Marked gene: CPT1A as ready
Mendeliome v0.13723 CPS1 Ain Roesley Marked gene: CPS1 as ready
Mendeliome v0.13722 CPS1 Ain Roesley reviewed gene: CPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8486760, 17310273, 21120950, 31268178; Phenotypes: Carbamoylphosphate synthetase I deficiency MIM#237300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13722 CPOX Ain Roesley Marked gene: CPOX as ready
Mendeliome v0.13722 CPOX Ain Roesley Phenotypes for gene: CPOX were changed from to Coproporphyria, MIM#121300; Harderoporphyria, MIM#121300
Mendeliome v0.13720 CPOX Ain Roesley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 30828546, 28349448, 23582006, 24156084; Phenotypes: Coproporphyria, MIM#121300, Harderoporphyria, MIM#121300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13720 CPN1 Ain Roesley Marked gene: CPN1 as ready
Mendeliome v0.13720 CPN1 Ain Roesley Phenotypes for gene: CPN1 were changed from to Carboxypeptidase N deficiency MIM#212070
Mendeliome v0.13717 CPN1 Ain Roesley reviewed gene: CPN1: Rating: RED; Mode of pathogenicity: None; Publications: 12560874, 7437116; Phenotypes: Carboxypeptidase N deficiency MIM#212070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13717 COMP Ain Roesley Marked gene: COMP as ready
Mendeliome v0.13717 HSD11B1 Zornitza Stark Marked gene: HSD11B1 as ready
Mendeliome v0.13713 HRG Zornitza Stark Marked gene: HRG as ready
Mendeliome v0.13710 HP Zornitza Stark Marked gene: HP as ready
Mendeliome v0.13708 HOXD13 Zornitza Stark Marked gene: HOXD13 as ready
Mendeliome v0.13705 HOXA13 Zornitza Stark Marked gene: HOXA13 as ready
Mendeliome v0.13702 HOXA1 Zornitza Stark Marked gene: HOXA1 as ready
Mendeliome v0.13699 HOXA1 Zornitza Stark changed review comment from: At least 10 families reported.

175-176insG is known as the Saudi Arabian variant, while 76C>T is known as the Native American variant.

Features include:
Conotruncal heart defects, Abnormalities of the internal carotid artery and other cerebral arteries, Abnormal skull base

Biallelic variants in this gene cause a syndrome affecting hindbrain development, with BSAS and ABDS allelic disorders.; to: Biallelic variants in this gene cause a syndrome affecting hindbrain development, with BSAS and ABDS allelic disorders.

At least 10 families reported.

175-176insG is known as the Saudi Arabian variant, while 76C>T is known as the Native American variant.

Features include:
Conotruncal heart defects, Abnormalities of the internal carotid artery and other cerebral arteries, Abnormal skull base
Mendeliome v0.13699 HNRNPA1 Zornitza Stark Marked gene: HNRNPA1 as ready
Mendeliome v0.13696 HNF4A Zornitza Stark Marked gene: HNF4A as ready
Mendeliome v0.13696 HNF4A Zornitza Stark Phenotypes for gene: HNF4A were changed from to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026; MODY, type I, OMIM # 125850
Mendeliome v0.13693 HNF4A Zornitza Stark reviewed gene: HNF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31875549, 24285859, 22802087, 30005691, 28458902; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026, MODY, type I, OMIM # 125850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13693 HNF1A Zornitza Stark Marked gene: HNF1A as ready
Mendeliome v0.13690 HMX1 Zornitza Stark Marked gene: HMX1 as ready
Mendeliome v0.13690 HMX1 Zornitza Stark Phenotypes for gene: HMX1 were changed from to Oculoauricular syndrome, MIM#612109
Mendeliome v0.13687 HMX1 Zornitza Stark changed review comment from: Oculoauricular syndrome (OCACS) is characterized by complex ocular anomalies, including congenital cataract, anterior segment dysgenesis, iris coloboma, and early-onset retinal dystrophy, and dysplastic ears with abnormal external ear cartilage.

At least two families and two animal models. Also evidence that duplication of long-range enhancer causes microbial.; to: Oculoauricular syndrome (OCACS) is characterized by complex ocular anomalies, including congenital cataract, anterior segment dysgenesis, iris coloboma, and early-onset retinal dystrophy, and dysplastic ears with abnormal external ear cartilage.

At least two families and two animal models. Also evidence that duplication of long-range enhancer causes microtia.
Mendeliome v0.13687 HMX1 Zornitza Stark reviewed gene: HMX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18423520, 25574057, 33465110, 32552830, 31691317; Phenotypes: Oculoauricular syndrome, MIM#612109; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13687 COL9A1 Ain Roesley Marked gene: COL9A1 as ready
Mendeliome v0.13683 DUSP6 Krithika Murali changed review comment from: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing.

Summary of DUSP6 variants identified in this study
c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3
c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual
c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant)
c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant

No segregation information provided.

PMID: 23643382 - Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. In 5 unrelated individuals with congenital hypogonadotropic hypogonadism 4 heterozygous missense were identified. In 3 of the probands, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene. 3 of the 4 variants have subpopulation allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Thr346Met (AJ AF 0.002797), p.Ser182Phe (NFE AF 0.001396), p.Asn189Ser (NFE AF 0.0003641). No functional assays were conducted.

PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted.; to: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing.

Summary of DUSP6 variants identified in this study
c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3
c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual
c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant)
c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant

No segregation information provided. Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism.

PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted.
Mendeliome v0.13683 DUSP6 Krithika Murali changed review comment from: 1 study cited by OMIM (Miraoui et al 2013) - heterozygous variants in 5 unrelated individuals with congenital hypogonadotrophic hypogonadism (CHH). 4/5 variants highly prevalent in healthy population and/or in conjunction with variants in other genes either known to be associated with CHH or possibly associated. No additional studies published since this paper.

PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing.

Summary of DUSP6 variants identified in this study
c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3
c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual
c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant)
c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant

No segregation information provided.; to: PMID: 23643382 Miraoui et al 2013 - - candidate gene study for genes in the FGFR1 pathway that may be associated with CHH, either as causative genes or disease modifiers. A cohort of 386 CHH individuals and 155 unaffected controls of European descent. A number of affected individuals included in this cohort already had known causative variants in CHH-associated genes. The coding exons and proximal introns (≥15 bp from splice sites) of FGF17, FGF18, IL17RD, DUSP6, SPRY2, SPRY4, and FLRT3 were amplified by PCR and determined by direct sequencing.

Summary of DUSP6 variants identified in this study
c.229 T>A p.(Phe77Ile) - absent gnomAD v2 and v3
c.545C>T p.(Ser182Phe) - 203 hets gnomad v2, 137 hets and 1 hom - v3 - identified in conjunction with FGFR1 variant in this individual
c.566A>G p.Asn189Ser - v2 57 hets, v3 29 hets (another individual identified with this variant and an SPRY4 variant)
c.1037C>T p.Thr346Met - 81 hets v2, 27 hets and 1 hom v3 (identified in conjunction with SPRY4 variant

No segregation information provided.

PMID: 23643382 - Dusp6 null mouse model reportedly has craniofacial defects and hearing defects, but no mention of hypogonadotropic hypogonadism. In 5 unrelated individuals with congenital hypogonadotropic hypogonadism 4 heterozygous missense were identified. In 3 of the probands, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene. 3 of the 4 variants have subpopulation allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Thr346Met (AJ AF 0.002797), p.Ser182Phe (NFE AF 0.001396), p.Asn189Ser (NFE AF 0.0003641). No functional assays were conducted.

PMID: 32389901 - 6 unrelated male Chinese Kallman syndrome cases with 4 DUSP6 missense variants. 2 of 4 variants have East Asian allele frequencies in gnomAD v2.1 that are higher than expected for a dominant condition: p.Pro188Leu (EAS AF 0.001203), p.Arg83Gln (EAS AF 0.001129). No functional assays conducted.
Mendeliome v0.13683 COQ9 Ain Roesley Marked gene: COQ9 as ready
Mendeliome v0.13683 COQ9 Ain Roesley Phenotypes for gene: COQ9 were changed from to Coenzyme Q10 deficiency, primary, 5, MIM#614654
Mendeliome v0.13681 COQ9 Ain Roesley reviewed gene: COQ9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19375058, 26081641, 23255162, 31821167; Phenotypes: Coenzyme Q10 deficiency, primary, 5, MIM#614654; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13681 COQ8B Ain Roesley Marked gene: COQ8B as ready
Mendeliome v0.13680 COQ8A Ain Roesley Marked gene: COQ8A as ready
Mendeliome v0.13680 COQ8A Ain Roesley Phenotypes for gene: COQ8A were changed from to Coenzyme Q10 deficiency, primary, 4 MIM#612016
Mendeliome v0.13679 COQ8A Ain Roesley reviewed gene: COQ8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32337771; Phenotypes: Coenzyme Q10 deficiency, primary, 4 MIM#612016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13679 COQ7 Ain Roesley Marked gene: COQ7 as ready
Mendeliome v0.13679 COQ7 Ain Roesley Phenotypes for gene: COQ7 were changed from to Coenzyme Q10 deficiency, primary, 8 MIM#616733
Mendeliome v0.13678 COQ7 Ain Roesley reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26084283, 31240163, 33215859, 28409910; Phenotypes: Coenzyme Q10 deficiency, primary, 8 MIM#616733; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13678 COQ6 Ain Roesley Marked gene: COQ6 as ready
Mendeliome v0.13678 COQ6 Ain Roesley Phenotypes for gene: COQ6 were changed from to Coenzyme Q10 deficiency, primary, 6 MIM#614650
Mendeliome v0.13677 COQ6 Ain Roesley reviewed gene: COQ6: Rating: GREEN; Mode of pathogenicity: None; Publications: 28125198; Phenotypes: Coenzyme Q10 deficiency, primary, 6 MIM#614650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13675 COL9A2 Ain Roesley Marked gene: COL9A2 as ready
Mendeliome v0.13674 COL6A3 Ain Roesley Marked gene: COL6A3 as ready
Mendeliome v0.13674 COL6A3 Ain Roesley Phenotypes for gene: COL6A3 were changed from to Bethlem myopathy 1 MIM#158810; Dystonia 27 MIM#616411; Ullrich congenital muscular dystrophy 1 MIM#254090
Mendeliome v0.13673 COL6A3 Ain Roesley reviewed gene: COL6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301676; Phenotypes: Bethlem myopathy 1 MIM#158810, Dystonia 27 MIM#616411, Ullrich congenital muscular dystrophy 1 MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13673 COL6A2 Ain Roesley changed review comment from: GeneReviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly

COL621 accounts for 44-46% of Collagen VI-Related Dystrophies cases; to: GeneReviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly

COL6A2 accounts for 44-46% of Collagen VI-Related Dystrophies cases
Mendeliome v0.13673 COL6A2 Ain Roesley Marked gene: COL6A2 as ready
Mendeliome v0.13673 COL6A2 Ain Roesley Phenotypes for gene: COL6A2 were changed from to Bethlem myopathy 1 MIM#158810; Ullrich congenital muscular dystrophy 1 MIM#254090
Mendeliome v0.13671 COL6A2 Ain Roesley reviewed gene: COL6A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301676; Phenotypes: Bethlem myopathy 1 MIM#158810, Ullrich congenital muscular dystrophy 1 MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13671 COL6A1 Ain Roesley changed review comment from: Well established association

Genereviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly; to: Well established association

Genereviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly

COL6A1 accounts for 35-38% of Collagen VI-Related Dystrophies cases
Mendeliome v0.13671 COL6A1 Ain Roesley Marked gene: COL6A1 as ready
Mendeliome v0.13671 COL6A1 Ain Roesley Phenotypes for gene: COL6A1 were changed from to Bethlem myopathy MIM#158810; Ullrich congenital muscular dystrophy MIM#254090
Mendeliome v0.13669 COL6A1 Ain Roesley changed review comment from: Well established association

Both loss-of-function and dominant negative mechanism has been reported for this gene. Mutations result in a spectrum of disease, ranging from the milder Bethlem myopathy (monoallelic) to the more severe Ullrich congenital muscular dystrophy (biallelic) (PMID: 29277723; 24443028).
Sources: Literature; to: Well established association

Genereviews PMID:20301676

AD variants typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes

AR variants are usually nonsense or fs, or biallelic variants located near the C-terminal end of the TH domain, where they will be excluded from assembly
Mendeliome v0.13669 COL6A1 Ain Roesley reviewed gene: COL6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25535305, 15955946, 23738969, 29277723, 24443028; Phenotypes: Bethlem myopathy MIM#158810, Ullrich congenital muscular dystrophy MIM#254090; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13669 COL5A2 Ain Roesley Marked gene: COL5A2 as ready
Mendeliome v0.13668 COL4A4 Ain Roesley Marked gene: COL4A4 as ready
Mendeliome v0.13666 COL4A3 Ain Roesley Marked gene: COL4A3 as ready
Mendeliome v0.13665 COL4A2 Ain Roesley Marked gene: COL4A2 as ready
Mendeliome v0.13664 COL4A1 Ain Roesley Marked gene: COL4A1 as ready
Mendeliome v0.13664 COL4A1 Ain Roesley Phenotypes for gene: COL4A1 were changed from to Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps MIM#611773; Brain small vessel disease with or without ocular anomalies MIM#175780; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant MIM#618564
Mendeliome v0.13662 COL4A1 Ain Roesley reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24628545, 25719457, 21625620, 23225343, 23065703, 20818663, 20301768; Phenotypes: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps MIM#611773, Brain small vessel disease with or without ocular anomalies MIM#175780, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant MIM#618564; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13662 HMOX1 Zornitza Stark Marked gene: HMOX1 as ready
Mendeliome v0.13658 COL27A1 Ain Roesley Marked gene: COL27A1 as ready
Mendeliome v0.13656 COL1A2 Ain Roesley edited their review of gene: COL1A2: Changed phenotypes: Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, MIM# 619120, Ehlers-Danlos syndrome, arthrochalasia type, 2, MIM# 617821, Ehlers-Danlos syndrome, cardiac valvular type, MIM# 225320, Osteogenesis imperfecta, type II, MIM# 166210, Osteogenesis imperfecta, type III, MIM# 259420, Osteogenesis imperfecta, type IV, MIM# 166220
Mendeliome v0.13656 COL1A2 Ain Roesley Marked gene: COL1A2 as ready
Mendeliome v0.13656 COL1A2 Ain Roesley Phenotypes for gene: COL1A2 were changed from to Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, MIM# 619120; Ehlers-Danlos syndrome, arthrochalasia type, 2, MIM# 617821; Ehlers-Danlos syndrome, cardiac valvular type, MIM# 225320; Osteogenesis imperfecta, type II, MIM# 166210; Osteogenesis imperfecta, type III, MIM# 259420; Osteogenesis imperfecta, type IV, MIM# 166220
Mendeliome v0.13653 COL1A2 Ain Roesley reviewed gene: COL1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 32091183, 2993307, 30821104; Phenotypes: Ehlers-Danlos syndrome, arthrochalasia type, 2 MIM#617821, Ehlers-Danlos syndrome, cardiac valvular type MIM#225320; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13653 COL1A1 Ain Roesley changed review comment from: COL1A1 is mostly associated with osteogenesis imperfecta however, substitutions of arginine by cysteine in the triple helical domain) have been reported in individuals w/classic EDS & aneurysm & dissection of large vessels (PMID: 20301422;20301667)

The mild forms are usually caused by haploinsufficiency and result in a reduced amount of normal type I collagen, the severe and lethal forms result from dominant negative variants which produce structural defects in the collagen molecule (PMID:12362985).; to: COL1A1 is mostly associated with osteogenesis imperfecta however, substitutions of arginine by cysteine in the triple helical domain) have been reported in individuals w/classic EDS & aneurysm & dissection of large vessels (PMID: 20301422;20301667)

For skeletal phenotypes:
The mild forms are usually caused by haploinsufficiency and result in a reduced amount of normal type I collagen, the severe and lethal forms result from dominant negative variants which produce structural defects in the collagen molecule (PMID:12362985).
Mendeliome v0.13653 COL1A1 Ain Roesley changed review comment from: COL1A1 is mostly associated with osteogenesis imperfecta however, substitutions of arginine by cysteine in the triple helical domain) have been reported in individuals w/classic EDS & aneurysm & dissection of large vessels (PMID: 20301422;20301667); to: COL1A1 is mostly associated with osteogenesis imperfecta however, substitutions of arginine by cysteine in the triple helical domain) have been reported in individuals w/classic EDS & aneurysm & dissection of large vessels (PMID: 20301422;20301667)

The mild forms are usually caused by haploinsufficiency and result in a reduced amount of normal type I collagen, the severe and lethal forms result from dominant negative variants which produce structural defects in the collagen molecule (PMID:12362985).
Mendeliome v0.13653 COL1A1 Ain Roesley Marked gene: COL1A1 as ready
Mendeliome v0.13653 COL1A1 Ain Roesley Phenotypes for gene: COL1A1 were changed from to Caffey disease MIM#114000; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 MIM#619115; Ehlers-Danlos syndrome, arthrochalasia type, 1 MIM#130060; Osteogenesis imperfecta, type I MIM#166200; Osteogenesis imperfecta, type II MIM#166210; Osteogenesis imperfecta, type III MIM#259420; Osteogenesis imperfecta, type IV MIM#166220
Mendeliome v0.13652 COL1A1 Ain Roesley reviewed gene: COL1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301422, 20301667, 30071989, 28981071, 12362985, 28956891; Phenotypes: Caffey disease MIM#114000, Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 MIM#619115, Ehlers-Danlos syndrome, arthrochalasia type, 1 MIM#130060, Osteogenesis imperfecta, type I MIM#166200, Osteogenesis imperfecta, type II MIM#166210, Osteogenesis imperfecta, type III MIM#259420, Osteogenesis imperfecta, type IV MIM#166220; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13652 COL18A1 Ain Roesley Marked gene: COL18A1 as ready
Mendeliome v0.13650 COL17A1 Ain Roesley Marked gene: COL17A1 as ready
Mendeliome v0.13649 COL17A1 Ain Roesley commented on gene: COL17A1: For Epithelial recurrent erosion dystrophy, AD:
Multiple families reported, c.3156C>T is recurrent.

For EB, AR:
well established association (GeneReviews PMID:20301304)
Mendeliome v0.13649 COL12A1 Ain Roesley Marked gene: COL12A1 as ready
Mendeliome v0.13648 COL12A1 Ain Roesley Phenotypes for gene: COL12A1 were changed from to Myopathic EDS; Bethlem myopathy 2 MIM#616471; Ullrich congenital muscular dystrophy 2 MIM#616470
Mendeliome v0.13647 COL12A1 Ain Roesley reviewed gene: COL12A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28306229, 31273343, 24334604; Phenotypes: Myopathic EDS, Bethlem myopathy 2 MIM#616471, Ullrich congenital muscular dystrophy 2 MIM#616470; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13647 COL11A2 Ain Roesley Marked gene: COL11A2 as ready
Mendeliome v0.13645 COG7 Ain Roesley Marked gene: COG7 as ready
Mendeliome v0.13643 COASY Ain Roesley Marked gene: COASY as ready
Mendeliome v0.13643 COASY Ain Roesley Phenotypes for gene: COASY were changed from to Neurodegeneration with brain iron accumulation 6 MIM#615643; Pontocerebellar hypoplasia, type 12 MIM#v618266
Mendeliome v0.13642 COASY Ain Roesley changed review comment from: Green for both NBIA and PCH; to: Green for both NBIA and PCH

only 2 variants reported for PCH - a fs (c.1549_1550delAG) and c.1486-3C>G (Recurrent)
Mendeliome v0.13642 COASY Ain Roesley reviewed gene: COASY: Rating: GREEN; Mode of pathogenicity: None; Publications: 30089828, 28489334, 24360804, 35499143; Phenotypes: Neurodegeneration with brain iron accumulation 6 MIM#615643, Pontocerebellar hypoplasia, type 12 MIM#v618266; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13642 HMBS Zornitza Stark Marked gene: HMBS as ready
Mendeliome v0.13642 HMBS Zornitza Stark Phenotypes for gene: HMBS were changed from to Porphyria, acute intermittent, MIM#176000; Porphyria, acute intermittent, non-erythroid variant, MIM#176000
Mendeliome v0.13640 HMBS Zornitza Stark reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, acute intermittent, MIM#176000, Porphyria, acute intermittent, non-erythroid variant, MIM#176000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13640 HK1 Zornitza Stark Marked gene: HK1 as ready
Mendeliome v0.13640 HK1 Zornitza Stark Phenotypes for gene: HK1 were changed from to Neuropathy, hereditary motor and sensory, Russe type , MIM#605285; Haemolytic anaemia due to hexokinase deficiency, MIM# 235700; Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547; Retinitis pigmentosa 79, MIM# 617460
Mendeliome v0.13637 HK1 Zornitza Stark changed review comment from: HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy.

Founder variant in the Roma, -3818-195G-C, AltT2 EXON in 5'UTR identified in multiple families.

Note gene is associated with other phenotypes.; to: Bi-allelic variants and neuropathy: HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy.

Founder variant in the Roma, -3818-195G-C, AltT2 EXON in 5'UTR identified in multiple families.

Note gene is associated with other phenotypes.
Mendeliome v0.13637 HK1 Zornitza Stark edited their review of gene: HK1: Added comment: Mono-allelic variants and ID: PMID30778173, 7 patients from 6 unrelated families with denovo missense variants in the N-terminal half of HK1

Mono-allelic variants and RP: Seven families reported with the same heterozygous missense variant, p.Glu847Lys and RP from different ethnicities. Some supportive evidence. Variant is present in 3 hets in gnomad.

Bi-allelic variants and haemolytic anaemia: more than 10 families reported.; Changed publications: 19536174, 30778173, 25316723, 25190649, 31621442, 32814480, 7655856, 12393545, 33361148, 31119733, 27282571; Changed phenotypes: Neuropathy, hereditary motor and sensory, Russe type , MIM#605285, Haemolytic anaemia due to hexokinase deficiency, MIM# 235700, Neurodevelopmental disorder with visual defects and brain anomalies, MIM# 618547, Retinitis pigmentosa 79, MIM# 617460; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13636 RPE65 Zornitza Stark Marked gene: RPE65 as ready
Mendeliome v0.13633 SLC24A1 Zornitza Stark Marked gene: SLC24A1 as ready
Mendeliome v0.13633 SLC24A1 Zornitza Stark Phenotypes for gene: SLC24A1 were changed from to Night blindness, congenital stationary (complete), 1D, autosomal recessive, MIM#613830, MONDO:0013450
Mendeliome v0.13630 SLC25A1 Zornitza Stark Marked gene: SLC25A1 as ready
Mendeliome v0.13630 SLC25A1 Zornitza Stark Phenotypes for gene: SLC25A1 were changed from to Combined D-2- and L-2-hydroxyglutaric aciduria MIM#: 615182, MONDO:0014072; Myasthenic syndrome, congenital, 23, presynaptic, MIM#618197, MONDO:0032596
Mendeliome v0.13627 RRAS Zornitza Stark Marked gene: RRAS as ready
Mendeliome v0.13623 SLC11A1 Zornitza Stark Marked gene: SLC11A1 as ready
Mendeliome v0.13619 SIL1 Zornitza Stark Marked gene: SIL1 as ready
Mendeliome v0.13619 SIL1 Zornitza Stark Phenotypes for gene: SIL1 were changed from to Marinesco-Sjogren syndrome, MIM#248800; MONDO#0009567
Mendeliome v0.13616 SLC24A1 Manny Jacobs reviewed gene: SLC24A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35486108, 35446361, 20850105, 26822852; Phenotypes: Night blindness, congenital stationary (complete), 1D, autosomal recessive, MIM#613830, MONDO:0013450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13616 SIK1 Zornitza Stark Marked gene: SIK1 as ready
Mendeliome v0.13613 SLC25A1 Manny Jacobs reviewed gene: SLC25A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26870663, 31527857, 31808147, 23561848, 23393310; Phenotypes: Combined D-2- and L-2-hydroxyglutaric aciduria MIM#: 615182, MONDO:0014072, Myasthenic syndrome, congenital, 23, presynaptic, MIM#618197, MONDO:0032596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13613 RRAS Belinda Chong changed review comment from: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents.

Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018).; to: Catts et al (2021) identified a 7-year-old boy with a history of craniosynostosis, congenital heart defect, and mild dysmorphic features who was incidentally found to have pediatric MDS with monosomy 7 in the context of previously unrecognized germline RRAS mutation. A heterozygous c.116_118dup (NM_006270.5) variant resulting in p.G39dup was identified and excluded in an unaffected sibling, and both parents.

Two individuals reported. One de novo variant, the inheritance of the other variant uncertain. Some supportive functional data. Rated as LIMITED by ClinGen (reviewed 27/04/2018).
Mendeliome v0.13613 HIBCH Zornitza Stark Marked gene: HIBCH as ready
Mendeliome v0.13610 HGF Zornitza Stark Marked gene: HGF as ready
Mendeliome v0.13607 HGD Zornitza Stark Marked gene: HGD as ready
Mendeliome v0.13604 HFE Zornitza Stark Marked gene: HFE as ready
Mendeliome v0.13602 HESX1 Zornitza Stark Marked gene: HESX1 as ready
Mendeliome v0.13602 HESX1 Zornitza Stark Phenotypes for gene: HESX1 were changed from to Growth hormone deficiency with pituitary anomalies, MIM#182230; Pituitary hormone deficiency, combined, 5, MIM#182230; Septooptic dysplasia, MIM#182230
Mendeliome v0.13600 HESX1 Zornitza Stark reviewed gene: HESX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Growth hormone deficiency with pituitary anomalies, MIM#182230, Pituitary hormone deficiency, combined, 5, MIM#182230, Septooptic dysplasia, MIM#182230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13599 HERC1 Zornitza Stark Marked gene: HERC1 as ready
Mendeliome v0.13599 HERC1 Zornitza Stark Phenotypes for gene: HERC1 were changed from to Macrocephaly, dysmorphic facies, and psychomotor retardation, MIM# 617011
Mendeliome v0.13596 HERC1 Zornitza Stark reviewed gene: HERC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28323226, 27108999, 26153217, 26138117, 20041218; Phenotypes: Macrocephaly, dysmorphic facies, and psychomotor retardation, MIM# 617011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13596 HEPACAM Zornitza Stark Marked gene: HEPACAM as ready
Mendeliome v0.13596 HEPACAM Zornitza Stark Phenotypes for gene: HEPACAM were changed from to Megalencephalic leukoencephalopathy with subcortical cysts 2A, MIM# 613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, MIM# 613926
Mendeliome v0.13593 HEPACAM Zornitza Stark reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 21419380, 21419380; Phenotypes: Megalencephalic leukoencephalopathy with subcortical cysts 2A, MIM# 613925, Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, MIM# 613926; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13593 LIPT2 Alison Yeung Marked gene: LIPT2 as ready
Mendeliome v0.13592 SIL1 Samantha Ayres reviewed gene: SIL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24176978, 16282977, 20301371; Phenotypes: Marinesco-Sjogren syndrome, MIM#248800, MONDO#0009567; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13592 DNASE2 Zornitza Stark Phenotypes for gene: DNASE2 were changed from Auto-inflammatory disorder; splenomegaly; glomerulonephritis; liver fibrosis; arthritis; HLH to Autoinflammatory-pancytopaenia syndrome, MIM# 619858
Mendeliome v0.13589 LIPH Alison Yeung Marked gene: LIPH as ready
Mendeliome v0.13587 LIPC Alison Yeung Marked gene: LIPC as ready
Mendeliome v0.13585 LIPC Alison Yeung Added comment: Comment on mode of inheritance: PMID: 1671786, 12777476, 1883393, 22798447 - 7 cases from 3 unrelated families with hepatic lipase deficiency and biallelic variants.
PMID: 26423094 - null mouse had dyslipidemia on a high cholesterol and fat diet
PMID: 23219720, 22464213 - 2 cases with hyperalphalipoproteinemia and heterozygous variants, with supporting in vitro funcitonal assays
Mendeliome v0.13583 LINS1 Alison Yeung Marked gene: LINS1 as ready
Mendeliome v0.13581 HCRT Zornitza Stark Marked gene: HCRT as ready
Mendeliome v0.13581 HCRT Zornitza Stark Phenotypes for gene: HCRT were changed from to Narcolepsy 1 , MIM# 161400
Mendeliome v0.13577 LIM2 Alison Yeung Marked gene: LIM2 as ready
Mendeliome v0.13577 HCRT Zornitza Stark reviewed gene: HCRT: Rating: RED; Mode of pathogenicity: None; Publications: 10973318, 11148249, 11723284; Phenotypes: Narcolepsy 1 , MIM# 161400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13577 LIM2 Alison Yeung Phenotypes for gene: LIM2 were changed from to Cataract 19, multiple types, MIM# 615277
Mendeliome v0.13574 LIM2 Alison Yeung reviewed gene: LIM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27814360, 11917274, 18596884, 33708862, 32202185, 21617753; Phenotypes: Cataract 19, multiple types, MIM# 615277; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13574 HCN1 Zornitza Stark Marked gene: HCN1 as ready
Mendeliome v0.13571 HCCS Zornitza Stark Marked gene: HCCS as ready
Mendeliome v0.13571 HCCS Zornitza Stark Phenotypes for gene: HCCS were changed from to Linear skin defects with multiple congenital anomalies 1, MIM# 309801
Mendeliome v0.13568 HCCS Zornitza Stark reviewed gene: HCCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033964, 30068298, 24735900; Phenotypes: Linear skin defects with multiple congenital anomalies 1, MIM# 309801; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.13568 HBA2 Zornitza Stark Marked gene: HBA2 as ready
Mendeliome v0.13565 HBA1 Zornitza Stark Marked gene: HBA1 as ready
Mendeliome v0.13563 HAO1 Zornitza Stark Marked gene: HAO1 as ready
Mendeliome v0.13562 HAMP Zornitza Stark Marked gene: HAMP as ready
Mendeliome v0.13559 HADHB Zornitza Stark Marked gene: HADHB as ready
Mendeliome v0.13556 HADHA Zornitza Stark Marked gene: HADHA as ready
Mendeliome v0.13554 HADH Zornitza Stark Marked gene: HADH as ready
Mendeliome v0.13552 HACD1 Zornitza Stark Marked gene: HACD1 as ready
Mendeliome v0.13549 HAAO Zornitza Stark Marked gene: HAAO as ready
Mendeliome v0.13549 HAAO Zornitza Stark Phenotypes for gene: HAAO were changed from to Vertebral, cardiac, renal, and limb defects syndrome 1 MIM#617660; NAD deficiency
Mendeliome v0.13546 H6PD Zornitza Stark Marked gene: H6PD as ready
Mendeliome v0.13543 BUD23 Zornitza Stark Marked gene: BUD23 as ready
Mendeliome v0.13542 BTNL2 Zornitza Stark Marked gene: BTNL2 as ready
Mendeliome v0.13542 BTNL2 Zornitza Stark Phenotypes for gene: BTNL2 were changed from to {Sarcoidosis, susceptibility to, 2} 612387
Mendeliome v0.13539 BTNL2 Zornitza Stark reviewed gene: BTNL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Sarcoidosis, susceptibility to, 2} 612387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13539 BTK Zornitza Stark Marked gene: BTK as ready
Mendeliome v0.13536 BRIP1 Zornitza Stark Marked gene: BRIP1 as ready
Mendeliome v0.13533 BRAF Zornitza Stark Marked gene: BRAF as ready
Mendeliome v0.13533 BRAF Zornitza Stark Phenotypes for gene: BRAF were changed from to Noonan syndrome 7, MIM# 613706; Cardiofaciocutaneous syndrome, MIM# 115150
Mendeliome v0.13531 BRAF Zornitza Stark Mode of pathogenicity for gene: BRAF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.13529 BRAF Zornitza Stark reviewed gene: BRAF: 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: 19206169, 18042262; Phenotypes: Noonan syndrome 7, MIM# 613706, Cardiofaciocutaneous syndrome, MIM# 115150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13529 BPGM Zornitza Stark Marked gene: BPGM as ready
Mendeliome v0.13525 BMPR1A Zornitza Stark Marked gene: BMPR1A as ready
Mendeliome v0.13522 BLVRA Zornitza Stark Marked gene: BLVRA as ready
Mendeliome v0.13518 BLK Zornitza Stark Marked gene: BLK as ready
Mendeliome v0.13518 BLK Zornitza Stark Phenotypes for gene: BLK were changed from to Common variable immunodeficiency, MONDO:0015517
Mendeliome v0.13514 BLK Zornitza Stark reviewed gene: BLK: Rating: AMBER; Mode of pathogenicity: None; Publications: 25926555; Phenotypes: Common variable immunodeficiency, MONDO:0015517; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13514 BHLHE41 Zornitza Stark Marked gene: BHLHE41 as ready
Mendeliome v0.13511 BFSP1 Zornitza Stark Marked gene: BFSP1 as ready
Mendeliome v0.13511 BFSP1 Zornitza Stark Phenotypes for gene: BFSP1 were changed from to Cataract 33, multiple types, MIM# 611391
Mendeliome v0.13508 BFSP1 Zornitza Stark reviewed gene: BFSP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17225135, 26694549, 24379646, 28450710, 31842807, 26694549; Phenotypes: Cataract 33, multiple types, MIM# 611391; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13508 BCL2 Zornitza Stark Marked gene: BCL2 as ready
Mendeliome v0.13507 BCKDK Zornitza Stark Marked gene: BCKDK as ready
Mendeliome v0.13504 BCL10 Zornitza Stark Marked gene: BCL10 as ready
Mendeliome v0.13501 BCHE Zornitza Stark Marked gene: BCHE as ready
Mendeliome v0.13499 BBS2 Zornitza Stark Marked gene: BBS2 as ready
Mendeliome v0.13499 BBS2 Zornitza Stark Phenotypes for gene: BBS2 were changed from to Bardet-Biedl syndrome 2, MIM# 615981; Retinitis pigmentosa 74, MIM# 616562
Mendeliome v0.13496 BBS12 Zornitza Stark Marked gene: BBS12 as ready
Mendeliome v0.13496 BBS12 Zornitza Stark Phenotypes for gene: BBS12 were changed from to Bardet-Biedl syndrome 12, MIM# 615989
Mendeliome v0.13493 BBS10 Zornitza Stark Marked gene: BBS10 as ready
Mendeliome v0.13493 BBS10 Zornitza Stark Phenotypes for gene: BBS10 were changed from to Bardet-Biedl syndrome 10, MIM# 615987
Mendeliome v0.13490 BBS1 Zornitza Stark Marked gene: BBS1 as ready
Mendeliome v0.13490 BBS1 Zornitza Stark Phenotypes for gene: BBS1 were changed from to Bardet-Biedl syndrome 1, MIM# 209900
Mendeliome v0.13487 BAG3 Zornitza Stark Marked gene: BAG3 as ready
Mendeliome v0.13487 BAG3 Zornitza Stark Phenotypes for gene: BAG3 were changed from to Cardiomyopathy, dilated, 1HH, MIM# 613881; Myopathy, myofibrillar, 6, MIM# 612954
Mendeliome v0.13484 BAG3 Zornitza Stark reviewed gene: BAG3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21353195, 25008357, 25448463, 24623017, 27391596, 28211974, 30442290, 31983221, 28737513, 29323723, 33947203, 25208129, 32453099, 22734908; Phenotypes: Cardiomyopathy, dilated, 1HH, MIM# 613881, Myopathy, myofibrillar, 6, MIM# 612954; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13484 BACH2 Zornitza Stark Marked gene: BACH2 as ready
Mendeliome v0.13481 B4GALT1 Zornitza Stark Marked gene: B4GALT1 as ready
Mendeliome v0.13478 B4GALT1 Zornitza Stark changed review comment from: Intellectual disability is part of CDG, although non-neurological forms of this CDG have been described.
Sources: Expert list; to: At least 3 unrelated families.
Sources: Expert list
Mendeliome v0.13478 B4GALNT1 Zornitza Stark Marked gene: B4GALNT1 as ready
Mendeliome v0.13478 B4GALNT1 Zornitza Stark Phenotypes for gene: B4GALNT1 were changed from to Spastic paraplegia 26, autosomal recessive (MIM #609195)
Mendeliome v0.13474 B4GALNT1 Zornitza Stark reviewed gene: B4GALNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23746551 24103911; Phenotypes: Spastic paraplegia 26, autosomal recessive (MIM #609195); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13474 B3GLCT Zornitza Stark Marked gene: B3GLCT as ready
Mendeliome v0.13471 APOA5 Zornitza Stark Marked gene: APOA5 as ready
Mendeliome v0.13471 AP1S2 Zornitza Stark Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, MIM#304340 to Pettigrew syndrome, MIM# 304340
Mendeliome v0.13469 APCDD1 Zornitza Stark Marked gene: APCDD1 as ready
Mendeliome v0.13466 ANO10 Zornitza Stark Phenotypes for gene: ANO10 were changed from Spinocerebellar ataxia, autosomal recessive 10 MIM#613728 to Spinocerebellar ataxia, autosomal recessive 10, MIM#613728
Mendeliome v0.13464 ANO10 Zornitza Stark reviewed gene: ANO10: Rating: GREEN; Mode of pathogenicity: None; Publications: 21092923, 25182700; Phenotypes: Spinocerebellar ataxia, autosomal recessive 10, MIM#613728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13464 PHOX2B Zornitza Stark Marked gene: PHOX2B as ready
Mendeliome v0.13461 PEX26 Zornitza Stark Marked gene: PEX26 as ready
Mendeliome v0.13458 PEX2 Zornitza Stark Marked gene: PEX2 as ready
Mendeliome v0.13455 PEX19 Zornitza Stark Marked gene: PEX19 as ready
Mendeliome v0.13454 PEX16 Zornitza Stark Marked gene: PEX16 as ready
Mendeliome v0.13451 PEX14 Zornitza Stark Marked gene: PEX14 as ready
Mendeliome v0.13448 PEX13 Zornitza Stark Marked gene: PEX13 as ready
Mendeliome v0.13446 PEX12 Zornitza Stark Marked gene: PEX12 as ready
Mendeliome v0.13443 ENTPD1 Zornitza Stark commented on gene: ENTPD1: PMID 35471564: 27 individuals from 17 families published, expanding the phenotype to a complex neurodevelopmental disorder characterised by ID, white matter abnormalities and spastic paraplegia.
Mendeliome v0.13443 RSPH1 Zornitza Stark Marked gene: RSPH1 as ready
Mendeliome v0.13443 RSPH1 Zornitza Stark Phenotypes for gene: RSPH1 were changed from to Ciliary dyskinesia, primary, 24 MIM#615481
Mendeliome v0.13437 APOA2 Elena Savva Marked gene: APOA2 as ready
Mendeliome v0.13435 APOA1 Elena Savva Marked gene: APOA1 as ready
Mendeliome v0.13435 APOA1 Elena Savva Phenotypes for gene: APOA1 were changed from to Amyloidosis, 3 or more types MIM#105200; Hypoalphalipoproteinemia, primary, 2 MIM#618463; Hypoalphalipoproteinemia, primary, 2, intermediate MIM#619836
Mendeliome v0.13434 APOA1 Elena Savva reviewed gene: APOA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyloidosis, 3 or more types MIM#105200, Hypoalphalipoproteinemia, primary, 2 MIM#618463, Hypoalphalipoproteinemia, primary, 2, intermediate MIM#619836; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13434 AP1S2 Elena Savva Marked gene: AP1S2 as ready
Mendeliome v0.13434 AP1S2 Elena Savva Phenotypes for gene: AP1S2 were changed from to Mental retardation, X-linked syndromic 5, MIM#304340
Mendeliome v0.13432 ANO10 Elena Savva Phenotypes for gene: ANO10 were changed from Spinocerebellar ataxia, autosomal recessive 10 MIM#613728 to Spinocerebellar ataxia, autosomal recessive 10 MIM#613728
Mendeliome v0.13430 ANO10 Elena Savva Phenotypes for gene: ANO10 were changed from to Spinocerebellar ataxia, autosomal recessive 10 MIM#613728
Mendeliome v0.13430 ANO10 Elena Savva Marked gene: ANO10 as ready
Mendeliome v0.13429 DIO1 Zornitza Stark Marked gene: DIO1 as ready
Mendeliome v0.13422 TUBA8 Zornitza Stark changed review comment from: Two families reported initially (PMID 19896110). However, note that mouse model does not have a brain phenotype and WES in the original families identified homozygous, previously reported as pathogenic, LoF variant in SNAP29, which is much more likely to be causative (28388629).; to: Bi-allelic variants and cortical dysplasia: Two families reported initially (PMID 19896110). However, note that mouse model does not have a brain phenotype and WES in the original families identified homozygous, previously reported as pathogenic, LoF variant in SNAP29, which is much more likely to be causative (28388629).
Mendeliome v0.13422 TUBA8 Zornitza Stark edited their review of gene: TUBA8: Added comment: Mono-allelic variants and macrothrombocytopaenia: 6 unrelated individuals with missense variants found in a large cohort of blood donors, some functional data. Individuals were generally asymptomatic.; Changed rating: AMBER; Changed publications: 34704371; Changed phenotypes: Macrothrombocytopaenia, isolated, 2, autosomal dominant, MIM# 619840; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13422 NRCAM Zornitza Stark Phenotypes for gene: NRCAM were changed from neurodevelopmental disorder, NRCAM-related, MONDO:0700092 to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, MIM# 619833
Mendeliome v0.13421 NRCAM Zornitza Stark reviewed gene: NRCAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, MIM# 619833; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13420 PEX3 Zornitza Stark Marked gene: PEX3 as ready
Mendeliome v0.13417 PEX5 Zornitza Stark Marked gene: PEX5 as ready
Mendeliome v0.13414 PEX7 Zornitza Stark Marked gene: PEX7 as ready
Mendeliome v0.13411 PFKM Zornitza Stark Marked gene: PFKM as ready
Mendeliome v0.13408 PGAM2 Zornitza Stark Marked gene: PGAM2 as ready
Mendeliome v0.13405 PHF11 Zornitza Stark Marked gene: PHF11 as ready
Mendeliome v0.13404 PHIP Zornitza Stark Marked gene: PHIP as ready
Mendeliome v0.13401 PHIP Zornitza Stark changed review comment from: Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioral abnormalities, dysmorphic features, and obesity.

More than 20 individuals reported.; to: Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioural abnormalities, dysmorphic features, and obesity.

More than 20 individuals reported.
Mendeliome v0.13401 PHKA2 Zornitza Stark Marked gene: PHKA2 as ready
Mendeliome v0.13398 PIK3CA Zornitza Stark Marked gene: PIK3CA as ready
Mendeliome v0.13398 PIK3CA Zornitza Stark Phenotypes for gene: PIK3CA were changed from to Megalencephaly-capillary malformation (MCAP) syndrome , MIM#602501; CLAPO syndrome, somatic, MIM# 613089; CLOVE syndrome, somatic, MIM# 612918
Mendeliome v0.13396 PIK3CA Zornitza Stark reviewed gene: PIK3CA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Megalencephaly-capillary malformation (MCAP) syndrome , MIM#602501, CLAPO syndrome, somatic, MIM# 613089, CLOVE syndrome, somatic, MIM# 612918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13396 PISD Zornitza Stark Phenotypes for gene: PISD were changed from to Liberfarb syndrome, MIM# 618889; Intellectual disability; cataracts; retinal degeneration; microcephaly; deafness; short stature; white matter abnormalities
Mendeliome v0.13393 PISD Zornitza Stark edited their review of gene: PISD: Changed phenotypes: Liberfarb syndrome, MIM# 618889, Intellectual disability, cataracts, retinal degeneration, microcephaly, deafness, short stature, white matter abnormalities
Mendeliome v0.13393 PHYH Zornitza Stark Marked gene: PHYH as ready
Mendeliome v0.13390 PHYH Zornitza Stark edited their review of gene: PHYH: Added comment: Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells.

Well established gene-disease association.; Changed publications: 9326939, 9326940
Mendeliome v0.13390 PIEZO2 Zornitza Stark Marked gene: PIEZO2 as ready
Mendeliome v0.13390 PIEZO2 Zornitza Stark Phenotypes for gene: PIEZO2 were changed from to Marden-Walker syndrome (MIM#248700); Arthrogryposis, distal, type 3 (MIM#114300); Arthrogryposis, distal, type 5 (MIM#108145); Arthrogryposis, distal, with impaired proprioception and touch, MIM# 617146
Mendeliome v0.13387 PIEZO2 Zornitza Stark changed review comment from: Bi-allelic variants: more than 5 unrelated families reported.

Mono-allelic variants:
DA5, more than 20 families reported.
DA3, more than 10 families reported, R2686H is recurrent.; to: Bi-allelic variants: more than 5 unrelated families reported.

Mono-allelic variants:
DA5, more than 20 families reported.
DA3, more than 10 families reported, R2686H is recurrent.
Marden-Walker: 2 families reported.
Mendeliome v0.13387 PIEZO2 Zornitza Stark edited their review of gene: PIEZO2: Changed phenotypes: Marden-Walker syndrome (MIM#248700), Arthrogryposis, distal, type 3 (MIM#114300), Arthrogryposis, distal, type 5 (MIM#108145), Arthrogryposis, distal, with impaired proprioception and touch, MIM# 617146
Mendeliome v0.13387 PIEZO2 Zornitza Stark changed review comment from: Bi-allelic variants: more than 5 unrelated families reported.

Mono-allelic variants:
DA5, more than 20 families reported.; to: Bi-allelic variants: more than 5 unrelated families reported.

Mono-allelic variants:
DA5, more than 20 families reported.
DA3, more than 10 families reported, R2686H is recurrent.
Mendeliome v0.13387 PIEZO2 Zornitza Stark changed review comment from: Bi-allelic variants: more than 5 unrelated families reported.

Mono-allelic variants:
DA3, more than 20 families reported.; to: Bi-allelic variants: more than 5 unrelated families reported.

Mono-allelic variants:
DA5, more than 20 families reported.
Mendeliome v0.13387 PIEZO2 Zornitza Stark changed review comment from: Bi-allelic variants: more than 5 unrelated families reported.; to: Bi-allelic variants: more than 5 unrelated families reported.

Mono-allelic variants:
DA3, more than 20 families reported.
Mendeliome v0.13387 RSPH1 Belinda Chong reviewed gene: RSPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23993197; Phenotypes: Ciliary dyskinesia, primary, 24 MIM#615481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13387 PIEZO2 Zornitza Stark reviewed gene: PIEZO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27653382, 27607563, 27843126, 27974811; Phenotypes: Marden-Walker syndrome (MIM#248700), Arthrogryposis, distal, type 3 (MIM#114300), Arthrogryposis, distal, type 5 (MIM#108145); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13387 BSCL2 Zornitza Stark Marked gene: BSCL2 as ready
Mendeliome v0.13387 BSCL2 Zornitza Stark Phenotypes for gene: BSCL2 were changed from to Neuropathy, distal hereditary motor, type VC, MIM# 619112; Encephalopathy, progressive, with or without lipodystrophy, MIM#615924; Lipodystrophy, congenital generalized, type 2, MIM# 269700; Silver spastic paraplegia syndrome, MIM# 270685; Developmental and epileptic encephalopathy, BSCL2-related, dominant, MONDO:0100062
Mendeliome v0.13384 BSCL2 Zornitza Stark edited their review of gene: BSCL2: Added comment: Multiple families reported with bi-allelic variants and isolated or syndromic lipodystrophy.

Mono-allelic variants and DEE: Two families reported with de novo variants in PMIDs 31369919 and 35290466. We are aware of further three individuals identified as a result of clinical testing, so a total of 4 with a change at position p.Pro149; Changed publications: 14981520, 15732094, 11479539, 15181077, 15126564, 23564749, 31369919, 35290466
Mendeliome v0.13384 BSCL2 Zornitza Stark edited their review of gene: BSCL2: Changed phenotypes: Neuropathy, distal hereditary motor, type VC, MIM# 619112, Encephalopathy, progressive, with or without lipodystrophy, MIM#615924, Lipodystrophy, congenital generalized, type 2, MIM# 269700, Silver spastic paraplegia syndrome, MIM# 270685, Developmental and epileptic encephalopathy, BSCL2-related, dominant, MONDO:0100062; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13384 CNNM2 Ain Roesley Marked gene: CNNM2 as ready
Mendeliome v0.13384 CNNM2 Ain Roesley Phenotypes for gene: CNNM2 were changed from to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418
Mendeliome v0.13382 CNNM2 Ain Roesley reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34604137, 35170241; Phenotypes: Hypomagnesemia 6, renal MIM#613882, Hypomagnesemia, seizures, and mental retardation MIM#616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13382 PIGC Zornitza Stark Marked gene: PIGC as ready
Mendeliome v0.13379 CNGB1 Ain Roesley Marked gene: CNGB1 as ready
Mendeliome v0.13377 CNGA1 Ain Roesley Marked gene: CNGA1 as ready
Mendeliome v0.13375 CLN8 Ain Roesley Marked gene: CLN8 as ready
Mendeliome v0.13375 CLN8 Ain Roesley Phenotypes for gene: CLN8 were changed from to Ceroid lipofuscinosis, neuronal, 8, MIM# 600143; Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant, MIM# 610003
Mendeliome v0.13374 CLN8 Ain Roesley reviewed gene: CLN8: Rating: GREEN; Mode of pathogenicity: None; Publications: 10508524, 15024724, 16570191; Phenotypes: Ceroid lipofuscinosis, neuronal, 8, MIM# 600143, Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant, MIM# 610003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13374 CLN6 Ain Roesley Marked gene: CLN6 as ready
Mendeliome v0.13372 CLEC7A Ain Roesley Marked gene: CLEC7A as ready
Mendeliome v0.13370 PIGW Zornitza Stark Marked gene: PIGW as ready
Mendeliome v0.13367 PIK3R2 Zornitza Stark Marked gene: PIK3R2 as ready
Mendeliome v0.13364 PITX2 Zornitza Stark Marked gene: PITX2 as ready
Mendeliome v0.13361 PITX3 Zornitza Stark Marked gene: PITX3 as ready
Mendeliome v0.13361 PITX3 Zornitza Stark Phenotypes for gene: PITX3 were changed from Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250; Cataract 11, multiple types, MIM# 610623; Microphthalmia to Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250; Cataract 11, multiple types, MIM# 610623; Microphthalmia MONDO:0021129
Mendeliome v0.13360 PITX3 Zornitza Stark Phenotypes for gene: PITX3 were changed from to Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250; Cataract 11, multiple types, MIM# 610623; Microphthalmia
Mendeliome v0.13357 PITX3 Zornitza Stark reviewed gene: PITX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29405783; Phenotypes: Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250, Cataract 11, multiple types, MIM# 610623, Microphthalmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13357 CLDN19 Zornitza Stark Phenotypes for gene: CLDN19 were changed from Hypomagnesemia 5, renal, with ocular involvement, MIM#248190 to Hypomagnesaemia 5, renal, with ocular involvement, MIM#248190
Mendeliome v0.13356 PEX11B Zornitza Stark Marked gene: PEX11B as ready
Mendeliome v0.13356 PEX11B Zornitza Stark Added comment: Comment when marking as ready: Two published families and one International.
Mendeliome v0.13353 PER2 Zornitza Stark Marked gene: PER2 as ready
Mendeliome v0.13349 PDZD7 Zornitza Stark Marked gene: PDZD7 as ready
Mendeliome v0.13346 PDYN Zornitza Stark Marked gene: PDYN as ready
Mendeliome v0.13346 PDYN Zornitza Stark Added comment: Comment when marking as ready: The presence of some of these variants in the population is concerning. However, functional data also supports gene-disease association.
Mendeliome v0.13346 PDYN Zornitza Stark Phenotypes for gene: PDYN were changed from to Spinocerebellar ataxia 23 - MIM#610245
Mendeliome v0.13343 PDGFRA Zornitza Stark Marked gene: PDGFRA as ready
Mendeliome v0.13340 RSPH3 Zornitza Stark Marked gene: RSPH3 as ready
Mendeliome v0.13340 RSPH3 Zornitza Stark Phenotypes for gene: RSPH3 were changed from to Ciliary dyskinesia, primary, 32 MIM#616481
Mendeliome v0.13337 RSPH4A Zornitza Stark Marked gene: RSPH4A as ready
Mendeliome v0.13337 RSPH4A Zornitza Stark Phenotypes for gene: RSPH4A were changed from to Ciliary dyskinesia, primary, 11, OMIM#612649
Mendeliome v0.13334 RSPH9 Zornitza Stark Marked gene: RSPH9 as ready
Mendeliome v0.13334 RSPH9 Zornitza Stark Phenotypes for gene: RSPH9 were changed from to Ciliary dyskinesia, primary, 12, MIM#612650
Mendeliome v0.13331 BVES Zornitza Stark Marked gene: BVES as ready
Mendeliome v0.13331 BVES Zornitza Stark Phenotypes for gene: BVES were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 25, MIM# 616812
Mendeliome v0.13327 BVES Zornitza Stark changed review comment from: PMID: 26642364 - 1 family (3 affecteds) with cardiac arrhythmia and limb-girdle muscular dystrophy. Supported by functional studies. The proband showed lower limb girdle weakness at ~40 years old with muscle biopsy proving dystrophic changes. His 2 affected grandchildren had onset in teenage years.

PMID: 32528171 - 1 patient with limb girdle weakness.

PMID: 31119192 - 3 families (4 affecteds) with limb-girdle muscular weakness and cardiac abnormalities/arrhythmia. All had onset in adulthood, with exercise intolerance or proximal weakness.; to: PMID: 26642364 - 1 family (3 affecteds) with cardiac arrhythmia and limb-girdle muscular dystrophy. Supported by functional studies: zebrafish model. The proband showed lower limb girdle weakness at ~40 years old with muscle biopsy proving dystrophic changes. His 2 affected grandchildren had onset in teenage years.

PMID: 32528171 - 1 patient with limb girdle weakness.

PMID: 31119192 - 3 families (4 affecteds) with limb-girdle muscular weakness and cardiac abnormalities/arrhythmia. All had onset in adulthood, with exercise intolerance or proximal weakness.
Mendeliome v0.13327 BVES Zornitza Stark reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: 26642364, 32528171, 31119192; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 25, MIM# 616812; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13327 FLII Bryony Thompson Phenotypes for gene: FLII were changed from Dilated cardiomyopathy to Dilated cardiomyopathy MONDO:0005021
Mendeliome v0.13326 CLDN19 Ain Roesley Marked gene: CLDN19 as ready
Mendeliome v0.13326 CLDN19 Ain Roesley Phenotypes for gene: CLDN19 were changed from to Hypomagnesemia 5, renal, with ocular involvement, MIM#248190
Mendeliome v0.13324 CLDN19 Ain Roesley reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033971, 22422540, 27530400]; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM#248190; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13324 CLDN16 Ain Roesley Marked gene: CLDN16 as ready
Mendeliome v0.13323 CLDN1 Ain Roesley Marked gene: CLDN1 as ready
Mendeliome v0.13322 CLCNKB Ain Roesley Marked gene: CLCNKB as ready
Mendeliome v0.13322 CLCNKB Ain Roesley Phenotypes for gene: CLCNKB were changed from to Bartter syndrome, type 3, MIM# 607364; Bartter syndrome, type 4b, digenic, MIM# 613090
Mendeliome v0.13320 CLCNKB Ain Roesley reviewed gene: CLCNKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 9326936, 15044642, 18310267; Phenotypes: Bartter syndrome, type 3, MIM# 607364, Bartter syndrome, type 4b, digenic, MIM# 613090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13320 CLCF1 Ain Roesley Marked gene: CLCF1 as ready
Mendeliome v0.13318 CIT Ain Roesley Marked gene: CIT as ready
Mendeliome v0.13317 CIT Ain Roesley Phenotypes for gene: CIT were changed from Microcephaly 17, primary, autosomal recessive (MIM#617090) to Microcephaly 17, primary, autosomal recessive (MIM#617090)
Mendeliome v0.13317 CIT Ain Roesley Phenotypes for gene: CIT were changed from to Microcephaly 17, primary, autosomal recessive (MIM#617090)
Mendeliome v0.13315 CIT Ain Roesley reviewed gene: CIT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27453578, 27503289, 27453579; Phenotypes: Microcephaly 17, primary, autosomal recessive (MIM#617090); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13315 CISH Ain Roesley Marked gene: CISH as ready
Mendeliome v0.13314 CISD2 Ain Roesley Marked gene: CISD2 as ready
Mendeliome v0.13313 CILP Ain Roesley Marked gene: CILP as ready
Mendeliome v0.13312 PDYN Krithika Murali reviewed gene: PDYN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301317, 23471613, 23108490, 22243190, 22287014; Phenotypes: Spinocerebellar ataxia 23 - MIM#610245; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13312 CIC Ain Roesley Marked gene: CIC as ready
Mendeliome v0.13310 CHST14 Ain Roesley Marked gene: CHST14 as ready
Mendeliome v0.13308 CHRNA2 Ain Roesley Marked gene: CHRNA2 as ready
Mendeliome v0.13306 CHRM2 Ain Roesley Marked gene: CHRM2 as ready
Mendeliome v0.13306 CHRM2 Ain Roesley Phenotypes for gene: CHRM2 were changed from to Familial Dilated Cardiomyopathy MONDO#0016333, CHRM2-related
Mendeliome v0.13304 CHRM2 Ain Roesley reviewed gene: CHRM2: Rating: RED; Mode of pathogenicity: None; Publications: 23743182, 18451336; Phenotypes: Familial Dilated Cardiomyopathy MONDO#0016333, CHRM2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13304 CHN1 Ain Roesley Marked gene: CHN1 as ready
Mendeliome v0.13302 CHN1 Ain Roesley Mode of pathogenicity for gene: CHN1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.13301 CHN1 Ain Roesley reviewed gene: CHN1: 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: 20301369; Phenotypes: Duane retraction syndrome 2,MIM#604356; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13301 CHMP4B Ain Roesley Marked gene: CHMP4B as ready
Mendeliome v0.13301 CHMP4B Ain Roesley Phenotypes for gene: CHMP4B were changed from to Cataract 31, multiple types MIM#605387
Mendeliome v0.13299 CHMP4B Ain Roesley reviewed gene: CHMP4B: Rating: GREEN; Mode of pathogenicity: None; Publications: 34722561, 17701905, 10682967, 30078984; Phenotypes: Cataract 31, multiple types MIM#605387; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13299 CHM Ain Roesley Marked gene: CHM as ready
Mendeliome v0.13297 CHIT1 Ain Roesley Marked gene: CHIT1 as ready
Mendeliome v0.13297 PDGFRA Krithika Murali changed review comment from: ?Suitability for Incidentalome versus Mendeliome based on adult age of diagnosis in reported cases.

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Six unrelated families reported with heterozygous germline variants associated with familial GIST and/or inflammatory fibroid polyps - IFP (benign lesions caused by excessive tissue proliferation and inflammatory cell infiltration into the lumen of the GI tract). Note that reported individuals diagnosed as adults. One individual reported with diagnosis of gastric mass/polyps age 22 (in 1977) raising the possibility of pre-symptomatic disease onset in adolescence. Green PanelApp England in the following panels: tumour predisposition - childhood onset; inherited predisposition to GIST; sarcoma cancer susceptibility.

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PMID 34107389 Hodan et al 2021 - report a 35 yo F with jejunal IFP and a heterozygous germline missense PDGFRA variant (c.1664A>G p.Y555C) . The variant segregated with 3 relatives with confirmed IFPs. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This variant was also reported in an unrelated family with multiple IFPs in 2006.

PMID 29486293 Manley et al 2018 - proband is a 50 yo M with multiple ileal intusussceptions and IFPs and GIST. Heterozygous D846V germline variant identified. Variant identified in daughter and 2 siblings. Coarser face, coarser skin, broader hands and feet, unexplained premature loss of teeth requiring dentures in their 40s described in relatives with the variant, no polyps or tumour identified in screened family members. Pdgfra +/K mutant mice recapitulated the human phenotype. Mice with the constitutively activated mutant PDGFRA shown to have diffuse expansion of the gastrointestinal submucosa, which exhibits an increased number of spindled fibroblast-like cells and marked collagen deposition. Mutant mice also develop intestinal polyps morphologically similar to IFPs. The Pdgfra +/K mice also exhibit thickened skin due to excess collagen deposition within the dermis and subcutaneous tissues.

PMID 25975287 Ricci et al 2015 - report a family with het germline P653L PDGFRA missense variant. The proband was a 67 yo M with multiple intra-abdominal GIST and gastric/colonic inflammatory fibroid polyps. Multiple adult relatives (youngest age 31) were diagnosed with IFPs/fibrous tumours with the variant segregating with disease.

PMID: 18670346 Carney et al 2008 and PMID: 17566086 Pasini et al 2007 - heterozygous germline PDGFRA mutation (V561D) in an individual with GIST and multiple polyps, diagnosed initially aged 22 with multiple GIST/polyps. No other relatives available for genotyping and no other significant family history reported.

PMID: 17087943 de Raedt et al 2006 - heterozygous PDGFRA(Y555C) variant reported in a family with multiple relatives affected by IFP, including one death from secondary bowel obstruction age 35.

PMID: 14699510 Chompret et al 2004 - Heterozygous c.2675G>T D846Y germline variant detected in a French family with 5 relatives developing adult-onset GIST, variant segregated with disease.

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Gain of function somatic variants associated with sporadic GIST. Somatic chromosomal rearrangements resulting in PDGFRA and FIP1L1 gene fusion associated with idiopathic hypereosinophilic syndrome.; to: Six unrelated families reported with heterozygous germline variants associated with familial GIST and/or inflammatory fibroid polyps - IFP (benign lesions caused by excessive tissue proliferation and inflammatory cell infiltration into the lumen of the GI tract). Note that reported individuals diagnosed as adults. One individual reported with diagnosis of gastric mass/polyps age 22 (in 1977) raising the possibility of pre-symptomatic disease onset in adolescence. Green PanelApp England in the following panels: tumour predisposition - childhood onset; inherited predisposition to GIST; sarcoma cancer susceptibility.

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PMID 34107389 Hodan et al 2021 - report a 35 yo F with jejunal IFP and a heterozygous germline missense PDGFRA variant (c.1664A>G p.Y555C) . The variant segregated with 3 relatives with confirmed IFPs. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This variant was also reported in an unrelated family with multiple IFPs in 2006.

PMID 29486293 Manley et al 2018 - proband is a 50 yo M with multiple ileal intusussceptions and IFPs and GIST. Heterozygous D846V germline variant identified. Variant identified in daughter and 2 siblings. Coarser face, coarser skin, broader hands and feet, unexplained premature loss of teeth requiring dentures in their 40s described in relatives with the variant, no polyps or tumour identified in screened family members. Pdgfra +/K mutant mice recapitulated the human phenotype. Mice with the constitutively activated mutant PDGFRA shown to have diffuse expansion of the gastrointestinal submucosa, which exhibits an increased number of spindled fibroblast-like cells and marked collagen deposition. Mutant mice also develop intestinal polyps morphologically similar to IFPs. The Pdgfra +/K mice also exhibit thickened skin due to excess collagen deposition within the dermis and subcutaneous tissues.

PMID 25975287 Ricci et al 2015 - report a family with het germline P653L PDGFRA missense variant. The proband was a 67 yo M with multiple intra-abdominal GIST and gastric/colonic inflammatory fibroid polyps. Multiple adult relatives (youngest age 31) were diagnosed with IFPs/fibrous tumours with the variant segregating with disease.

PMID: 18670346 Carney et al 2008 and PMID: 17566086 Pasini et al 2007 - heterozygous germline PDGFRA mutation (V561D) in an individual with GIST and multiple polyps, diagnosed initially aged 22 with multiple GIST/polyps. No other relatives available for genotyping and no other significant family history reported.

PMID: 17087943 de Raedt et al 2006 - heterozygous PDGFRA(Y555C) variant reported in a family with multiple relatives affected by IFP, including one death from secondary bowel obstruction age 35.

PMID: 14699510 Chompret et al 2004 - Heterozygous c.2675G>T D846Y germline variant detected in a French family with 5 relatives developing adult-onset GIST, variant segregated with disease.

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Gain of function somatic variants associated with sporadic GIST. Somatic chromosomal rearrangements resulting in PDGFRA and FIP1L1 gene fusion associated with idiopathic hypereosinophilic syndrome.
Mendeliome v0.13296 CHD1 Ain Roesley Marked gene: CHD1 as ready
Mendeliome v0.13296 CHD1 Ain Roesley Phenotypes for gene: CHD1 were changed from to Pilarowski-Bjornsson syndrome, MIM#617682
Mendeliome v0.13294 CHD1 Ain Roesley reviewed gene: CHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28866611; Phenotypes: Pilarowski-Bjornsson syndrome, MIM#617682; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13294 CFP Ain Roesley Marked gene: CFP as ready
Mendeliome v0.13292 CFI Ain Roesley Marked gene: CFI as ready
Mendeliome v0.13292 CFI Ain Roesley Marked gene: CFI as ready
Mendeliome v0.13289 RSPH3 Belinda Chong reviewed gene: RSPH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26073779; Phenotypes: Ciliary dyskinesia, primary, 32 MIM#616481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13289 HSPG2 Zornitza Stark changed review comment from: Allelic disorders with some phenotypic overlap.

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia; blepharophimosis is a key feature. More than 20 families reported.

Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage. Two families reported.; to: Allelic disorders with some phenotypic overlap.

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia; blepharophimosis is a key feature. More than 20 families reported.

Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage. Two families reported. Appears associated with null variants.
Mendeliome v0.13289 PKD1 Zornitza Stark Marked gene: PKD1 as ready
Mendeliome v0.13287 PKD2 Zornitza Stark Marked gene: PKD2 as ready
Mendeliome v0.13285 PKLR Zornitza Stark Marked gene: PKLR as ready
Mendeliome v0.13282 PKP1 Zornitza Stark Marked gene: PKP1 as ready
Mendeliome v0.13279 PLA2G5 Zornitza Stark Marked gene: PLA2G5 as ready
Mendeliome v0.13276 PLCE1 Zornitza Stark Marked gene: PLCE1 as ready
Mendeliome v0.13273 PLCG2 Zornitza Stark Marked gene: PLCG2 as ready
Mendeliome v0.13273 PLCG2 Zornitza Stark Phenotypes for gene: PLCG2 were changed from to Common variable immunodeficiency; Autoinflammation, antibody deficiency, and immune dysregulation syndrome MIM#614878
Mendeliome v0.13266 PLEKHM1 Zornitza Stark changed review comment from: Three individuals reported with mono allelic variants, and one with bi-allelic. Animal model.; to: Three individuals reported with mono allelic variants, and two with bi-allelic. Animal models.
Mendeliome v0.13266 PLEKHM1 Zornitza Stark Marked gene: PLEKHM1 as ready
Mendeliome v0.13263 RSPH4A Belinda Chong changed review comment from: Radial spokes are regularly spaced along cilia, sperm, and flagella axonemes and have a multisubunit 'stalk' and 'head' that form a signal transduction scaffold between the central microtubule pair and dynein arms. RSPH4A is predicted to be a component of the radial spoke head based on homology with proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates (Castleman et al., 2009; PMID19200523)

9 families with primary ciliary dyskinesia without situs inversus (Kott et al. 2013 (PMID:23993197), Castleman et al., 2009 (PMID19200523) and Daniels et al. 2013; (PMID:23798057)):
- In affected members of 4 Pakistani families with CILD11, Castleman et al. (2009) identified a homozygous mutation in the RSPH4A gene.
- In affected members of a family of northern European descent with CILD11, Castleman et al. (2009) identified compound heterozygosity for 2 mutations in the RSPH4A gene
- Kott et al. (2013) identified pathogenic mutations in the RSPH4A gene in 7 (14%) of 48 families with a specific CILD.

Common founder mutation:
- Daniels et al. (2013) identified a common founder mutation in the RSPH4A gene in 9 patients with CILD11, all of whom had Puerto Rican ancestry.

Multiple individuals in ClinVar with primary ciliary dyskinesia; to: Radial spokes are regularly spaced along cilia, sperm, and flagella axonemes and have a multisubunit 'stalk' and 'head' that form a signal transduction scaffold between the central microtubule pair and dynein arms. RSPH4A is predicted to be a component of the radial spoke head based on homology with proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates (Castleman et al., 2009; PMID19200523)

9 families with primary ciliary dyskinesia without situs inversus (Kott et al. 2013 (PMID:23993197), Castleman et al., 2009 (PMID19200523) and Daniels et al. 2013; (PMID:23798057)):
- In affected members of 4 Pakistani families with CILD11, Castleman et al. (2009) identified a homozygous mutation in the RSPH4A gene.
- In affected members of a family of northern European descent with CILD11, Castleman et al. (2009) identified compound heterozygosity for 2 mutations in the RSPH4A gene
- Kott et al. (2013) identified pathogenic mutations in the RSPH4A gene in 7 (14%) of 48 families with a specific CILD.

Common founder mutation:
- Daniels et al. (2013) identified a common founder mutation in the RSPH4A gene in 9 patients with CILD11, all of whom had Puerto Rican ancestry.

Multiple individuals in ClinVar with primary ciliary dyskinesia

PMID: 25789548; Frommer 2015: 8 PCD families reported, only 4 different variants identified. Functional studies performed.

PMID: 22448264; Ziętkiewicz 2012: 4 additional families/variants reported.
Mendeliome v0.13263 RSPH4A Belinda Chong reviewed gene: RSPH4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23798057, 23798057, 23798057; Phenotypes: Ciliary dyskinesia, primary, 11 OMIM#612649; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13263 RSPH9 Belinda Chong reviewed gene: RSPH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25789548, 22384920, 23993197, 19200523, 27626380; Phenotypes: Ciliary dyskinesia, primary, 12 MIM#612650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13263 PLN Zornitza Stark Marked gene: PLN as ready
Mendeliome v0.13263 PLN Zornitza Stark Phenotypes for gene: PLN were changed from to Cardiomyopathy, dilated, 1P, MIM# 609909; Cardiomyopathy, hypertrophic, 18 (MIM #613874)
Mendeliome v0.13260 PLN Zornitza Stark reviewed gene: PLN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33947203; Phenotypes: Cardiomyopathy, dilated, 1P, MIM# 609909, Cardiomyopathy, hypertrophic, 18 (MIM #613874); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13260 PLOD1 Zornitza Stark Marked gene: PLOD1 as ready
Mendeliome v0.13257 PLOD2 Zornitza Stark Marked gene: PLOD2 as ready
Mendeliome v0.13254 PMFBP1 Zornitza Stark Marked gene: PMFBP1 as ready
Mendeliome v0.13251 PMPCA Zornitza Stark Marked gene: PMPCA as ready
Mendeliome v0.13251 PMPCA Zornitza Stark Phenotypes for gene: PMPCA were changed from to Spinocerebellar ataxia, autosomal recessive 2, MIM# 213200
Mendeliome v0.13248 PMPCA Zornitza Stark reviewed gene: PMPCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25808372, 26657514, 33272776, 30617178; Phenotypes: Spinocerebellar ataxia, autosomal recessive 2, MIM# 213200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13248 PMPCB Zornitza Stark Marked gene: PMPCB as ready
Mendeliome v0.13245 PNPO Zornitza Stark Marked gene: PNPO as ready
Mendeliome v0.13242 PODXL Zornitza Stark Marked gene: PODXL as ready
Mendeliome v0.13239 POFUT1 Zornitza Stark Marked gene: POFUT1 as ready
Mendeliome v0.13236 POLG Zornitza Stark Marked gene: POLG as ready
Mendeliome v0.13233 POMGNT1 Zornitza Stark Marked gene: POMGNT1 as ready
Mendeliome v0.13233 POMGNT1 Zornitza Stark Phenotypes for gene: POMGNT1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 MIM#614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 MIM#618135; Retinitis pigmentosa 76 617123
Mendeliome v0.13230 POMGNT1 Zornitza Stark reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27391550, 26908613, 30961548, 30937090; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 MIM#614830, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 MIM#618135, Retinitis pigmentosa 76 617123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13230 POMGNT2 Zornitza Stark Marked gene: POMGNT2 as ready
Mendeliome v0.13230 POMGNT2 Zornitza Stark Phenotypes for gene: POMGNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, MIM# 614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, MIM# 618135
Mendeliome v0.13227 POMGNT2 Zornitza Stark reviewed gene: POMGNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34301702, 27066570, 26060116, 22958903; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, MIM# 614830, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, MIM# 618135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13227 POMK Zornitza Stark Marked gene: POMK as ready
Mendeliome v0.13227 POMK Zornitza Stark Phenotypes for gene: POMK were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 12, MIM# 615249; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 12, MIM# 616094
Mendeliome v0.13224 POMK Zornitza Stark reviewed gene: POMK: Rating: GREEN; Mode of pathogenicity: None; Publications: 32907597, 31833209, 29910097, 28109637, 24925318, 24556084; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 12, MIM# 615249, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 12, MIM# 616094; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13224 RAX2 Zornitza Stark Marked gene: RAX2 as ready
Mendeliome v0.13221 RASA1 Zornitza Stark Marked gene: RASA1 as ready
Mendeliome v0.13220 PDX1 Zornitza Stark Marked gene: PDX1 as ready
Mendeliome v0.13220 PDX1 Zornitza Stark Phenotypes for gene: PDX1 were changed from to Pancreatic agenesis 1 - MIM#260370 (AR); MODY, type IV - MIM#606392(AD)
Mendeliome v0.13215 PDP1 Zornitza Stark Marked gene: PDP1 as ready
Mendeliome v0.13212 PDHB Zornitza Stark Marked gene: PDHB as ready
Mendeliome v0.13210 RSPO1 Zornitza Stark Marked gene: RSPO1 as ready
Mendeliome v0.13210 RSPO1 Zornitza Stark Phenotypes for gene: RSPO1 were changed from to Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644; Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644
Mendeliome v0.13203 PDHA1 Zornitza Stark Marked gene: PDHA1 as ready
Mendeliome v0.13200 PDE6H Zornitza Stark Marked gene: PDE6H as ready
Mendeliome v0.13197 PDE6G Zornitza Stark Marked gene: PDE6G as ready
Mendeliome v0.13193 PDE6C Zornitza Stark Marked gene: PDE6C as ready
Mendeliome v0.13190 PDE6B Zornitza Stark Marked gene: PDE6B as ready
Mendeliome v0.13190 PDE6B Zornitza Stark Phenotypes for gene: PDE6B were changed from to Night blindness, congenital stationary, autosomal dominant 2 - MIM#163500; Retinitis pigmentosa-40 - MIM#613801
Mendeliome v0.13187 PDE6A Zornitza Stark Marked gene: PDE6A as ready
Mendeliome v0.13184 PDE4D Zornitza Stark Marked gene: PDE4D as ready
Mendeliome v0.13181 PDE3A Zornitza Stark Marked gene: PDE3A as ready
Mendeliome v0.13179 PDE11A Zornitza Stark Marked gene: PDE11A as ready
Mendeliome v0.13179 PDE11A Zornitza Stark Phenotypes for gene: PDE11A were changed from to Pigmented nodular adrenocortical disease, primary, 2 - MIM#610475
Mendeliome v0.13175 SHH Zornitza Stark Marked gene: SHH as ready
Mendeliome v0.13175 SHH Zornitza Stark Added comment: Comment when marking as ready: DISPUTED association with schizencephaly
Mendeliome v0.13175 SHH Zornitza Stark Phenotypes for gene: SHH were changed from to Holoprosencephaly 3, MIM#142945; Microphthalmia with coloboma 5, MIM#611638; Single median maxillary central incisor, MIM#147250
Mendeliome v0.13172 FAM111B Zornitza Stark reviewed gene: FAM111B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary sclerosing poikiloderma with tendon and pulmonary involvement MONDO:0014310; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13172 SH3BP2 Zornitza Stark commented on gene: SH3BP2: Cherubism is characterized by a loss of bone, restricted to the jaws, and by the replacement of this bone with fibrous tissues, leading to facial swelling. Involvement of the infraorbital rim and the orbital floor leads to the upward tilting of the eyeballs and consequent exposure of the inferior part of the sclerae, giving a 'cherubic' appearance. Submandibular lymph node enlargement is often reported. Functional impairment includes mastication and speech problems, tooth alterations, and loss of normal vision. Onset of the disease is usually between 14 months and 4 years of age. The disease progresses through puberty, then stabilizes, and in some cases regresses without treatment.
Mendeliome v0.13172 SH3BP2 Zornitza Stark Marked gene: SH3BP2 as ready
Mendeliome v0.13170 SH3BP2 Zornitza Stark Mode of pathogenicity for gene: SH3BP2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.13168 SH3BP2 Zornitza Stark reviewed gene: SH3BP2: 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: ; Phenotypes: Cherubism, MIM#118400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13167 TLR8 Zornitza Stark Phenotypes for gene: TLR8 were changed from Immunodeficiency; bone marrow failure; Autoinflammatory syndrome MONDO:0019751 to Immunodeficiency 98 with autoinflammation, X-linked, MIM# 301078
Mendeliome v0.13159 CDKN1B Zornitza Stark Marked gene: CDKN1B as ready
Mendeliome v0.13158 DNAJB11 Elena Savva reviewed gene: DNAJB11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34177435, 29706351, 29777155, 33129895; Phenotypes: Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061, Ivermark II syndrome, Prenatal Polycystic Kidney Disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.13157 SLC12A3 Zornitza Stark Marked gene: SLC12A3 as ready
Mendeliome v0.13153 PIDD1 Zornitza Stark Phenotypes for gene: PIDD1 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum to Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827
Mendeliome v0.13152 PIDD1 Zornitza Stark edited their review of gene: PIDD1: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827
Mendeliome v0.13152 SLC12A1 Zornitza Stark Marked gene: SLC12A1 as ready
Mendeliome v0.13152 SLC12A1 Zornitza Stark Phenotypes for gene: SLC12A1 were changed from to Bartter syndrome, type 1, MIM# 601678
Mendeliome v0.13149 SLC12A1 Zornitza Stark reviewed gene: SLC12A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8640224, 9355073, 28095294; Phenotypes: Bartter syndrome, type 1, MIM# 601678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13149 FGF23 Bryony Thompson Marked gene: FGF23 as ready
Mendeliome v0.13147 PDX1 Krithika Murali reviewed gene: PDX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9326926, 10545531, 10720084, 12970316, 20009086, 19496967; Phenotypes: Pancreatic agenesis 1 - MIM#260370 (AR), MODY, type IV - MIM#606392(AD); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13144 FGF14 Bryony Thompson Phenotypes for gene: FGF14 were changed from Spinocerebellar ataspinocerebellar ataxia type 27 MONDO:0012247; hereditary episodic ataxia MONDO:0016227xia 27 MIM#609307 to Spinocerebellar ataspinocerebellar ataxia type 27 MONDO:0012247; hereditary episodic ataxia MONDO:0016227
Mendeliome v0.13142 FGF14 Bryony Thompson Phenotypes for gene: FGF14 were changed from Spinocerebellar ataxia 27 MIM#609307 to Spinocerebellar ataspinocerebellar ataxia type 27 MONDO:0012247; hereditary episodic ataxia MONDO:0016227xia 27 MIM#609307
Mendeliome v0.13141 FGF14 Bryony Thompson edited their review of gene: FGF14: Added comment: 4 families with spinocerebellar ataxia and 7 families with episodic ataxia. Supporting animal models for both SCA and EA.; Changed publications: 12123606, 12489043, 15470364, 29253853, 30017992, 32112487, 32162847; Changed phenotypes: spinocerebellar ataxia type 27 MONDO:0012247, hereditary episodic ataxia MONDO:0016227; Set current diagnostic: yes
Mendeliome v0.13141 FGF10 Bryony Thompson Marked gene: FGF10 as ready
Mendeliome v0.13141 FGF10 Bryony Thompson Phenotypes for gene: FGF10 were changed from to congenital alveolar dysplasia due to FGF10 MONDO:0100090; acinar dysplasia caused by mutation in FGF10 MONDO:0600017
Mendeliome v0.13138 FGF10 Bryony Thompson reviewed gene: FGF10: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916808, 15654336, 16501574, 16630169, 17213838, 33967277, 30639323; Phenotypes: congenital alveolar dysplasia due to FGF10 MONDO:0100090, acinar dysplasia caused by mutation in FGF10 MONDO:0600017; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13138 FFAR4 Bryony Thompson Marked gene: FFAR4 as ready
Mendeliome v0.13138 FFAR4 Bryony Thompson Gene: ffar4 has been classified as Red List (Low Evidence).
Mendeliome v0.13138 FFAR4 Bryony Thompson Phenotypes for gene: FFAR4 were changed from to {Obesity, susceptibility to} MIM#607514
Mendeliome v0.13137 FFAR4 Bryony Thompson Publications for gene: FFAR4 were set to
Mendeliome v0.13136 FFAR4 Bryony Thompson Classified gene: FFAR4 as Red List (low evidence)
Mendeliome v0.13136 FFAR4 Bryony Thompson Gene: ffar4 has been classified as Red List (Low Evidence).
Mendeliome v0.13135 FFAR4 Bryony Thompson reviewed gene: FFAR4: Rating: RED; Mode of pathogenicity: None; Publications: 22343897, 34043793; Phenotypes: {Obesity, susceptibility to} MIM#607514; Mode of inheritance: Unknown
Mendeliome v0.13135 FDX2 Bryony Thompson Marked gene: FDX2 as ready
Mendeliome v0.13132 FDFT1 Bryony Thompson Marked gene: FDFT1 as ready
Mendeliome v0.13129 FBXO7 Bryony Thompson Marked gene: FBXO7 as ready
Mendeliome v0.13129 FBXO7 Bryony Thompson Phenotypes for gene: FBXO7 were changed from to parkinsonian-pyramidal syndrome MONDO:0009830
Mendeliome v0.13125 FBXO7 Bryony Thompson reviewed gene: FBXO7: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513678, 19038853, 34781237; Phenotypes: parkinsonian-pyramidal syndrome MONDO:0009830; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13125 RSPO1 Belinda Chong reviewed gene: RSPO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17041600, 18085567, 18250098, 18250097; Phenotypes: Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644, Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13125 FBP1 Bryony Thompson Marked gene: FBP1 as ready
Mendeliome v0.13121 FBP1 Bryony Thompson changed review comment from: Well-established gene-disease association. Fructose-1,6-bisphosphatase (FBP1) deficiency is metabolic disorder characterised by episodic acute crises of lactic acidosis and ketotic hypoglycaemia, manifesting as hyperventilation, apneic spells, seizures, and/or coma. Both SNVs and CNVs have been reported.; to: Well-established gene-disease association. Fructose-1,6-bisphosphatase (FBP1) deficiency is a metabolic disorder characterised by episodic acute crises of lactic acidosis and ketotic hypoglycaemia, manifesting as hyperventilation, apneic spells, seizures, and/or coma. Both SNVs and CNVs have been reported.
Mendeliome v0.13121 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.13120 CLPB Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835, Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.13120 GLRA2 Zornitza Stark Marked gene: GLRA2 as ready
Mendeliome v0.13119 GLRA2 Zornitza Stark gene: GLRA2 was added
gene: GLRA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GLRA2 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: GLRA2 were set to 26370147; 20479760; 35294868
Phenotypes for gene: GLRA2 were set to Intellectual developmental disorder, X-linked, syndromic, Pilorge type, MIM# 301076
Review for gene: GLRA2 was set to GREEN
Added comment: More than 10 unrelated families reported. Both males and females affected, though some mothers are asymptomatic or mild. Zebrafish model.
Sources: Expert list
Mendeliome v0.13117 FASTKD2 Bryony Thompson Marked gene: FASTKD2 as ready
Mendeliome v0.13115 FASLG Bryony Thompson Marked gene: FASLG as ready
Mendeliome v0.13112 FAS Bryony Thompson Marked gene: FAS as ready
Mendeliome v0.13109 FARSB Bryony Thompson Marked gene: FARSB as ready
Mendeliome v0.13109 FARSB Bryony Thompson Gene: farsb has been classified as Green List (High Evidence).
Mendeliome v0.13109 FARSB Bryony Thompson Phenotypes for gene: FARSB were changed from to Rajab interstitial lung disease with brain calcifications 1 MONDO:0100215
Mendeliome v0.13108 FARSB Bryony Thompson Publications for gene: FARSB were set to
Mendeliome v0.13107 FARSB Bryony Thompson Mode of inheritance for gene: FARSB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13106 FARSB Bryony Thompson reviewed gene: FARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573043, 30014610, 29979980; Phenotypes: Rajab interstitial lung disease with brain calcifications 1 MONDO:0100215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13106 FARS2 Bryony Thompson Marked gene: FARS2 as ready
Mendeliome v0.13106 FARS2 Bryony Thompson Gene: fars2 has been classified as Green List (High Evidence).
Mendeliome v0.13106 FARS2 Bryony Thompson Phenotypes for gene: FARS2 were changed from to combined oxidative phosphorylation defect type 14 MONDO:0013986; hereditary spastic paraplegia 77 MONDO:0014882
Mendeliome v0.13105 FARS2 Bryony Thompson Publications for gene: FARS2 were set to
Mendeliome v0.13104 FARS2 Bryony Thompson Mode of inheritance for gene: FARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13103 FARS2 Bryony Thompson reviewed gene: FARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30250868, 30177229, 29126765, 28043061; Phenotypes: combined oxidative phosphorylation defect type 14 MONDO:0013986, hereditary spastic paraplegia 77 MONDO:0014882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13103 FAM58A Bryony Thompson Marked gene: FAM58A as ready
Mendeliome v0.13100 PDE6B Krithika Murali reviewed gene: PDE6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 8394174, 8075643, 17044014, 7599633, 18854872; Phenotypes: Night blindness, congenital stationary, autosomal dominant 2 - MIM#163500, Retinitis pigmentosa-40 - MIM#613801; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13100 FAM161A Bryony Thompson Marked gene: FAM161A as ready
Mendeliome v0.13100 PDE11A Krithika Murali reviewed gene: PDE11A: Rating: RED; Mode of pathogenicity: None; Publications: 16767104, 18559625, 21047926, 17178847; Phenotypes: Pigmented nodular adrenocortical disease, primary, 2 - MIM#610475; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13097 FAM126A Bryony Thompson Marked gene: FAM126A as ready
Mendeliome v0.13096 SHH Samantha Ayres reviewed gene: SHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 21976454, 12503095, 22791840, 19057928, 19533790; Phenotypes: Holoprosencephaly 3, MIM#142945, Microphthalmia with coloboma 5, MIM#611638, Schizencephaly, MIM#269160, Single median maxillary central incisor, MIM#147250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13094 FAM111B Bryony Thompson Marked gene: FAM111B as ready
Mendeliome v0.13094 FAM111B Bryony Thompson Phenotypes for gene: FAM111B were changed from to hereditary sclerosing poikiloderma with tendon and pulmonary involvement MONDO:0014310
Mendeliome v0.13090 FAM111B Bryony Thompson reviewed gene: FAM111B: Rating: ; Mode of pathogenicity: Other; Publications: 24268661, 26471370, 26495788, 27406236; Phenotypes: hereditary sclerosing poikiloderma with tendon and pulmonary involvement MONDO:0014310; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.13090 FAM111A Bryony Thompson Marked gene: FAM111A as ready
Mendeliome v0.13086 FADD Bryony Thompson Marked gene: FADD as ready
Mendeliome v0.13085 FAH Bryony Thompson Marked gene: FAH as ready
Mendeliome v0.13080 F12 Bryony Thompson Marked gene: F12 as ready
Mendeliome v0.13080 F12 Bryony Thompson Phenotypes for gene: F12 were changed from to Hereditary angioedema type 3 MONDO:0012526
Mendeliome v0.13078 POMP Zornitza Stark Marked gene: POMP as ready
Mendeliome v0.13078 POMP Zornitza Stark Phenotypes for gene: POMP were changed from to Keratosis linearis with ichthyosis congenita and sclerosing keratoderma MIM#601952; Proteasome-associated autoinflammatory syndrome 2, MIM# 618048
Mendeliome v0.13075 POMP Zornitza Stark reviewed gene: POMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 20226437, 27503413, 29805043; Phenotypes: Keratosis linearis with ichthyosis congenita and sclerosing keratoderma MIM#601952, Proteasome-associated autoinflammatory syndrome 2, MIM# 618048; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.13075 POMT1 Zornitza Stark Marked gene: POMT1 as ready
Mendeliome v0.13075 POMT1 Zornitza Stark Phenotypes for gene: POMT1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 1 613155; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308
Mendeliome v0.13073 POMT1 Zornitza Stark reviewed gene: POMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 1 613155, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13073 POMT2 Zornitza Stark Marked gene: POMT2 as ready
Mendeliome v0.13073 POMT2 Zornitza Stark Phenotypes for gene: POMT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 2 613150; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 2 613156; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 2 613158
Mendeliome v0.13071 POMT2 Zornitza Stark edited their review of gene: POMT2: Changed phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 2 613150, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 2 613156, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 2 613158
Mendeliome v0.13071 POMT2 Zornitza Stark reviewed gene: POMT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 2 613150 Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 2 613156 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 2 613158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13071 PPARA Zornitza Stark Marked gene: PPARA as ready
Mendeliome v0.13071 PPARA Zornitza Stark Gene: ppara has been classified as Red List (Low Evidence).
Mendeliome v0.13071 PPARA Zornitza Stark Phenotypes for gene: PPARA were changed from to {Hyperapobetalipoproteinemia, susceptibility to}
Mendeliome v0.13070 PPARA Zornitza Stark Mode of inheritance for gene: PPARA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13069 PPARA Zornitza Stark Classified gene: PPARA as Red List (low evidence)
Mendeliome v0.13069 PPARA Zornitza Stark Gene: ppara has been classified as Red List (Low Evidence).
Mendeliome v0.13068 PPARA Zornitza Stark reviewed gene: PPARA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Hyperapobetalipoproteinemia, susceptibility to}; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13068 PPM1K Zornitza Stark Marked gene: PPM1K as ready
Mendeliome v0.13068 PPM1K Zornitza Stark Phenotypes for gene: PPM1K were changed from to Maple syrup urine disease, mild variant, MIM#615135
Mendeliome v0.13064 PPM1K Zornitza Stark reviewed gene: PPM1K: Rating: RED; Mode of pathogenicity: None; Publications: 23086801; Phenotypes: Maple syrup urine disease, mild variant, MIM#615135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13064 PPOX Zornitza Stark Marked gene: PPOX as ready
Mendeliome v0.13064 PPOX Zornitza Stark Phenotypes for gene: PPOX were changed from to Porphyria variegata , MIM#176200
Mendeliome v0.13061 PPOX Zornitza Stark reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 12357337, 32247286, 23324528, 27982422; Phenotypes: Porphyria variegata , MIM#176200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13061 PPP1R15B Zornitza Stark Marked gene: PPP1R15B as ready
Mendeliome v0.13061 SGCG Samantha Ayres reviewed gene: SGCG: Rating: GREEN; Mode of pathogenicity: None; Publications: 18285821, 8923014, 7481775, 8968757, 27708273; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 5 MIM#253700, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13061 CFHR5 Ain Roesley Marked gene: CFHR5 as ready
Mendeliome v0.13059 CFH Ain Roesley Marked gene: CFH as ready
Mendeliome v0.13059 CFH Ain Roesley Phenotypes for gene: CFH were changed from to Basal laminar drusen MIM#126700; Complement factor H deficiency MIM#609814; {Hemolytic uremic syndrome, atypical, susceptibility to, 1} MIMI#235400
Mendeliome v0.13058 CFH Ain Roesley reviewed gene: CFH: Rating: GREEN; Mode of pathogenicity: None; Publications: 27572114, 25814826, 20301541, 9312129, 10803850, 29888403, 30905644; Phenotypes: Basal laminar drusen MIM#126700, Complement factor H deficiency MIM#609814, {Hemolytic uremic syndrome, atypical, susceptibility to, 1} MIMI#235400; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13054 PPP1R3A Zornitza Stark Marked gene: PPP1R3A as ready
Mendeliome v0.13050 PRCD Zornitza Stark Marked gene: PRCD as ready
Mendeliome v0.13047 PRDM16 Zornitza Stark Marked gene: PRDM16 as ready
Mendeliome v0.13047 PRDM16 Zornitza Stark Phenotypes for gene: PRDM16 were changed from to Cardiomyopathy, dilated, 1LL MIM#615373; Left ventricular noncompaction 8 MIM#615373
Mendeliome v0.13043 PRDM16 Zornitza Stark reviewed gene: PRDM16: Rating: AMBER; Mode of pathogenicity: None; Publications: 23768516, 29367541, 34915728, 31965688, 29367541; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13043 CFD Ain Roesley Marked gene: CFD as ready
Mendeliome v0.13040 CEP78 Ain Roesley Marked gene: CEP78 as ready
Mendeliome v0.13040 CEP78 Ain Roesley Phenotypes for gene: CEP78 were changed from to Cone-rod dystrophy and hearing loss MIM#617236
Mendeliome v0.13038 CEP78 Ain Roesley reviewed gene: CEP78: Rating: GREEN; Mode of pathogenicity: None; Publications: 28005958, 27588451, 27588452, 27627988; Phenotypes: Cone-rod dystrophy and hearing loss MIM#617236; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.13038 CEBPA Ain Roesley Marked gene: CEBPA as ready
Mendeliome v0.13037 CEACAM16 Ain Roesley Marked gene: CEACAM16 as ready
Mendeliome v0.13036 CDKN2A Ain Roesley Marked gene: CDKN2A as ready
Mendeliome v0.13033 CDK4 Ain Roesley Marked gene: CDK4 as ready
Mendeliome v0.13031 CDK10 Ain Roesley changed review comment from: >5 families; to: 6 families thus far
Mendeliome v0.13031 CDK10 Ain Roesley Marked gene: CDK10 as ready
Mendeliome v0.13030 CDHR1 Ain Roesley Marked gene: CDHR1 as ready
Mendeliome v0.13028 CDC73 Ain Roesley Marked gene: CDC73 as ready
Mendeliome v0.13028 CDC73 Ain Roesley Phenotypes for gene: CDC73 were changed from to Hyperparathyroidism-jaw tumour syndrome, MIM# 145001; Hyperparathyroidism, familial primary, MIM# 145000
Mendeliome v0.13027 CDC73 Ain Roesley reviewed gene: CDC73: Rating: GREEN; Mode of pathogenicity: None; Publications: 12434154; Phenotypes: Hyperparathyroidism-jaw tumour syndrome, MIM# 145001, Hyperparathyroidism, familial primary, MIM# 145000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.13025 CDC42 Ain Roesley Marked gene: CDC42 as ready
Mendeliome v0.13024 CDC14A Ain Roesley Marked gene: CDC14A as ready
Mendeliome v0.13022 CD79B Ain Roesley Marked gene: CD79B as ready
Mendeliome v0.13020 PRDM5 Zornitza Stark Marked gene: PRDM5 as ready
Mendeliome v0.13017 PREPL Zornitza Stark Marked gene: PREPL as ready
Mendeliome v0.13014 PRG4 Zornitza Stark Marked gene: PRG4 as ready
Mendeliome v0.13014 PRG4 Zornitza Stark Phenotypes for gene: PRG4 were changed from to Camptodactyly-arthropathy-coxa vara-pericarditis syndrome, MIM# 208250
Mendeliome v0.13011 PRG4 Zornitza Stark reviewed gene: PRG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 10545950, 29397575; Phenotypes: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome, MIM# 208250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13010 PRICKLE1 Zornitza Stark Marked gene: PRICKLE1 as ready
Mendeliome v0.13007 PRKAR1A Zornitza Stark Marked gene: PRKAR1A as ready
Mendeliome v0.13007 PRKAR1A Zornitza Stark Gene: prkar1a has been classified as Green List (High Evidence).
Mendeliome v0.13007 PRKAR1A Zornitza Stark Phenotypes for gene: PRKAR1A were changed from to Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Carney complex, type 1, MIM# 160980; Myxoma, intracardiac, MIM# 255960; Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489
Mendeliome v0.13006 PRKAR1A Zornitza Stark Publications for gene: PRKAR1A were set to
Mendeliome v0.13005 PRKAR1A Zornitza Stark Mode of inheritance for gene: PRKAR1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13004 PRKAR1A Zornitza Stark reviewed gene: PRKAR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 10973256, 11115848, 12424709, 21651393; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800, Carney complex, type 1, MIM# 160980, Myxoma, intracardiac, MIM# 255960, Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13004 PRKCG Zornitza Stark Marked gene: PRKCG as ready
Mendeliome v0.13004 PRKCG Zornitza Stark Phenotypes for gene: PRKCG were changed from to Spinocerebellar ataxia 14, MIM# 605361
Mendeliome v0.13001 PRKCG Zornitza Stark reviewed gene: PRKCG: Rating: GREEN; Mode of pathogenicity: None; Publications: 12644968, 14676051, 14694043, 16193476, 33739604, 34292398; Phenotypes: Spinocerebellar ataxia 14, MIM# 605361; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.13001 PRKG1 Zornitza Stark Marked gene: PRKG1 as ready
Mendeliome v0.12998 PRMT7 Zornitza Stark Marked gene: PRMT7 as ready
Mendeliome v0.12995 PRODH Zornitza Stark Marked gene: PRODH as ready
Mendeliome v0.12992 PROK2 Zornitza Stark Marked gene: PROK2 as ready
Mendeliome v0.12989 PROM1 Zornitza Stark Marked gene: PROM1 as ready
Mendeliome v0.12989 PROM1 Zornitza Stark Phenotypes for gene: PROM1 were changed from to Inherited retinal dystrophy, MONDO:0019118; Cone-rod dystrophy 12, MIM# 612657; Macular dystrophy, retinal, 2, MI# 608051; Retinitis pigmentosa 41, MIM# 612095; Stargardt disease 4, MIM# 603786
Mendeliome v0.12986 PROM1 Zornitza Stark reviewed gene: PROM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10587575, 17605048, 18654668, 29416601, 31576780, 34664634, 32820593; Phenotypes: Inherited retinal dystrophy, MONDO:0019118, Cone-rod dystrophy 12, MIM# 612657, Macular dystrophy, retinal, 2, MI# 608051, Retinitis pigmentosa 41, MIM# 612095, Stargardt disease 4, MIM# 603786; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12986 PROS1 Zornitza Stark Marked gene: PROS1 as ready
Mendeliome v0.12983 PRPF3 Zornitza Stark Marked gene: PRPF3 as ready
Mendeliome v0.12980 PRPF4 Zornitza Stark Marked gene: PRPF4 as ready
Mendeliome v0.12977 PRPF6 Zornitza Stark Marked gene: PRPF6 as ready
Mendeliome v0.12973 PRPH Zornitza Stark Marked gene: PRPH as ready
Mendeliome v0.12969 PRSS1 Zornitza Stark Marked gene: PRSS1 as ready
Mendeliome v0.12969 PRSS1 Zornitza Stark Phenotypes for gene: PRSS1 were changed from to Pancreatitis, hereditary, MIM# 167800
Mendeliome v0.12966 PRSS1 Zornitza Stark reviewed gene: PRSS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8841182, 10204851, 10529393, 11097832, 11702203, 15776435, 16791840, 18461367, 17072318; Phenotypes: Pancreatitis, hereditary, MIM# 167800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12966 PRSS12 Zornitza Stark Marked gene: PRSS12 as ready
Mendeliome v0.12962 PSMC2 Zornitza Stark Marked gene: PSMC2 as ready
Mendeliome v0.12961 PSMC3IP Zornitza Stark Marked gene: PSMC3IP as ready
Mendeliome v0.12961 PSMC3IP Zornitza Stark Phenotypes for gene: PSMC3IP were changed from to Ovarian dysgenesis 3, MIM# 614324
Mendeliome v0.12958 PSMC3IP Zornitza Stark reviewed gene: PSMC3IP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21963259, 35352317, 34878148, 30406445, 29240891; Phenotypes: Ovarian dysgenesis 3, MIM# 614324; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12958 PSMD12 Zornitza Stark Marked gene: PSMD12 as ready
Mendeliome v0.12955 PSPH Zornitza Stark Marked gene: PSPH as ready
Mendeliome v0.12952 PSTPIP1 Zornitza Stark Marked gene: PSTPIP1 as ready
Mendeliome v0.12952 PSTPIP1 Zornitza Stark Phenotypes for gene: PSTPIP1 were changed from to Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Mendeliome v0.12949 PSTPIP1 Zornitza Stark reviewed gene: PSTPIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11971877, 34938582, 34778321, 34745107, 34492165, 34047005; Phenotypes: Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12949 PTGDR Zornitza Stark Marked gene: PTGDR as ready
Mendeliome v0.12946 PTH Zornitza Stark Marked gene: PTH as ready
Mendeliome v0.12946 PTH Zornitza Stark Phenotypes for gene: PTH were changed from to Hypoparathyroidism, familial isolated 1, MIM# 146200
Mendeliome v0.12943 PTH Zornitza Stark reviewed gene: PTH: Rating: GREEN; Mode of pathogenicity: None; Publications: 2212001, 1302009, 10523031, 35165722, 32421798; Phenotypes: Hypoparathyroidism, familial isolated 1, MIM# 146200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12943 PTH1R Zornitza Stark Marked gene: PTH1R as ready
Mendeliome v0.12943 PTH1R Zornitza Stark Phenotypes for gene: PTH1R were changed from to Failure of tooth eruption, primary MIM#125350; Eiken syndrome MIM#600002; Metaphyseal chondrodysplasia, Murk Jansen type MIM#156400; Chondrodysplasia, Blomstrand type MIM#215045
Mendeliome v0.12940 PTH1R Zornitza Stark reviewed gene: PTH1R: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Failure of tooth eruption, primary MIM#125350, Eiken syndrome MIM#600002, Metaphyseal chondrodysplasia, Murk Jansen type MIM#156400, Chondrodysplasia, Blomstrand type MIM#215045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12940 PTHLH Zornitza Stark Marked gene: PTHLH as ready
Mendeliome v0.12937 PTPN14 Zornitza Stark Marked gene: PTPN14 as ready
Mendeliome v0.12934 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.12933 CLPB Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Mendeliome v0.12933 GCNA Zornitza Stark Phenotypes for gene: GCNA were changed from primary spermatogenic failure to Spermatogenic failure, X-linked, 4, MIM# 301077
Mendeliome v0.12930 PTPN22 Zornitza Stark Marked gene: PTPN22 as ready
Mendeliome v0.12928 PTPRO Zornitza Stark Marked gene: PTPRO as ready
Mendeliome v0.12925 PTRH2 Zornitza Stark Marked gene: PTRH2 as ready
Mendeliome v0.12922 PTRH2 Zornitza Stark commented on gene: PTRH2: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-1 (IMNEPD1) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy.

More than 5 unrelated families reported. The Q85P missense variant is reported in several families, likely founder effect.
Mendeliome v0.12922 PTS Zornitza Stark Marked gene: PTS as ready
Mendeliome v0.12920 PUM1 Zornitza Stark Marked gene: PUM1 as ready
Mendeliome v0.12920 PUM1 Zornitza Stark Phenotypes for gene: PUM1 were changed from to Spinocerebellar ataxia 47, MIM# 617931; Neurodevelopmental disorder, MONDO:0700092, PUM1-related
Mendeliome v0.12917 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905, 30903679, 31859446; Phenotypes: Spinocerebellar ataxia 47, MIM# 617931, Neurodevelopmental disorder, MONDO:0700092, PUM1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12917 PYCR2 Zornitza Stark Marked gene: PYCR2 as ready
Mendeliome v0.12913 PYROXD1 Zornitza Stark Marked gene: PYROXD1 as ready
Mendeliome v0.12913 PYROXD1 Zornitza Stark Phenotypes for gene: PYROXD1 were changed from to Myopathy, myofibrillar, 8 , MIM#617258
Mendeliome v0.12910 F12 Bryony Thompson commented on gene: F12: Also associated with FXII deficiency - PMID: 29383625, 20022356, 18024408, 20386432, 26709783, 21264442, 28007010, 15205584, 30700128 - Biallalelic loss-of-function variants are a well-established cause of FXII deficiency. FXII deficiency is not associated with bleeding risk unlike other coagulation factors, it is either asymptomatic or characterized by a prolonged activated partial thromboplastin time. DEFINITIVE gene-disease validity classification by the ClinGen Hemostasis Thrombosis VCEP, Classification - 01/22/2020
Mendeliome v0.12910 PYROXD1 Zornitza Stark reviewed gene: PYROXD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27745833; Phenotypes: Myopathy, myofibrillar, 8 , MIM#617258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12910 F12 Bryony Thompson reviewed gene: F12: Rating: GREEN; Mode of pathogenicity: Other; Publications: 26193639, 16638441, 17381464, 21849258, 17186468, 19178938, 30463937, 23994767; Phenotypes: Hereditary angioedema type 3 MONDO:0012526; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12910 SGCD Zornitza Stark Marked gene: SGCD as ready
Mendeliome v0.12910 SGCD Zornitza Stark Phenotypes for gene: SGCD were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 6, MIM# 601287; autosomal recessive limb-girdle muscular dystrophy MONDO:0015152
Mendeliome v0.12907 SGCD Zornitza Stark reviewed gene: SGCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 8841194, 19259135, 20623375, 10838250, 10735275, 9832045, 30733730; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 6, MIM# 601287, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12907 SGCB Zornitza Stark Marked gene: SGCB as ready
Mendeliome v0.12907 SGCB Zornitza Stark Phenotypes for gene: SGCB were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 4 MIM#604286; autosomal recessive limb-girdle muscular dystrophy, MONDO:0015152
Mendeliome v0.12904 SGCA Zornitza Stark Marked gene: SGCA as ready
Mendeliome v0.12904 SGCA Zornitza Stark Phenotypes for gene: SGCA were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 3 MIM#608099; autosomal recessive limb-girdle muscular dystrophy, MONDO:0015152
Mendeliome v0.12901 SFXN4 Zornitza Stark Marked gene: SFXN4 as ready
Mendeliome v0.12898 SFRP4 Zornitza Stark Marked gene: SFRP4 as ready
Mendeliome v0.12895 RASGRP1 Zornitza Stark Marked gene: RASGRP1 as ready
Mendeliome v0.12892 PDCD1 Zornitza Stark Marked gene: PDCD1 as ready
Mendeliome v0.12887 PCK2 Zornitza Stark Marked gene: PCK2 as ready
Mendeliome v0.12883 PCCB Zornitza Stark Marked gene: PCCB as ready
Mendeliome v0.12880 PCCA Zornitza Stark Marked gene: PCCA as ready
Mendeliome v0.12874 PC Zornitza Stark Marked gene: PC as ready
Mendeliome v0.12874 PC Zornitza Stark Phenotypes for gene: PC were changed from to Pyruvate carboxylase deficiency - MIM#266150
Mendeliome v0.12871 PAX9 Zornitza Stark Marked gene: PAX9 as ready
Mendeliome v0.12866 SET Zornitza Stark Marked gene: SET as ready
Mendeliome v0.12863 SERPING1 Zornitza Stark Marked gene: SERPING1 as ready
Mendeliome v0.12863 SERPING1 Zornitza Stark Phenotypes for gene: SERPING1 were changed from to Angioedema, hereditary, 1 and 2, MIM#106100; Complement component 4, partial deficiency of, MIM#120790
Mendeliome v0.12859 SGCD Samantha Ayres edited their review of gene: SGCD: Added comment: Variants identified in multiple cases of cardiomyopathy, however most are too common in the general population to explain the disease.
First described in the literature with potential association to cardiomyopathy in 2000 (Tsubata et al 10974018).
Case-control study by Mazzarotto et al 2020, did not identify enrichment of SGCD in DCM cohort.

Animal models demonstrate mild cardiomyopathy phenotype.

Curated as 'limited' gene-disease association by ClinGen; Changed rating: RED; Changed publications: 10974018, 31983221, 23695275; Changed phenotypes: Cardiomyopathy, dilated, 1L, MIM#606685, dilated cardiomyopathy MONDO:0005021; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12859 SGCD Samantha Ayres reviewed gene: SGCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 8841194, 30733730, 10838250; Phenotypes: autosomal recessive limb-girdle muscular dystrophy MONDO:0015152, Muscular dystrophy, limb-girdle, autosomal recessive 6, MIM#601287; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12859 SGCB Samantha Ayres reviewed gene: SGCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 18285821; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 4 MIM#604286, autosomal recessive limb-girdle muscular dystrophy, MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12859 SGCA Samantha Ayres reviewed gene: SGCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 30007747, 9192266, 34404573; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 3 MIM#608099, autosomal recessive limb-girdle muscular dystrophy, MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12859 SERPIND1 Zornitza Stark Marked gene: SERPIND1 as ready
Mendeliome v0.12859 SERPIND1 Zornitza Stark Phenotypes for gene: SERPIND1 were changed from to heparin cofactor 2 deficiency, MONDO:0012876; Thrombophilia 10 due to heparin cofactor II deficiency, MIM#612356
Mendeliome v0.12855 PDCD1 Krithika Murali changed review comment from: No OMIM gene disease association.

1 individual from a consanguineous family reported with PDCD1 deficiency.

PMID: 34183838 (Nat Medicine 2021) - proband is the son of consanguineous Turkish parents. He was diagnosed with type 1 diabetes (T1D), hypothyroidism, and juvenile idiopathic arthritis (JIA) at the age of three years. He developed abdominal TB age 10 and died from pulmonary alveolar haemorrhage age 11. WES identified homozygous intragenic PDCD1 gene duplication (c.105dupC p.T36Hfs*70). Absent from population databases and unaffected parents confirmed to be heterozygous. Supportive in vitro studies showing absent expression or function of PD-1 protein. Proband's older brother died at the age of 3 from unexplained pneumonitis and had a history of T1DM and juvenile idiopathic arthritis.; to: No OMIM gene disease association.

1 individual from a consanguineous family reported with PDCD1 deficiency.

PMID: 34183838 (Nat Medicine 2021) - proband is the son of consanguineous Turkish parents. He was diagnosed with type 1 diabetes (T1D), hypothyroidism, and juvenile idiopathic arthritis (JIA) at the age of three years. He developed abdominal TB age 10 and died from pulmonary alveolar haemorrhage age 11. WES identified homozygous intragenic PDCD1 gene duplication (c.105dupC p.T36Hfs*70). Absent from population databases and unaffected parents confirmed to be heterozygous. Supportive in vitro studies showing absent expression or function of PD-1 protein. Proband's older brother died at the age of 3 from unexplained pneumonitis and had a history of T1DM and juvenile idiopathic arthritis.
Mendeliome v0.12855 CD79A Ain Roesley Marked gene: CD79A as ready
Mendeliome v0.12853 CD70 Ain Roesley Marked gene: CD70 as ready
Mendeliome v0.12851 CD55 Ain Roesley Marked gene: CD55 as ready
Mendeliome v0.12849 CD46 Ain Roesley Marked gene: CD46 as ready
Mendeliome v0.12848 PC Krithika Murali reviewed gene: PC: Rating: GREEN; Mode of pathogenicity: None; Publications: 9585612, 12112657; Phenotypes: Pyruvate carboxylase deficiency - MIM#266150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12848 CD40 Ain Roesley Marked gene: CD40 as ready
Mendeliome v0.12846 CD36 Ain Roesley Marked gene: CD36 as ready
Mendeliome v0.12846 CD36 Ain Roesley Phenotypes for gene: CD36 were changed from to Platelet glycoprotein IV deficiency MIM#608404; {Malaria, cerebral, reduced risk of} MIM#611162; {Malaria, cerebral, susceptibility to} MIM#611162
Mendeliome v0.12844 CD36 Ain Roesley reviewed gene: CD36: Rating: GREEN; Mode of pathogenicity: None; Publications: 7686693, 11950861, 10890433, 24960640, 10890433; Phenotypes: Platelet glycoprotein IV deficiency MIM#608404, {Malaria, cerebral, reduced risk of} MIM#611162, {Malaria, cerebral, susceptibility to} MIM#611162; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12844 CD36 Ain Roesley reviewed gene: CD36: Rating: GREEN; Mode of pathogenicity: None; Publications: 7533783, 11950861, 10890433, 12506336; Phenotypes: {Malaria, cerebral, reduced risk of} MIM#611162, {Malaria, cerebral, susceptibility to} MIM#611162, Platelet glycoprotein IV deficiency MIM#608404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12844 CD209 Ain Roesley Marked gene: CD209 as ready
Mendeliome v0.12843 CD151 Ain Roesley Marked gene: CD151 as ready
Mendeliome v0.12841 CCR5 Ain Roesley Marked gene: CCR5 as ready
Mendeliome v0.12838 CCR2 Ain Roesley changed review comment from: Currently no mendelian gene-disease association; to: Vall64Ile has been associated with reduction in the progression to AIDS. Mutant results in normal expression levels of the CCR2 receptor and has no effect on the incidence of HIV infection. However, in contrast to normal CCR2 peptides, the mutant protein preferentially dimerizes with the CXCR4 polypeptide, isolating it in the endoplasmic reticulum. It is also thought that the inhibitory effect is dependent on the stages of HIV-1 infection and interactions with other genetic variants.
Mendeliome v0.12836 CCR2 Ain Roesley Marked gene: CCR2 as ready
Mendeliome v0.12836 SLC25A12 Zornitza Stark Marked gene: SLC25A12 as ready
Mendeliome v0.12833 SLC25A13 Zornitza Stark Marked gene: SLC25A13 as ready
Mendeliome v0.12830 SLC25A15 Zornitza Stark Marked gene: SLC25A15 as ready
Mendeliome v0.12827 SLC25A19 Zornitza Stark Marked gene: SLC25A19 as ready
Mendeliome v0.12824 SLC25A22 Zornitza Stark Marked gene: SLC25A22 as ready
Mendeliome v0.12821 TRPM1 Zornitza Stark Marked gene: TRPM1 as ready
Mendeliome v0.12821 TRPM1 Zornitza Stark Phenotypes for gene: TRPM1 were changed from to Night blindness, congenital stationary (complete), 1C, autosomal recessive, MIM# 613216
Mendeliome v0.12818 TRPM1 Zornitza Stark reviewed gene: TRPM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19878917, 19896113, 19896109; Phenotypes: Night blindness, congenital stationary (complete), 1C, autosomal recessive, MIM# 613216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12818 TRPC6 Zornitza Stark Marked gene: TRPC6 as ready
Mendeliome v0.12815 TRAPPC2 Zornitza Stark Marked gene: TRAPPC2 as ready
Mendeliome v0.12815 TRAPPC2 Zornitza Stark Phenotypes for gene: TRAPPC2 were changed from to Spondyloepiphyseal dysplasia tarda, MIM# 313400
Mendeliome v0.12812 TRAPPC2 Zornitza Stark reviewed gene: TRAPPC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10431248, 14755465, 33726005, 20301324, 32953644; Phenotypes: Spondyloepiphyseal dysplasia tarda, MIM# 313400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.12812 TRAPPC12 Zornitza Stark Marked gene: TRAPPC12 as ready
Mendeliome v0.12812 TRAPPC11 Zornitza Stark Marked gene: TRAPPC11 as ready
Mendeliome v0.12812 TRAPPC11 Zornitza Stark Phenotypes for gene: TRAPPC11 were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 18, MIM# 615356
Mendeliome v0.12809 TRAPPC11 Zornitza Stark reviewed gene: TRAPPC11: Rating: GREEN; Mode of pathogenicity: None; Publications: 23830518, 26322222, 29855340, 30105108; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 18, MIM# 615356; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12809 TRAK1 Zornitza Stark Marked gene: TRAK1 as ready
Mendeliome v0.12806 TPMT Zornitza Stark Marked gene: TPMT as ready
Mendeliome v0.12804 TRNT1 Zornitza Stark Marked gene: TRNT1 as ready
Mendeliome v0.12801 TRMU Zornitza Stark Marked gene: TRMU as ready
Mendeliome v0.12798 TRMT5 Zornitza Stark Marked gene: TRMT5 as ready
Mendeliome v0.12793 ETV1 Bryony Thompson Marked gene: ETV1 as ready
Mendeliome v0.12793 EXT1 Bryony Thompson reviewed gene: EXT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7550340, 8981950, 20534475; Phenotypes: hereditary multiple osteochondromas MONDO:0005508, exostoses, multiple, type 1 MONDO:0007585; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.12790 EXOC3L2 Bryony Thompson Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation; renal dysplasia; bone marrow failure to Dandy-Walker malformation, MONDO:0009072; renal dysplasia; bone marrow failure
Mendeliome v0.12789 ETFDH Bryony Thompson Marked gene: ETFDH as ready
Mendeliome v0.12787 SERPING1 Samantha Ayres reviewed gene: SERPING1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35386643, 31517426, 29753808; Phenotypes: Angioedema, hereditary, 1 and 2, MIM#106100, Complement component 4, partial deficiency of, MIM#120790; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12787 SERPIND1 Samantha Ayres reviewed gene: SERPIND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2863444, 8902986, 2647747, 15337701, 31064749, 11204559, 8562924, 29296762; Phenotypes: heparin cofactor 2 deficiency, MONDO:0012876, Thrombophilia 10 due to heparin cofactor II deficiency, MIM#612356; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12787 TRMT10C Zornitza Stark Marked gene: TRMT10C as ready
Mendeliome v0.12784 PDHA2 Zornitza Stark Marked gene: PDHA2 as ready
Mendeliome v0.12784 PDHA2 Zornitza Stark gene: PDHA2 was added
gene: PDHA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDHA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDHA2 were set to 29581481; 35172124
Phenotypes for gene: PDHA2 were set to Spermatogenic failure-70, MIM#619828
Review for gene: PDHA2 was set to RED
Added comment: Three individuals reported from different families with same homozygous missense variant. Same ethnic background, likely founder effect.
Sources: Literature
Mendeliome v0.12783 TRDN Zornitza Stark Marked gene: TRDN as ready
Mendeliome v0.12783 TRDN Zornitza Stark Phenotypes for gene: TRDN were changed from to Cardiac arrhythmia syndrome, with or without skeletal muscle weakness, MIM# 615441
Mendeliome v0.12780 TRDN Zornitza Stark reviewed gene: TRDN: Rating: GREEN; Mode of pathogenicity: None; Publications: 31983240, 25922419, 30649896, 22422768; Phenotypes: Cardiac arrhythmia syndrome, with or without skeletal muscle weakness, MIM# 615441; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12780 TRHR Zornitza Stark Marked gene: TRHR as ready
Mendeliome v0.12777 TRIM37 Zornitza Stark Marked gene: TRIM37 as ready
Mendeliome v0.12774 TRIM32 Zornitza Stark Marked gene: TRIM32 as ready
Mendeliome v0.12774 TRIM32 Zornitza Stark Phenotypes for gene: TRIM32 were changed from to Bardet-Biedl syndrome 11, MIM# 615988; Muscular dystrophy, limb-girdle, autosomal recessive 8 MIM#254110
Mendeliome v0.12771 TRIM32 Zornitza Stark edited their review of gene: TRIM32: Added comment: >3 unrelated cases with myopathy, adult onset reported; Changed rating: GREEN; Changed publications: 16606853, 31309175, 11822024; Changed phenotypes: Bardet-Biedl syndrome 11, MIM# 615988, Muscular dystrophy, limb-girdle, autosomal recessive 8 MIM#254110
Mendeliome v0.12771 TRPM4 Zornitza Stark Marked gene: TRPM4 as ready
Mendeliome v0.12771 TRPM4 Zornitza Stark Phenotypes for gene: TRPM4 were changed from to Progressive familial heart block, type IB, MIM# 604559; Erythrokeratodermia variabilis et progressiva 6, MIM# 618531
Mendeliome v0.12767 TRPM4 Zornitza Stark reviewed gene: TRPM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 19726882, 20562447, 21887725, 20562447, 35205305, 34897640, 30528822; Phenotypes: Progressive familial heart block, type IB, MIM# 604559, Erythrokeratodermia variabilis et progressiva 6 618531; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12767 TRPV4 Zornitza Stark Marked gene: TRPV4 as ready
Mendeliome v0.12767 TRPV4 Zornitza Stark Phenotypes for gene: TRPV4 were changed from to Hereditary motor and sensory neuropathy, type IIc, MIM# 606071; Neuronopathy, distal hereditary motor, type VIII, MIM# 600175
Mendeliome v0.12765 TTPA Zornitza Stark Marked gene: TTPA as ready
Mendeliome v0.12762 TTC19 Zornitza Stark Marked gene: TTC19 as ready
Mendeliome v0.12762 TTC19 Zornitza Stark Phenotypes for gene: TTC19 were changed from to Mitochondrial complex III deficiency, nuclear type 2, MIM#615157
Mendeliome v0.12759 TTC19 Zornitza Stark edited their review of gene: TTC19: Added comment: Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life. The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances.

At least 4 unrelated families reported.; Changed publications: 21278747, 23532514, 24368687, 24397319
Mendeliome v0.12759 TSFM Zornitza Stark Marked gene: TSFM as ready
Mendeliome v0.12756 TSFM Zornitza Stark changed review comment from: Ataxia is a reported feature of this mitochondrial disorder.; to: At least 5 families reported, however 3 had the same homozygous variant, ?founder.
Mendeliome v0.12756 TPK1 Zornitza Stark Marked gene: TPK1 as ready
Mendeliome v0.12753 TP63 Zornitza Stark Marked gene: TP63 as ready
Mendeliome v0.12753 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from to ADULT syndrome, OMIM #103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292; Hay-Wells syndrome, OMIM #106260; Limb-mammary syndrome, OMIM #603543; Orofacial cleft 8, OMIM #618149; Rapp-Hodgkin syndrome, OMIM #129400; Split-hand/foot malformation 4, OMIM #605289
Mendeliome v0.12750 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: 20556892; Phenotypes: ADULT syndrome, OMIM #103285, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292, Hay-Wells syndrome, OMIM #106260, Limb-mammary syndrome, OMIM #603543, Orofacial cleft 8, OMIM #618149, Rapp-Hodgkin syndrome, OMIM #129400, Split-hand/foot malformation 4, OMIM #605289; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12750 TOR1A Zornitza Stark Marked gene: TOR1A as ready
Mendeliome v0.12750 TOR1A Zornitza Stark Phenotypes for gene: TOR1A were changed from to Arthrogryposis multiplex congenita, MIM#618947; Dystonia-1, torsion, MIM#128100
Mendeliome v0.12747 TOR1A Zornitza Stark reviewed gene: TOR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30244176, 9288096, 19955557, 18477710, 32243914, 31583275, 31347572; Phenotypes: Arthrogryposis multiplex congenita, MIM#618947, Dystonia-1, torsion, MIM#128100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12747 TNXB Zornitza Stark Marked gene: TNXB as ready
Mendeliome v0.12744 TNPO3 Zornitza Stark Marked gene: TNPO3 as ready
Mendeliome v0.12744 TNPO3 Zornitza Stark Phenotypes for gene: TNPO3 were changed from to Muscular dystrophy, limb-girdle, autosomal dominant 2, MIM# 608423
Mendeliome v0.12741 TNPO3 Zornitza Stark reviewed gene: TNPO3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23667635, 23543484, 31071488, 31192305; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 2, MIM# 608423; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12741 RSPO2 Zornitza Stark Marked gene: RSPO2 as ready
Mendeliome v0.12738 PIGA Zornitza Stark changed review comment from: PIGA 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.; to: PMID 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.
Mendeliome v0.12737 PIGA Zornitza Stark edited their review of gene: PIGA: Added comment: PIGA 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.; Changed publications: 22305531, 24357517, 24706016, 26545172, 33333793, 32694024, 34875027; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466, Neurodevelopmental disorder with epilepsy and haemochromatosis, MIM# 301072
Mendeliome v0.12733 TNNC1 Zornitza Stark Marked gene: TNNC1 as ready
Mendeliome v0.12733 CACNA2D1 Alison Yeung Marked gene: CACNA2D1 as ready
Mendeliome v0.12731 TTC21B Dean Phelan edited their review of gene: TTC21B: Added comment: Correcting typographical error; Changed phenotypes: Glomerular disorder (MONDO:0019722), TTC21B-related
Mendeliome v0.12731 CACNA2D1 Michelle Torres gene: CACNA2D1 was added
gene: CACNA2D1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990
Phenotypes for gene: CACNA2D1 were set to developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related
Review for gene: CACNA2D1 was set to GREEN
Added comment: PMID 35293990: WES of 2x unrelated individuals with early-onset developmental epileptic encephalopathy, microcephaly, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia, and 2 cortical visual impairment, corpus callosum hypoplasia and progressive volume loss. Patient 2 also had a tiny patent foramen ovale.

Patient 1 is homozygous for p.(Ser275Asnfs*13). mRNA and protein expression were reduced to ~10% of WT in fibroblasts

Patient 2 is cHet for p.(Leu9Alafs*5) and p.(Gly209Asp). mRNA expression in patients fibroblasts was similar to controls, and protein expression reduced to 31-38%. Functional of the p.(Gly209Asp) showed impaired localization and mutagenesis showed complete loss of channel function.
Sources: Literature
Mendeliome v0.12731 TTC21B Dean Phelan edited their review of gene: TTC21B: Added comment: Updated to include additional publications linking glomerular disorder.; Changed rating: GREEN; Changed publications: PMID: 35289079, 26940125, 28124483, 31208513, 34805047; Changed phenotypes: Glomerular disorder (MONOD:0019722), TTC21B-related
Mendeliome v0.12731 TRAPPC10 Zornitza Stark Marked gene: TRAPPC10 as ready
Mendeliome v0.12730 TNNC1 Zornitza Stark Phenotypes for gene: TNNC1 were changed from to Cardiomyopathy, dilated, 1Z, MIM# 611879; Cardiomyopathy, hypertrophic, 13 (MIM# 613243)
Mendeliome v0.12729 TTC21B Zornitza Stark Phenotypes for gene: TTC21B were changed from Nephronophthisis 12, MIM# 613820; Short-rib thoracic dysplasia 4 with or without polydactyly, MIM# 613819; Joubert syndrome to Nephronophthisis 12, MIM# 613820; Short-rib thoracic dysplasia 4 with or without polydactyly, MIM# 613819; Joubert syndrome; Glomerular disorder MONDO:0019722, TTC21B-related
Mendeliome v0.12728 TRAPPC10 Naomi Baker gene: TRAPPC10 was added
gene: TRAPPC10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC10 were set to PMID: 35298461; 30167849
Phenotypes for gene: TRAPPC10 were set to neurodevelopmental disorder (MONDO:0700092), TRAPPC10-related
Review for gene: TRAPPC10 was set to GREEN
Added comment: PMID: 35298461 – two Pakistani families reported with homozygous variants. Family 1 has frameshift variant in 8 affected individual and family 2 has missense variant in 2 affected individuals. Patients present with microcephaly, short stature, hypotonia, severe ID and behavioural abnormalities. Seizures also reported in 4/10 individuals. Paper also reported brain abnormalities in null mouse model and other functional in transfected cell lines.

PMID: 30167849 – initial report of family 2 above.
Sources: Literature
Mendeliome v0.12726 TNNI1 Zornitza Stark Marked gene: TNNI1 as ready
Mendeliome v0.12725 TNNI1 Zornitza Stark Phenotypes for gene: TNNI1 were changed from arthrogryposis; joint contractures to Arthrogryposis MONDO:0008779, TNNI1-related
Mendeliome v0.12724 SLC35B2 Alison Yeung Marked gene: SLC35B2 as ready
Mendeliome v0.12723 ATP2B1 Zornitza Stark Marked gene: ATP2B1 as ready
Mendeliome v0.12722 SLC35B2 Melanie Marty changed review comment from: 2 x individuals with homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2. Phenotypes included pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy.

Functional analysis on patient cells showed that the variants result in a decreased expression of mRNA and affect protein subcellular localization leading to functional impairment of the protein.
Sources: Literature; to: 2 x individuals with homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2. Phenotypes included pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy.

Functional analysis on patient cells showed that the variants result in a decreased expression of mRNA and affect protein subcellular localization leading to functional impairment of the protein.
Sources: Literature
Mendeliome v0.12721 ADAM22 Alison Yeung Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, MIM# 617933 to Developmental and epileptic encephalopathy 61 (MIM#617933)
Mendeliome v0.12720 MDFIC Zornitza Stark Marked gene: MDFIC as ready
Mendeliome v0.12720 TTC21B Dean Phelan reviewed gene: TTC21B: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35289079; Phenotypes: early onset hypertension, proteinuria, progressive kidney disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12720 FUZ Anna Ritchie changed review comment from: Novel missense p.(Arg284Pro) mutation in FUZ identified in twins presenting with craniosynostosis. Loss of Fuz resulted in increased mineralisation in both in vitro embryonic primary osteoblast cultures and in fibroblasts undergoing an osteogenic challenge. No previous reports have implicated changes in human FUZ in craniosynostosis. However, variations in FUZ have been found in patients with neural tube defects.; to: Novel missense p.(Arg284Pro) mutation in FUZ identified in twins presenting with craniosynostosis. Loss of Fuz resulted in increased mineralisation in both in vitro embryonic primary osteoblast cultures and in fibroblasts undergoing an osteogenic challenge. No previous reports have implicated changes in human FUZ in craniosynostosis. However, variations in FUZ have been found in patients with neural tube defects.
Mendeliome v0.12714 TNNI1 Krithika Murali gene: TNNI1 was added
gene: TNNI1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNNI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNNI1 were set to 34934811
Phenotypes for gene: TNNI1 were set to arthrogryposis; joint contractures
Review for gene: TNNI1 was set to AMBER
Added comment: No OMIM gene disease association reported

PMID 34934811 Nishimori et al report 2 individuals from a Japanese family with joint contractures, elevated CK and a novel heterozygous TNNI1 variant.

The proband was born with clasped thumbs (gestational age not stated) requiring surgical correction at 5 months of age. At age 14 was diagnosed with contractures of the neck, trunk, hip and knee with elevated serum CK (1689 IU/L). No muscle weakness noted. Muscle biopsy showed moth-eaten appearance of type I fibres and electron microscopy showed type 1 fibre Z disk streaming.

Trio exome sequencing identified a paternally heterozygous nonsense TNNI1 variant (c.523A>T p.K175*). The proband's father and paternal grandfather (not genotyped) also have a history of joint contractures with elevated CK.

The affected amino acid residue is in the tropomyosin binding site near the C-terminus and is highly conserved. The variant is absent from gnomAD. rt-PCR products of mRNA from the patient's muscle biopsy showed presence of both mutated and normal transcripts.
Sources: Literature
Mendeliome v0.12714 TNNC1 Zornitza Stark reviewed gene: TNNC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33947203, 31983221, 17977476, 19808376, 11385718, 8572189, 21262074, 22815480, 26779504; Phenotypes: Cardiomyopathy, dilated, 1Z, MIM# 611879, Cardiomyopathy, hypertrophic, 13 (MIM# 613243); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12714 SLC35B2 Melanie Marty gene: SLC35B2 was added
gene: SLC35B2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to PMID: 35325049
Phenotypes for gene: SLC35B2 were set to chondrodysplasia with hypomyelinating leukodystrophy, intellectual disability
Review for gene: SLC35B2 was set to AMBER
Added comment: 2 x individuals with homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2. Phenotypes included pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy.

Functional analysis on patient cells showed that the variants result in a decreased expression of mRNA and affect protein subcellular localization leading to functional impairment of the protein.
Sources: Literature
Mendeliome v0.12714 AHSG Elena Savva gene: AHSG was added
gene: AHSG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AHSG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AHSG were set to PMID: 28054173; 9395485; 31288248; 17389622
Phenotypes for gene: AHSG were set to ?Alopecia-intellectual disability syndrome 1 MIM#203650; infantile cortical hyperostosis
Review for gene: AHSG was set to RED
Added comment: PMID: 28054173 - 7 relatives within a large consanguinous fam w/ alopecia and ID, and a hom missense (p.Arg317His). Modelling predicts this variant to be a phosphorylation site, functional studies show a difference in protein size. Unclear biological significance.
Alt change with stronger GS (p.(Arg317Cys)) is a common poly with 19 homozygotes in gnomAD.

No hom PTCs in gnomAD

PMID: 9395485 - K/O mouse model shows no gross anatomical abnormalities, were fertile and "healthy". No mentioned of ID, alopecia
PMID: 17389622 - K/O mouse model on the calcification resistant genetic background C57BL/6, shows uraemia and phosphate challenge. No mentioned of ID, alopecia

PMID: 31288248 - 1 hom infant (p.K2*, within 5' NMD escape region) with infantile cortical hyperostosis, loss of enzyme in patient serum shown by ELISA. No mentioned of ID, alopecia
Sources: Literature
Mendeliome v0.12713 VPS16 Ain Roesley Phenotypes for gene: VPS16 were changed from Dystonia 30, MIM#619291 to Dystonia 30, MIM#619291; mucopolysaccharidosis-like disorder, VPS16-related MONDO#0100365
Mendeliome v0.12711 MDFIC Belinda Chong gene: MDFIC was added
gene: MDFIC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MDFIC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDFIC were set to 35235341
Phenotypes for gene: MDFIC were set to Central conducting lymphatic anomaly with lymphedema
Review for gene: MDFIC was set to GREEN
Added comment: Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise.

Seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax.
Sources: Literature
Mendeliome v0.12711 ATP2B1 Daniel Flanagan gene: ATP2B1 was added
gene: ATP2B1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP2B1 were set to PMID: 35358416
Phenotypes for gene: ATP2B1 were set to Neurodevelopmental delay; autism; seizures; distal limb abnormalities
Review for gene: ATP2B1 was set to GREEN
Added comment: 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism (5), dissimilar forms of seizures (6), and distal limb abnormalities (4). 9 variants proven to be de novo, other 3 variants had unknown inheritance. 9 missense and 3 nonsense reported. Supporting functional analysis for missense.
Sources: Expert list
Mendeliome v0.12711 VPS16 Ain Roesley changed review comment from: for AR MPS:
3 unrelated families - 2x hom c.2272‐18C>A and 1x hom p.Trp180Cys

RNA and functional studies done on the splice variant

for AD
see review below; to: for AR MPS:
3 unrelated families - 2x hom c.2272‐18C>A and 1x hom p.Trp180Cys

RNA and functional studies done on the splice variant

for AD
see review below

PMID:34901436 suggests dystonia is transcript specific
Mendeliome v0.12711 VPS16 Ain Roesley changed review comment from: for AR MPS:
3 unrelated families - 2x hom c.2272‐18C>A and 1x het p.Trp180Cys

RNA and functional studies done on the splice variant

for AD
see review below; to: for AR MPS:
3 unrelated families - 2x hom c.2272‐18C>A and 1x hom p.Trp180Cys

RNA and functional studies done on the splice variant

for AD
see review below
Mendeliome v0.12711 TNFSF4 Zornitza Stark Marked gene: TNFSF4 as ready
Mendeliome v0.12711 TNFSF4 Zornitza Stark Phenotypes for gene: TNFSF4 were changed from to {Myocardial infarction, susceptibility to} 608446
Mendeliome v0.12709 VPS16 Ain Roesley reviewed gene: VPS16: Rating: GREEN; Mode of pathogenicity: None; Publications: 33938619, 34013567; Phenotypes: mucopolysaccharidosis-like disorder, VPS16-related MONDO#0100365; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12708 TNFSF4 Zornitza Stark reviewed gene: TNFSF4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Myocardial infarction, susceptibility to} 608446; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12708 TNFSF11 Zornitza Stark Marked gene: TNFSF11 as ready
Mendeliome v0.12705 TNFRSF11B Zornitza Stark Marked gene: TNFRSF11B as ready
Mendeliome v0.12702 TMEM240 Zornitza Stark Marked gene: TMEM240 as ready
Mendeliome v0.12702 TMEM240 Zornitza Stark Phenotypes for gene: TMEM240 were changed from to Spinocerebellar ataxia 21, MIM# 607454
Mendeliome v0.12699 TMEM127 Zornitza Stark Marked gene: TMEM127 as ready
Mendeliome v0.12697 TMEM126B Zornitza Stark Marked gene: TMEM126B as ready
Mendeliome v0.12697 TMEM126B Zornitza Stark Phenotypes for gene: TMEM126B were changed from to Mitochondrial complex I deficiency, nuclear type 29, MIM# 618250
Mendeliome v0.12694 TMEM126B Zornitza Stark reviewed gene: TMEM126B: Rating: GREEN; Mode of pathogenicity: None; Publications: 27374774, 27374773; Phenotypes: Mitochondrial complex I deficiency, nuclear type 29, MIM# 618250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12694 TMEM106B Zornitza Stark Marked gene: TMEM106B as ready
Mendeliome v0.12691 TMEM106B Zornitza Stark changed review comment from: Cerebellar signs including ataxia prominent.; to: Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum.

At least 5 unrelated individuals reported.
Mendeliome v0.12691 RAPSN Zornitza Stark Marked gene: RAPSN as ready
Mendeliome v0.12688 RAD51C Zornitza Stark Marked gene: RAD51C as ready
Mendeliome v0.12686 LIG3 Zornitza Stark Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy to Mitochondrial DNA depletion syndrome 20 (MNGIE type), MIM# 619780
Mendeliome v0.12684 SLC25A26 Zornitza Stark Marked gene: SLC25A26 as ready
Mendeliome v0.12684 GGN Zornitza Stark Marked gene: GGN as ready
Mendeliome v0.12679 SLC25A3 Zornitza Stark Marked gene: SLC25A3 as ready
Mendeliome v0.12678 SLC25A3 Zornitza Stark Phenotypes for gene: SLC25A3 were changed from to Mitochondrial phosphate carrier deficiency, MIM# 610773
Mendeliome v0.12676 SLC25A3 Zornitza Stark reviewed gene: SLC25A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17273968, 21763135, 25681081; Phenotypes: Mitochondrial phosphate carrier deficiency, MIM# 610773; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12676 SLC25A4 Zornitza Stark Marked gene: SLC25A4 as ready
Mendeliome v0.12676 SLC25A4 Zornitza Stark Phenotypes for gene: SLC25A4 were changed from to Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD, MIM#617184; Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR, MIM#615418; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2, MIM#609283
Mendeliome v0.12673 SLC25A4 Zornitza Stark reviewed gene: SLC25A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30046662, 30013777, 29654543, 28823815; Phenotypes: Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD, MIM#617184, Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR, MIM#615418, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2, MIM#609283; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12673 SLC25A42 Zornitza Stark Marked gene: SLC25A42 as ready
Mendeliome v0.12673 SLC25A42 Zornitza Stark Phenotypes for gene: SLC25A42 were changed from to Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression , MIM#618416
Mendeliome v0.12670 SLC25A42 Zornitza Stark reviewed gene: SLC25A42: Rating: GREEN; Mode of pathogenicity: None; Publications: 26541337, 29327420, 29923093, 34258143; Phenotypes: Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression , MIM#618416; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12670 SLC2A10 Zornitza Stark Marked gene: SLC2A10 as ready
Mendeliome v0.12670 SLC2A10 Zornitza Stark Phenotypes for gene: SLC2A10 were changed from to Arterial tortuosity syndrome, MIM# 208050
Mendeliome v0.12667 SLC2A10 Zornitza Stark reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 16550171, 17935213; Phenotypes: Arterial tortuosity syndrome, MIM# 208050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12667 SLC2A2 Zornitza Stark changed review comment from: Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose.

> 5 patients previously reported with the associated condition, which is a glycogen storage disease. SLC2A2 encodes for the glucose transporter, GLUT2.; to: Fanconi-Bickel syndrome is characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose.

> 5 patients previously reported with the associated condition, which is a glycogen storage disease. SLC2A2 encodes for the glucose transporter, GLUT2.
Mendeliome v0.12667 SLC2A2 Zornitza Stark Marked gene: SLC2A2 as ready
Mendeliome v0.12664 SLC2A3 Zornitza Stark Marked gene: SLC2A3 as ready
Mendeliome v0.12663 SLC2A4 Zornitza Stark Marked gene: SLC2A4 as ready
Mendeliome v0.12662 SORT1 Zornitza Stark Marked gene: SORT1 as ready
Mendeliome v0.12659 SOX10 Zornitza Stark Marked gene: SOX10 as ready
Mendeliome v0.12659 SOX10 Zornitza Stark Phenotypes for gene: SOX10 were changed from to Kallman syndrome; PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266)
Mendeliome v0.12656 SOX10 Zornitza Stark reviewed gene: SOX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 23643381, 24845202; Phenotypes: Kallman syndrome, PCWH syndrome (MIM#609136), Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584), Waardenburg syndrome, type 4C (MIM#613266); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12656 SOX17 Zornitza Stark Marked gene: SOX17 as ready
Mendeliome v0.12656 SOX17 Zornitza Stark Phenotypes for gene: SOX17 were changed from to Vesicoureteral reflux 3 MIM#613674; Pulmonary arterial hypertension, MONDO:0015924
Mendeliome v0.12653 SOX17 Zornitza Stark reviewed gene: SOX17: Rating: GREEN; Mode of pathogenicity: None; Publications: 29650961, 31406341, 20960469; Phenotypes: Vesicoureteral reflux 3 MIM#613674, Pulmonary arterial hypertension, MONDO:0015924; Mode of inheritance: None
Mendeliome v0.12653 SOX18 Zornitza Stark Marked gene: SOX18 as ready
Mendeliome v0.12650 SOX5 Zornitza Stark Marked gene: SOX5 as ready
Mendeliome v0.12647 SOX9 Zornitza Stark Marked gene: SOX9 as ready
Mendeliome v0.12644 NKX2-1 Zornitza Stark reviewed gene: NKX2-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978, Chorea, hereditary benign MIM#118700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12644 SP7 Zornitza Stark Marked gene: SP7 as ready
Mendeliome v0.12641 SPAG7 Zornitza Stark Marked gene: SPAG7 as ready
Mendeliome v0.12641 SPAG7 Zornitza Stark Phenotypes for gene: SPAG7 were changed from to Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome, MONDO:0018540
Mendeliome v0.12637 SPAG7 Zornitza Stark reviewed gene: SPAG7: Rating: RED; Mode of pathogenicity: None; Publications: 24452265; Phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12637 SPATA5 Zornitza Stark Marked gene: SPATA5 as ready
Mendeliome v0.12637 SPATA5 Zornitza Stark Phenotypes for gene: SPATA5 were changed from to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, MIM# 616577
Mendeliome v0.12634 SPATA5 Zornitza Stark reviewed gene: SPATA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 30009132, 29343804; Phenotypes: Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, MIM# 616577; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12634 SPECC1L Zornitza Stark Marked gene: SPECC1L as ready
Mendeliome v0.12631 SSR4 Zornitza Stark Marked gene: SSR4 as ready
Mendeliome v0.12628 SRY Zornitza Stark Marked gene: SRY as ready
Mendeliome v0.12625 SRP54 Zornitza Stark Marked gene: SRP54 as ready
Mendeliome v0.12622 SRD5A2 Zornitza Stark Marked gene: SRD5A2 as ready
Mendeliome v0.12619 SPRY1 Zornitza Stark Marked gene: SPRY1 as ready
Mendeliome v0.12618 SPINK5 Zornitza Stark Marked gene: SPINK5 as ready
Mendeliome v0.12615 SPINK1 Zornitza Stark Marked gene: SPINK1 as ready
Mendeliome v0.12615 SPINK1 Zornitza Stark Phenotypes for gene: SPINK1 were changed from to Tropical calcific pancreatitis, MIM# 608189; Pancreatitis, hereditary, MIM# 167800
Mendeliome v0.12612 SPINK1 Zornitza Stark reviewed gene: SPINK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10835640, 11355022, 11938439, 16823394, 17274009, 27535533; Phenotypes: Tropical calcific pancreatitis, MIM# 608189, Pancreatitis, hereditary, MIM# 167800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12612 SPG7 Zornitza Stark Phenotypes for gene: SPG7 were changed from Spastic paraplegia 7, autosomal recessive, MIM# 607259 to Spastic paraplegia 7, autosomal recessive, MIM# 607259; Autosomal dominant optic atrophy, MONDO:0020250
Mendeliome v0.12610 SPG7 Zornitza Stark changed review comment from: SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes.

Well established for bi-allelic variants.

Enrichment of mono-allelic variants reported in a couple of cohorts, although a recent one suggests digenic inheritance.; to: SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes.

Well established for bi-allelic variants.

Enrichment of mono-allelic variants reported in a couple of cohorts, although a recent one suggests digenic inheritance.

Association with OA: 7 families reported for AD OA, including 5 missense and 2 frameshift variants, PMID 32548275
Mendeliome v0.12610 SPG7 Zornitza Stark edited their review of gene: SPG7: Changed publications: 9635427, 9635427, 16534102, 18799786, 22571692, 34500365, 33598982, 32548275; Changed phenotypes: Spastic paraplegia 7, autosomal recessive, MIM# 607259, Autosomal dominant optic atrophy, MONDO:0020250; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12610 SPG7 Zornitza Stark Marked gene: SPG7 as ready
Mendeliome v0.12610 SPG7 Zornitza Stark Phenotypes for gene: SPG7 were changed from to Spastic paraplegia 7, autosomal recessive, MIM# 607259
Mendeliome v0.12607 SPG7 Zornitza Stark reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 9635427, 9635427, 16534102, 18799786, 22571692, 34500365, 33598982; Phenotypes: Spastic paraplegia 7, autosomal recessive, MIM# 607259; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12607 RSPO4 Zornitza Stark Marked gene: RSPO4 as ready
Mendeliome v0.12604 RTN4IP1 Zornitza Stark Marked gene: RTN4IP1 as ready
Mendeliome v0.12604 RTN4IP1 Zornitza Stark Phenotypes for gene: RTN4IP1 were changed from to Optic atrophy 10 with or without ataxia, mental retardation, and seizures, MIM#616732
Mendeliome v0.12601 RUNX1 Zornitza Stark Marked gene: RUNX1 as ready
Mendeliome v0.12598 PAX6 Zornitza Stark Marked gene: PAX6 as ready
Mendeliome v0.12598 PAX6 Zornitza Stark Phenotypes for gene: PAX6 were changed from to Coloboma of optic nerve - MIM# 120430; Coloboma, ocular - MIM#120200; Morning glory disc anomaly - MIM#120430; Aniridia - MIM#106210; Anterior segment dysgenesis 5, multiple subtypes - MIM#604229; Cataract with late-onset corneal dystrophy - MIM#106210; Foveal hypoplasia 1- MIM#136520; Keratitis - MIM#148190; Optic nerve hypoplasia - MIM#165550
Mendeliome v0.12595 PAX2 Zornitza Stark Marked gene: PAX2 as ready
Mendeliome v0.12592 TSEN15 Zornitza Stark Marked gene: TSEN15 as ready
Mendeliome v0.12592 TSEN15 Zornitza Stark Phenotypes for gene: TSEN15 were changed from to Pontocerebellar hypoplasia, type 2F, MIM # 617026, MONDO:0014874
Mendeliome v0.12589 TSEN15 Zornitza Stark reviewed gene: TSEN15: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia, type 2F, MIM # 617026, MONDO:0014874; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12589 RAB33B Zornitza Stark Marked gene: RAB33B as ready
Mendeliome v0.12586 RAB28 Zornitza Stark Marked gene: RAB28 as ready
Mendeliome v0.12583 PAM16 Zornitza Stark Marked gene: PAM16 as ready
Mendeliome v0.12583 PAM16 Zornitza Stark Phenotypes for gene: PAM16 were changed from to Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, OMIM # 613320
Mendeliome v0.12580 PALLD Zornitza Stark Marked gene: PALLD as ready
Mendeliome v0.12578 AMPD3 Zornitza Stark Marked gene: AMPD3 as ready
Mendeliome v0.12573 RTN4IP1 Belinda Chong reviewed gene: RTN4IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26593267, 31077085; Phenotypes: Optic atrophy 10 with or without ataxia, mental retardation, and seizures, MIM#616732; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12573 PAX6 Krithika Murali reviewed gene: PAX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31700164, 30986449, 29930474, 22171686; Phenotypes: ?Coloboma of optic nerve - MIM# 120430, ?Coloboma, ocular - MIM#120200, ?Morning glory disc anomaly - MIM#120430, Aniridia - MIM#106210, Anterior segment dysgenesis 5, multiple subtypes - MIM#604229, Cataract with late-onset corneal dystrophy - MIM#106210, Foveal hypoplasia 1- MIM#136520, Keratitis - MIM#148190, Optic nerve hypoplasia - MIM#165550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12573 TSEN15 Manny Jacobs reviewed gene: TSEN15: Rating: ; Mode of pathogenicity: None; Publications: PMID: 25558065, 27392077; Phenotypes: Pontocerebellar hypoplasia, type 2F, MIM # 617026, MONDO:0014874; Mode of inheritance: None
Mendeliome v0.12571 SERPINC1 Zornitza Stark Marked gene: SERPINC1 as ready
Mendeliome v0.12571 SERPINC1 Zornitza Stark Phenotypes for gene: SERPINC1 were changed from to hereditary antithrombin deficiency MONDO:0013144; Thrombophilia 7 due to antithrombin III deficiency, MIM#613118
Mendeliome v0.12568 SERPINB8 Zornitza Stark Marked gene: SERPINB8 as ready
Mendeliome v0.12565 SERPINB6 Zornitza Stark Marked gene: SERPINB6 as ready
Mendeliome v0.12561 PAM16 Krithika Murali reviewed gene: PAM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 24786642, 27354339; Phenotypes: Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, OMIM # 613320; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12561 CCM2 Ain Roesley Marked gene: CCM2 as ready
Mendeliome v0.12559 CCL2 Ain Roesley Marked gene: CCL2 as ready
Mendeliome v0.12557 CCDC88A Ain Roesley Marked gene: CCDC88A as ready
Mendeliome v0.12555 ANK1 Elena Savva Marked gene: ANK1 as ready
Mendeliome v0.12554 ANKH Elena Savva Marked gene: ANKH as ready
Mendeliome v0.12554 CCDC50 Ain Roesley Marked gene: CCDC50 as ready
Mendeliome v0.12553 ANKLE2 Elena Savva Phenotypes for gene: ANKLE2 were changed from Microcephaly 16, primary, autosomal recessive, MIM# 616681 to Microcephaly 16, primary, autosomal recessive, MIM# 616681
Mendeliome v0.12552 ANKLE2 Elena Savva Phenotypes for gene: ANKLE2 were changed from Microcephaly 16, primary, autosomal recessive, MIM# 616681 to Microcephaly 16, primary, autosomal recessive, MIM# 616681
Mendeliome v0.12548 ANKLE2 Elena Savva Phenotypes for gene: ANKLE2 were changed from to Microcephaly 16, primary, autosomal recessive, MIM# 616681
Mendeliome v0.12547 ANKLE2 Elena Savva Marked gene: ANKLE2 as ready
Mendeliome v0.12546 CAV3 Ain Roesley Marked gene: CAV3 as ready
Mendeliome v0.12542 CATSPER2 Ain Roesley Marked gene: CATSPER2 as ready
Mendeliome v0.12541 CATSPER2 Ain Roesley Phenotypes for gene: CATSPER2 were changed from to spermatogenic failure; non-syndromic hearing loss
Mendeliome v0.12539 CATSPER2 Ain Roesley reviewed gene: CATSPER2: Rating: AMBER; Mode of pathogenicity: None; Publications: 17098888, 30629171, 12825070; Phenotypes: spermatogenic failure, non-syndromic hearing loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12539 ANGPTL3 Elena Savva Marked gene: ANGPTL3 as ready
Mendeliome v0.12536 CATSPER1 Ain Roesley Marked gene: CATSPER1 as ready
Mendeliome v0.12534 ETFA Bryony Thompson Marked gene: ETFA as ready
Mendeliome v0.12533 ERLIN2 Bryony Thompson Marked gene: ERLIN2 as ready
Mendeliome v0.12532 TSHB Zornitza Stark Marked gene: TSHB as ready
Mendeliome v0.12531 ERLIN2 Bryony Thompson Phenotypes for gene: ERLIN2 were changed from to hereditary spastic paraplegia 18 MONDO:0012639
Mendeliome v0.12528 TSHR Zornitza Stark Marked gene: TSHR as ready
Mendeliome v0.12525 CAT Ain Roesley Marked gene: CAT as ready
Mendeliome v0.12523 TSPAN7 Zornitza Stark Marked gene: TSPAN7 as ready
Mendeliome v0.12519 TSPAN7 Zornitza Stark changed review comment from: The P172H missense, which is reported in two families, is present at a high frequency in gnomad, including 66 hemizygotes.; to: The P172H missense, which is reported in two families, is present at a high frequency in gnomad, including 66 hemizygotes.

Most variants in ClinVar are either VOUS or LB.
Mendeliome v0.12518 ERLIN2 Bryony Thompson reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23109145, 21330303, 21796390, 29528531, 32094424, 34734492; Phenotypes: hereditary spastic paraplegia 18 MONDO:0012639; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12518 AMT Elena Savva Marked gene: AMT as ready
Mendeliome v0.12518 EPX Bryony Thompson Marked gene: EPX as ready
Mendeliome v0.12516 AMHR2 Elena Savva Marked gene: AMHR2 as ready
Mendeliome v0.12514 ALX4 Elena Savva Marked gene: ALX4 as ready
Mendeliome v0.12512 ALX4 Elena Savva Phenotypes for gene: ALX4 were changed from to Frontonasal dysplasia 2 MIM# 613451; Parietal foramina 2 MIM# 609597; {Craniosynostosis 5, susceptibility to} MIM#615529
Mendeliome v0.12510 ALX4 Elena Savva reviewed gene: ALX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22829454, 34586326; Phenotypes: Frontonasal dysplasia 2 MIM# 613451, Parietal foramina 2 MIM# 609597, {Craniosynostosis 5, susceptibility to} MIM#615529; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12508 ALMS1 Elena Savva Marked gene: ALMS1 as ready
Mendeliome v0.12508 ALDH6A1 Elena Savva Marked gene: ALDH6A1 as ready
Mendeliome v0.12508 ALDH18A1 Elena Savva Phenotypes for gene: ALDH18A1 were changed from Cutis laxa, autosomal recessive, type IIIA MIM#219150; Spastic paraplegia 9A, autosomal dominant MIM#601162; Spastic paraplegia 9B, autosomal recessive MIM#616586; Cutis laxa, autosomal dominant 3 MIM#616603; disorders of ornithine or proline metabolism to Cutis laxa, autosomal recessive, type IIIA MIM#219150; Spastic paraplegia 9A, autosomal dominant MIM#601162; Spastic paraplegia 9B, autosomal recessive MIM#616586; Cutis laxa, autosomal dominant 3 MIM#616603; disorders of ornithine or proline metabolism
Mendeliome v0.12505 ALDH18A1 Elena Savva Phenotypes for gene: ALDH18A1 were changed from to Cutis laxa, autosomal recessive, type IIIA MIM#219150; Spastic paraplegia 9A, autosomal dominant MIM#601162; Spastic paraplegia 9B, autosomal recessive MIM#616586; Cutis laxa, autosomal dominant 3 MIM#616603; disorders of ornithine or proline metabolism
Mendeliome v0.12504 ALDH18A1 Elena Savva Marked gene: ALDH18A1 as ready
Mendeliome v0.12503 SERPINC1 Samantha Ayres reviewed gene: SERPINC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31359133, 30356112, 23910795, 28317092, 29747524, 11018075, 14590998; Phenotypes: hereditary antithrombin deficiency MONDO:0013144, Thrombophilia 7 due to antithrombin III deficiency, MIM#613118; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.12503 CASR Ain Roesley Marked gene: CASR as ready
Mendeliome v0.12503 CASR Ain Roesley Phenotypes for gene: CASR were changed from to Hyperparathyroidism, neonatal MIM#239200; Hypocalcemia, autosomal dominant MIM#601198; Hypocalcemia autosomal dominant, with Bartter syndrome MIM#601198; hypercalcemia, type I MIM#145980
Mendeliome v0.12501 CASR Ain Roesley reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7916660, 7726161, 8675635, 17698911, 22620673, 26646938, 22422767; Phenotypes: Hyperparathyroidism, neonatal MIM#239200, Hypocalcemia, autosomal dominant MIM#601198, Hypocalcemia autosomal dominant, with Bartter syndrome MIM#601198, hypercalcemia, type I MIM#145980; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12500 CASQ1 Ain Roesley Marked gene: CASQ1 as ready
Mendeliome v0.12500 CASQ1 Ain Roesley Phenotypes for gene: CASQ1 were changed from to Myopathy, vacuolar, with CASQ1 aggregates MIM#616231
Mendeliome v0.12498 CASQ1 Ain Roesley reviewed gene: CASQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26136523, 30258016; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates MIM#616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.12498 TMEM98 Zornitza Stark Marked gene: TMEM98 as ready
Mendeliome v0.12495 TMEM70 Zornitza Stark Marked gene: TMEM70 as ready
Mendeliome v0.12495 TMEM70 Zornitza Stark Phenotypes for gene: TMEM70 were changed from to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, MIM# 614052
Mendeliome v0.12492 TMEM70 Zornitza Stark reviewed gene: TMEM70: Rating: GREEN; Mode of pathogenicity: None; Publications: 18953340, 21147908, 30950220; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, MIM# 614052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12492 TMEM38B Zornitza Stark Marked gene: TMEM38B as ready
Mendeliome v0.12489 TMEM199 Zornitza Stark Marked gene: TMEM199 as ready
Mendeliome v0.12486 TMEM173 Zornitza Stark Marked gene: TMEM173 as ready
Mendeliome v0.12483 TMC6 Zornitza Stark Marked gene: TMC6 as ready
Mendeliome v0.12480 TLR5 Zornitza Stark Marked gene: TLR5 as ready
Mendeliome v0.12479 TLR3 Zornitza Stark Marked gene: TLR3 as ready
Mendeliome v0.12476 TLR2 Zornitza Stark Marked gene: TLR2 as ready
Mendeliome v0.12475 FTCD Zornitza Stark Marked gene: FTCD as ready
Mendeliome v0.12472 FTCD Zornitza Stark Marked gene: FTCD as ready
Mendeliome v0.12469 FGF14 Zornitza Stark Marked gene: FGF14 as ready
Mendeliome v0.12469 FGF14 Zornitza Stark Phenotypes for gene: FGF14 were changed from to Spinocerebellar ataxia 27 MIM#609307
Mendeliome v0.12467 FAT4 Zornitza Stark Marked gene: FAT4 as ready
Mendeliome v0.12464 ERLIN1 Zornitza Stark Marked gene: ERLIN1 as ready
Mendeliome v0.12464 ERCC6 Zornitza Stark Marked gene: ERCC6 as ready
Mendeliome v0.12460 SLC30A2 Zornitza Stark Marked gene: SLC30A2 as ready
Mendeliome v0.12457 SLC2A9 Zornitza Stark Marked gene: SLC2A9 as ready
Mendeliome v0.12453 EPOR Bryony Thompson Phenotypes for gene: EPOR were changed from to primary familial polycythemia due to EPO receptor mutation MONDO:0007572
Mendeliome v0.12451 EPS8 Bryony Thompson reviewed gene: EPS8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24741995, 27344577, 30303587, 34637946, 21526224; Phenotypes: Autosomal recessive nonsyndromic hearing loss 102 MONDO:0014428; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12449 EPOR Bryony Thompson reviewed gene: EPOR: Rating: GREEN; Mode of pathogenicity: Other; Publications: 8506290, 11559951, 17488692, 18492694, 30507031; Phenotypes: primary familial polycythemia due to EPO receptor mutation MONDO:0007572; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12449 SLC30A8 Zornitza Stark Marked gene: SLC30A8 as ready
Mendeliome v0.12445 SLC34A1 Zornitza Stark changed review comment from: Infantile hypercalcaemia and bi-allelic variants: More than 5 unrelated families reported.

Nephrolithiasis and mono-allelic variants: multiple families reported.; to: Infantile hypercalcaemia and bi-allelic variants: More than 5 unrelated families reported.

Nephrolithiasis and mono-allelic variants: multiple families reported.

Single family reported with renal Fanconi and homozygous variant.
Mendeliome v0.12445 SLC34A1 Zornitza Stark Marked gene: SLC34A1 as ready
Mendeliome v0.12442 SLC34A2 Zornitza Stark Marked gene: SLC34A2 as ready
Mendeliome v0.12442 SLC34A2 Zornitza Stark Phenotypes for gene: SLC34A2 were changed from to Pulmonary alveolar microlithiasis, MIM# 265100
Mendeliome v0.12439 SLC34A2 Zornitza Stark reviewed gene: SLC34A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16960801, 34581165, 33884208, 32328294, 31941744; Phenotypes: Pulmonary alveolar microlithiasis, MIM# 265100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12439 SLC35A1 Zornitza Stark Marked gene: SLC35A1 as ready
Mendeliome v0.12439 EPO Bryony Thompson Marked gene: EPO as ready
Mendeliome v0.12435 SLC39A13 Zornitza Stark Marked gene: SLC39A13 as ready
Mendeliome v0.12432 SLC39A5 Zornitza Stark Marked gene: SLC39A5 as ready
Mendeliome v0.12430 EPO Bryony Thompson changed review comment from: PMID: 27651169, 29514032, 25985138 - At least 4 families reported with heterozygous variants segregating with erythrocytosis. Mechanism of disease is gain-of-function. Frameshift variants identified (c.32delG, c.19delC) use of an alternative promoter (P2) in intron 1 causing the production of functional transcripts and increased amounts of biologically active EPO compared to controls, and 5’UTR conserved variant (c.‐136G>A) and expected to have a similar mechanism.

PMID: 28283061 - single proband from a consanguineous family with severe anaemia (Diamond-Blackfan anaemia phenotype) reported with a homozygous missense (R150Q) showing a mild reduction in its affinity for the EPO receptor; to: PMID: 27651169, 29514032, 25985138 - At least 4 families reported with heterozygous variants segregating with erythrocytosis. Mechanism of disease is gain-of-function. Frameshift variants identified (c.32delG, c.19delC) use of an alternative promoter (P2) in intron 1 causing the production of functional transcripts and increased amounts of biologically active EPO compared to controls, and 5’UTR conserved variant (c.‐136G>A) expected to have a similar mechanism.

PMID: 28283061 - single proband from a consanguineous family with severe anaemia (Diamond-Blackfan anaemia phenotype) reported with a homozygous missense (R150Q) showing a mild reduction in its affinity for the EPO receptor
Mendeliome v0.12426 EPM2A Bryony Thompson Marked gene: EPM2A as ready
Mendeliome v0.12422 EPHA3 Bryony Thompson Marked gene: EPHA3 as ready
Mendeliome v0.12421 EPHA2 Bryony Thompson Marked gene: EPHA2 as ready
Mendeliome v0.12421 EPHA2 Bryony Thompson Phenotypes for gene: EPHA2 were changed from to cataract 6 multiple types MONDO:0007288
Mendeliome v0.12420 SLC40A1 Zornitza Stark Marked gene: SLC40A1 as ready
Mendeliome v0.12415 EPHA2 Bryony Thompson reviewed gene: EPHA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19005574, 19649315, 19306328, 33671840; Phenotypes: cataract 6 multiple types MONDO:0007288; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12415 SLC4A11 Zornitza Stark Marked gene: SLC4A11 as ready
Mendeliome v0.12413 SLC4A4 Zornitza Stark Marked gene: SLC4A4 as ready
Mendeliome v0.12413 SLC4A4 Zornitza Stark Phenotypes for gene: SLC4A4 were changed from to Renal tubular acidosis, proximal, with ocular abnormalities, MIM# 604278; Hemiplegic migraine
Mendeliome v0.12410 SLC4A4 Zornitza Stark reviewed gene: SLC4A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 10545938, 11274232, 35260236, 33439394, 29914390; Phenotypes: Renal tubular acidosis, proximal, with ocular abnormalities, MIM# 604278, Hemiplegic migraine; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12410 ENO3 Bryony Thompson Marked gene: ENO3 as ready
Mendeliome v0.12407 ENG Bryony Thompson Marked gene: ENG as ready
Mendeliome v0.12407 ENG Bryony Thompson Phenotypes for gene: ENG were changed from to hereditary hemorrhagic telangiectasia MONDO:0019180
Mendeliome v0.12404 ENG Bryony Thompson reviewed gene: ENG: Rating: GREEN; Mode of pathogenicity: None; Publications: 34012068, 30336550, 7894484, 10751092, 20414677, 30763665, 17384219, 20364125; Phenotypes: hereditary hemorrhagic telangiectasia MONDO:0019180; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.12404 EMP2 Bryony Thompson Marked gene: EMP2 as ready
Mendeliome v0.12400 ELP2 Bryony Thompson Marked gene: ELP2 as ready
Mendeliome v0.12397 ELOVL4 Bryony Thompson Marked gene: ELOVL4 as ready
Mendeliome v0.12397 ELOVL5 Bryony Thompson Marked gene: ELOVL5 as ready
Mendeliome v0.12397 ELOVL5 Bryony Thompson Phenotypes for gene: ELOVL5 were changed from to spinocerebellar ataxia type 38 MONDO:0014417
Mendeliome v0.12396 ELOVL4 Bryony Thompson Phenotypes for gene: ELOVL4 were changed from to congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome MONDO:0013760; spinocerebellar ataxia type 34 MONDO:0007574; Stargardt disease MONDO:0019353
Mendeliome v0.12390 ELOVL4 Bryony Thompson reviewed gene: ELOVL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11138005, 15028284, 11726641, 17208947, 22100072, 24566826, 34227061, 24571530, 26010696; Phenotypes: congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome MONDO:0013760, spinocerebellar ataxia type 34 MONDO:0007574, Stargardt disease MONDO:0019353; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12390 ELN Bryony Thompson Marked gene: ELN as ready
Mendeliome v0.12390 ELN Bryony Thompson Phenotypes for gene: ELN were changed from to cutis laxa, autosomal dominant 1 MONDO:0007411; supravalvular aortic stenosis MONDO:0008504
Mendeliome v0.12387 ELN Bryony Thompson reviewed gene: ELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 8132745, 9580666, 9873040, 10190324, 10190538, 22573328, 28383366; Phenotypes: cutis laxa, autosomal dominant 1 MONDO:0007411, supravalvular aortic stenosis MONDO:0008504; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.12387 ARPC4 Bryony Thompson Publications for gene: ARPC4 were set to DOI:https://doi.org/10.1016/j.xhgg.2021.100072
Mendeliome v0.12386 ARPC4 Bryony Thompson edited their review of gene: ARPC4: Changed publications: 35047857; Set current diagnostic: yes
Mendeliome v0.12386 SLC52A2 Zornitza Stark Marked gene: SLC52A2 as ready
Mendeliome v0.12384 SLC52A3 Zornitza Stark Marked gene: SLC52A3 as ready
Mendeliome v0.12382 DVL2 Bryony Thompson Marked gene: DVL2 as ready
Mendeliome v0.12381 SLC5A2 Zornitza Stark Marked gene: SLC5A2 as ready
Mendeliome v0.12381 DVL2 Bryony Thompson gene: DVL2 was added
gene: DVL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DVL2 were set to 35047859; 33599851; 30521570
Phenotypes for gene: DVL2 were set to Robinow syndrome MONDO:0019978
Review for gene: DVL2 was set to AMBER
Added comment: A single case with Robinow syndrome identified with a de novo frameshift variant in the last exon of the gene (c.2105dupC, p.Pro703Serfs*103). Also, a canine DVL2 frameshift variant has been associated with a Robinow-like syndrome in dogs, contributing to the brachycephalic phenotype and caudal vertebral anomalies.
Sources: Literature
Mendeliome v0.12379 SLC6A17 Zornitza Stark Marked gene: SLC6A17 as ready
Mendeliome v0.12379 TAMM41 Bryony Thompson Marked gene: TAMM41 as ready
Mendeliome v0.12378 TAMM41 Bryony Thompson gene: TAMM41 was added
gene: TAMM41 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAMM41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAMM41 were set to 35321494; 29253589
Phenotypes for gene: TAMM41 were set to inborn mitochondrial metabolism disorder MONDO:0004069; hypotonia; developmental delay; myopathy; ptosis
Review for gene: TAMM41 was set to GREEN
Added comment: Three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis with biallelic variants. Tissue-specific observations on OXPHOS were identified, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. The missense variants identified were defective in yeast models. In an in vitro cell model knockdown of TAMM41 resulted in decreased mitochondrial CDP diacylglycerol synthase activity, decreased cardiolipin levels and a decrease in oxygen consumption.
Sources: Literature
Mendeliome v0.12377 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from to Mental retardation, autosomal recessive 48, MIM# 616269
Mendeliome v0.12373 SLC6A17 Zornitza Stark reviewed gene: SLC6A17: Rating: AMBER; Mode of pathogenicity: None; Publications: 25704603, 23672601; Phenotypes: Mental retardation, autosomal recessive 48, MIM# 616269; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12373 SLC6A19 Zornitza Stark Marked gene: SLC6A19 as ready
Mendeliome v0.12373 SLC6A19 Zornitza Stark Phenotypes for gene: SLC6A19 were changed from to Hartnup disorder, MIM# 234500; Hyperglycinuria, MIM# 138500; Iminoglycinuria, MIM# 242600
Mendeliome v0.12371 BNIP1 Bryony Thompson Marked gene: BNIP1 as ready
Mendeliome v0.12370 BNIP1 Bryony Thompson gene: BNIP1 was added
gene: BNIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BNIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BNIP1 were set to 35266227; 31344970
Phenotypes for gene: BNIP1 were set to spondyloepiphyseal dysplasia MONDO:0016761
Review for gene: BNIP1 was set to AMBER
Added comment: Two apparently unrelated cases with spondyloepiphyseal dysplasia from India were identified with the same variant (c.84+3A>T). The kindred coefficient comparison of the 2 cases exome data suggested they were unrelated, however there was a stretch of shared homozygosity suggesting remote consanguinity. ~80% aberrantly spliced BNIP1 pre-mRNAs, reduced BNIP1 mRNA level to ~80%, and BNIP1 protein level reduction by ~50% were detected in one of the cases fibroblasts. A block at the terminal stage of autolysosome formation and/or clearance in patient fibroblasts was suggested based on the data. A drosophila model of the BNIP1 orthologue Sec20 also demonstrated defective autolysosome formation.
Sources: Literature
Mendeliome v0.12369 EIF4E Bryony Thompson Marked gene: EIF4E as ready
Mendeliome v0.12366 TLL1 Zornitza Stark Marked gene: TLL1 as ready
Mendeliome v0.12365 TK2 Zornitza Stark Marked gene: TK2 as ready
Mendeliome v0.12362 TJP2 Zornitza Stark Marked gene: TJP2 as ready
Mendeliome v0.12359 TIMP3 Zornitza Stark Marked gene: TIMP3 as ready
Mendeliome v0.12356 TIMM50 Zornitza Stark Marked gene: TIMM50 as ready
Mendeliome v0.12353 TIMM44 Zornitza Stark Marked gene: TIMM44 as ready
Mendeliome v0.12352 TICAM1 Zornitza Stark Marked gene: TICAM1 as ready
Mendeliome v0.12349 TTBK2 Zornitza Stark Marked gene: TTBK2 as ready
Mendeliome v0.12349 TTBK2 Zornitza Stark Phenotypes for gene: TTBK2 were changed from to Spinocerebellar ataxia 11, MIM# 604432, MONDO:0011464
Mendeliome v0.12346 TTBK2 Zornitza Stark reviewed gene: TTBK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301723; Phenotypes: Spinocerebellar ataxia 11, MIM# 604432, MONDO:0011464; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12346 TTLL5 Zornitza Stark Marked gene: TTLL5 as ready
Mendeliome v0.12343 TTR Zornitza Stark Marked gene: TTR as ready
Mendeliome v0.12343 TTR Zornitza Stark Phenotypes for gene: TTR were changed from to Amyloidosis, hereditary, transthyretin-related, MIM #105210; Carpal tunnel syndrome, familial, MIM# 115430
Mendeliome v0.12339 EIF2B4 Zornitza Stark Phenotypes for gene: EIF2B4 were changed from leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure to Leukoencephalopathy with vanishing white matter, MIM# 603896; leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure
Mendeliome v0.12338 PADI6 Zornitza Stark Marked gene: PADI6 as ready
Mendeliome v0.12335 PADI3 Zornitza Stark Marked gene: PADI3 as ready
Mendeliome v0.12332 PACS2 Zornitza Stark Marked gene: PACS2 as ready
Mendeliome v0.12329 PABPN1 Zornitza Stark Marked gene: PABPN1 as ready
Mendeliome v0.12329 PABPN1 Zornitza Stark Phenotypes for gene: PABPN1 were changed from to Oculopharyngeal muscular dystrophy - MIM#164300
Mendeliome v0.12326 AGK Zornitza Stark Marked gene: AGK as ready
Mendeliome v0.12326 AGK Zornitza Stark Phenotypes for gene: AGK were changed from to Sengers syndrome, MIM#212350; Cataract 38 MIM#614691
Mendeliome v0.12323 TTBK2 Manny Jacobs reviewed gene: TTBK2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 18037885, 31485862, 20667868, 27165044; Phenotypes: Spinocerebellar ataxia 11, MIM# 604432, MONDO:0011464; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12323 EIF2B5 Bryony Thompson Marked gene: EIF2B5 as ready
Mendeliome v0.12323 TTR Manny Jacobs reviewed gene: TTR: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:1570831, 1626570, 16115295, 16194874, 26537620; Phenotypes: Amyloidosis, hereditary, transthyretin-related, MIM #105210, Carpal tunnel syndrome, familial, MIM# 115430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12323 EIF2B5 Bryony Thompson Phenotypes for gene: EIF2B5 were changed from to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure
Mendeliome v0.12321 P3H2 Zornitza Stark Marked gene: P3H2 as ready
Mendeliome v0.12321 P3H2 Zornitza Stark Phenotypes for gene: P3H2 were changed from to Myopia, high, with cataract and vitreoretinal degeneration - MIM#614292
Mendeliome v0.12316 AKT3 Elena Savva Marked gene: AKT3 as ready
Mendeliome v0.12316 EIF2B4 Bryony Thompson Marked gene: EIF2B4 as ready
Mendeliome v0.12314 EIF2B4 Bryony Thompson Phenotypes for gene: EIF2B4 were changed from to leukoencephalopathy with vanishing white matter MONDO:0011380; ataxia; spasticity; optic atrophy; primary ovarian failure
Mendeliome v0.12311 EIF2B3 Bryony Thompson Marked gene: EIF2B3 as ready
Mendeliome v0.12311 AFP Zornitza Stark Marked gene: AFP as ready
Mendeliome v0.12311 AFP Zornitza Stark Added comment: Comment when marking as ready: Raised or low levels of AFP are observed in some medical conditions, kept Amber due to possible phenotypic overlap.
Mendeliome v0.12311 AFP Zornitza Stark Phenotypes for gene: AFP were changed from to Alpha-fetoprotein deficiency MIM#615969; [Hereditary persistence of alpha-fetoprotein] MIM#615970
Mendeliome v0.12304 AHCY Elena Savva Marked gene: AHCY as ready
Mendeliome v0.12302 EIF2B1 Bryony Thompson Marked gene: EIF2B1 as ready
Mendeliome v0.12302 AGL Elena Savva Marked gene: AGL as ready
Mendeliome v0.12298 EIF2AK3 Bryony Thompson Marked gene: EIF2AK3 as ready
Mendeliome v0.12293 THSD1 Zornitza Stark Marked gene: THSD1 as ready
Mendeliome v0.12289 EFNA4 Bryony Thompson Marked gene: EFNA4 as ready
Mendeliome v0.12288 RBMX Zornitza Stark Marked gene: RBMX as ready
Mendeliome v0.12287 RBMX Zornitza Stark gene: RBMX was added
gene: RBMX was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RBMX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RBMX were set to 25256757; 34260915
Phenotypes for gene: RBMX were set to Intellectual developmental disorder, syndromic 11, Shashi type, MIM#300238
Review for gene: RBMX was set to AMBER
Added comment: Hemizygous truncating variant reported segregating in multiple affected individuals in a single family. Some supportive functional data.
Sources: Expert Review
Mendeliome v0.12284 EHBP1 Bryony Thompson Marked gene: EHBP1 as ready
Mendeliome v0.12284 EHBP1 Bryony Thompson Phenotypes for gene: EHBP1 were changed from to {Prostate cancer, hereditary, 12} MIM#611868
Mendeliome v0.12282 EHBP1 Bryony Thompson reviewed gene: EHBP1: Rating: RED; Mode of pathogenicity: None; Publications: 18264098; Phenotypes: {Prostate cancer, hereditary, 12} MIM#611868; Mode of inheritance: None
Mendeliome v0.12282 PABPN1 Krithika Murali reviewed gene: PABPN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19080757, 33805441; Phenotypes: Oculopharyngeal muscular dystrophy - MIM#164300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12282 AGK Elena Savva reviewed gene: AGK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22415731, 25208612; Phenotypes: Sengers syndrome, MIM#212350, Cataract 38 MIM#614691; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12282 EDNRB Bryony Thompson Marked gene: EDNRB as ready
Mendeliome v0.12281 P3H2 Krithika Murali reviewed gene: P3H2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21885030, 24172257, 25469533; Phenotypes: Myopia, high, with cataract and vitreoretinal degeneration - MIM#614292; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12281 AFP Elena Savva reviewed gene: AFP: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 15280901, 18854864; Phenotypes: Alpha-fetoprotein deficiency MIM#615969, [Hereditary persistence of alpha-fetoprotein] MIM#615970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12281 ADRB2 Elena Savva Marked gene: ADRB2 as ready
Mendeliome v0.12279 THRB Zornitza Stark Marked gene: THRB as ready
Mendeliome v0.12279 THRB Zornitza Stark Phenotypes for gene: THRB were changed from to Thyroid hormone resistance, MIM# 188570; Thyroid hormone resistance, autosomal recessive, MIM# 274300; Thyroid hormone resistance, selective pituitary, MIM# 145650
Mendeliome v0.12276 THRB Zornitza Stark reviewed gene: THRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25135573, 31590893; Phenotypes: Thyroid hormone resistance, MIM# 188570, Thyroid hormone resistance, autosomal recessive, MIM# 274300, Thyroid hormone resistance, selective pituitary, MIM# 145650; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.12276 SLC6A2 Zornitza Stark Marked gene: SLC6A2 as ready
Mendeliome v0.12272 SMARCAD1 Zornitza Stark Marked gene: SMARCAD1 as ready
Mendeliome v0.12272 SMARCAD1 Zornitza Stark Gene: smarcad1 has been classified as Green List (High Evidence).
Mendeliome v0.12272 SMARCAD1 Zornitza Stark Phenotypes for gene: SMARCAD1 were changed from Huriez syndrome, OMIM #181600; Basan syndrome, MIM# 129200; Adermatoglyphia, MIM# 136000 to Huriez syndrome, OMIM #181600; Basan syndrome, MIM# 129200; Adermatoglyphia, MIM# 136000
Mendeliome v0.12272 SMARCAD1 Zornitza Stark Phenotypes for gene: SMARCAD1 were changed from to Huriez syndrome, OMIM #181600; Basan syndrome, MIM# 129200; Adermatoglyphia, MIM# 136000
Mendeliome v0.12271 SMARCAD1 Zornitza Stark Publications for gene: SMARCAD1 were set to
Mendeliome v0.12270 SMARCAD1 Zornitza Stark Mode of inheritance for gene: SMARCAD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12269 SMARCAD1 Zornitza Stark Mode of inheritance for gene: SMARCAD1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12268 SMARCAD1 Zornitza Stark reviewed gene: SMARCAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29409814; Phenotypes: Huriez syndrome, OMIM #181600, Basan syndrome, MIM# 129200, Adermatoglyphia, MIM# 136000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12268 SMARCB1 Zornitza Stark Marked gene: SMARCB1 as ready
Mendeliome v0.12268 SMARCB1 Zornitza Stark Gene: smarcb1 has been classified as Green List (High Evidence).
Mendeliome v0.12268 SMARCB1 Zornitza Stark Phenotypes for gene: SMARCB1 were changed from to Coffin-Siris syndrome 3, MIM# 614608
Mendeliome v0.12267 SMARCB1 Zornitza Stark Publications for gene: SMARCB1 were set to
Mendeliome v0.12266 SMARCB1 Zornitza Stark Mode of inheritance for gene: SMARCB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12265 SMARCB1 Zornitza Stark reviewed gene: SMARCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34205270, 31530938, 25168959; Phenotypes: Coffin-Siris syndrome 3, MIM# 614608; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12265 SMN2 Zornitza Stark Marked gene: SMN2 as ready
Mendeliome v0.12265 SMN2 Zornitza Stark Phenotypes for gene: SMN2 were changed from to {Spinal muscular atrophy, type III, modifier of} 253400
Mendeliome v0.12262 SMN2 Zornitza Stark reviewed gene: SMN2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: {Spinal muscular atrophy, type III, modifier of} 253400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12262 OTOG Zornitza Stark Marked gene: OTOG as ready
Mendeliome v0.12261 EDNRB Bryony Thompson Phenotypes for gene: EDNRB were changed from to Waardenburg syndrome type 4A MONDO:0010192; sensorineural hearing loss; pigmentary abnormalities; Hirschsprung disease
Mendeliome v0.12258 EDNRB Bryony Thompson reviewed gene: EDNRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 28502583, 25852447, 21373256, 16237557, 11773966, 11891690, 8001158, 10528251, 10528251, 19764031, 28236341; Phenotypes: Waardenburg syndrome type 4A (MONDO:0010192); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12255 OTC Zornitza Stark Marked gene: OTC as ready
Mendeliome v0.12255 OTC Zornitza Stark Phenotypes for gene: OTC were changed from to Ornithine transcarbamylase deficiency - MIM#311250
Mendeliome v0.12253 OSTM1 Zornitza Stark Marked gene: OSTM1 as ready
Mendeliome v0.12250 OSMR Zornitza Stark Marked gene: OSMR as ready
Mendeliome v0.12250 OSMR Zornitza Stark Phenotypes for gene: OSMR were changed from to Amyloidosis, primary localized cutaneous, 1 - MIM#105250
Mendeliome v0.12247 OSBPL2 Zornitza Stark Marked gene: OSBPL2 as ready
Mendeliome v0.12244 OR2J3 Zornitza Stark Marked gene: OR2J3 as ready
Mendeliome v0.12243 OPN1SW Zornitza Stark Marked gene: OPN1SW as ready
Mendeliome v0.12240 OPN1MW Zornitza Stark Marked gene: OPN1MW as ready
Mendeliome v0.12236 OPN1LW Zornitza Stark Marked gene: OPN1LW as ready
Mendeliome v0.12230 SERPINA6 Zornitza Stark Marked gene: SERPINA6 as ready
Mendeliome v0.12227 SERPINA1 Zornitza Stark Marked gene: SERPINA1 as ready
Mendeliome v0.12224 OTC Krithika Murali reviewed gene: OTC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ornithine transcarbamylase deficiency - MIM#311250; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.12224 OSMR Krithika Murali reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 19375894, 19528426, 25054142, 20507362, 19690585; Phenotypes: Amyloidosis, primary localized cutaneous, 1 - MIM#105250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12224 SERPINA1 Samantha Ayres changed review comment from: Well established gene-disease relationship

Rated as C by babyseq due to low penetrance in childhood. Can cause hepatic dysfunction in infancy. Identification would prevent further investigation and potentially lead to optimising respiratory health due to adult onset respiratory involvement.; to: Well established gene-disease relationship

Rated as C by babyseq due to low penetrance in childhood. Can cause hepatic dysfunction in infancy. Identification would prevent further investigation and potentially lead to optimising respiratory health due to adult onset respiratory involvement.

MUTATIONAL & CLINICAL SPECTRUM
ZZ genotype: 2% have severe, neonatal/early-onset liver disease (potentially fatal/requiring liver transplantation), up to 6% have childhood onset liver disease. Also associated with adult-onset lung disease particularly emphysema (50%+ penetrance) - smoking is an important risk factor (close to 100% penetrance).

TREATMENT
There is no specific treatment for liver disease beyond transplant. There is treatment (AAT augmentation therapy) available to delay progression of lung disease phenotype.
Mendeliome v0.12224 THRA Zornitza Stark Marked gene: THRA as ready
Mendeliome v0.12221 TGM1 Zornitza Stark Marked gene: TGM1 as ready
Mendeliome v0.12218 TGM3 Zornitza Stark Marked gene: TGM3 as ready
Mendeliome v0.12214 OAT Zornitza Stark Marked gene: OAT as ready
Mendeliome v0.12211 NUP93 Zornitza Stark Marked gene: NUP93 as ready
Mendeliome v0.12208 NUP62 Zornitza Stark Marked gene: NUP62 as ready
Mendeliome v0.12204 ADH1B Zornitza Stark Marked gene: ADH1B as ready
Mendeliome v0.12203 CASP8 Zornitza Stark Marked gene: CASP8 as ready
Mendeliome v0.12203 CASP8 Zornitza Stark Added comment: Comment when marking as ready: Amber in view of the functional data.
Mendeliome v0.12198 ADCY3 Zornitza Stark Marked gene: ADCY3 as ready
Mendeliome v0.12194 TGFB3 Zornitza Stark Marked gene: TGFB3 as ready
Mendeliome v0.12191 TGFB2 Zornitza Stark Marked gene: TGFB2 as ready
Mendeliome v0.12189 TGFB1 Zornitza Stark Marked gene: TGFB1 as ready
Mendeliome v0.12186 TG Zornitza Stark Marked gene: TG as ready
Mendeliome v0.12183 OAT Krithika Murali edited their review of gene: OAT: Added comment: Biallelic variants associated with deficiency of mitochondrial enzyme ornithine aminotransferase and elevation of plasma ornithine levels without elevation of ammonia. Characterized by ocular anomalies; however, neurological and muscular features may also be present.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12183 ADRB1 Elena Savva Phenotypes for gene: ADRB1 were changed from [Resting heart rate] MIM#607276; [Short sleep, familial natural, 2] MIM#618591 to [Resting heart rate] MIM#607276; [Short sleep, familial natural, 2] MIM#618591
Mendeliome v0.12182 ADRB1 Elena Savva Phenotypes for gene: ADRB1 were changed from to [Resting heart rate] MIM#607276; [Short sleep, familial natural, 2] MIM#618591
Mendeliome v0.12181 ADRB1 Elena Savva Marked gene: ADRB1 as ready
Mendeliome v0.12180 ADRB1 Elena Savva reviewed gene: ADRB1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 31473062, 34716504; Phenotypes: [Resting heart rate] MIM#607276, [Short sleep, familial natural, 2] MIM#618591; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.12180 NTN1 Zornitza Stark Marked gene: NTN1 as ready
Mendeliome v0.12177 NSD1 Zornitza Stark Marked gene: NSD1 as ready
Mendeliome v0.12174 NRCAM Zornitza Stark Marked gene: NRCAM as ready
Mendeliome v0.12174 NR4A3 Zornitza Stark Marked gene: NR4A3 as ready
Mendeliome v0.12173 NKX2-5 Zornitza Stark Marked gene: NKX2-5 as ready
Mendeliome v0.12172 NKX2-5 Zornitza Stark reviewed gene: NKX2-5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25742962, 26805889; Phenotypes: Ventricular septal defect 3 (MIM#614432), Tetralogy of Fallot (MIM#187500); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12172 NKX2-5 Zornitza Stark Phenotypes for gene: NKX2-5 were changed from to Atrial septal defect 7, with or without AV conduction defects, MIM# 108900; Ventricular septal defect 3 (MIM#614432); Tetralogy of Fallot (MIM#187500)
Mendeliome v0.12169 NKX2-1 Zornitza Stark Marked gene: NKX2-1 as ready
Mendeliome v0.12169 NKX2-1 Zornitza Stark Phenotypes for gene: NKX2-1 were changed from to Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700
Mendeliome v0.12166 NDUFAF5 Zornitza Stark Marked gene: NDUFAF5 as ready
Mendeliome v0.12166 NDUFAF5 Zornitza Stark Phenotypes for gene: NDUFAF5 were changed from to Mitochondrial complex I deficiency, nuclear type 3 MIM#618224
Mendeliome v0.12163 NDUFS4 Zornitza Stark Marked gene: NDUFS4 as ready
Mendeliome v0.12163 NDUFS4 Zornitza Stark Phenotypes for gene: NDUFS4 were changed from to Mitochondrial complex I deficiency, nuclear type 1 - MIM#252010
Mendeliome v0.12160 NDUFV2 Zornitza Stark Marked gene: NDUFV2 as ready
Mendeliome v0.12160 NDUFV2 Zornitza Stark Phenotypes for gene: NDUFV2 were changed from to Mitochondrial complex I deficiency, nuclear type 7 - MIM#618229
Mendeliome v0.12154 CA2 Zornitza Stark Phenotypes for gene: CA2 were changed from to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730
Mendeliome v0.12152 CASP8 Ain Roesley changed review comment from: Boderline red/amber

1 family (the 2nd family reported in PMID:25814141 was found to be distantly related to the one in PMID:12353035)

Mice with targeted T cell and B cell caspase-8 deficiency present normal thymocyte development but a marked decrease in peripheral blood T-cells. Besides, when challenged with the lymphocytic choriomeningitis virus (LCMV), these animals showed a significantly impaired immune response to the infection that included impaired CD8 cell expansion and an abrogated ability to generate virus-specific CD8+ cytotoxic T-cells.; to: Borderline red/amber

1 family (the 2nd family reported in PMID:25814141 was found to be distantly related to the one in PMID:12353035)

Mice with targeted T cell and B cell caspase-8 deficiency present normal thymocyte development but a marked decrease in peripheral blood T-cells. Besides, when challenged with the lymphocytic choriomeningitis virus (LCMV), these animals showed a significantly impaired immune response to the infection that included impaired CD8 cell expansion and an abrogated ability to generate virus-specific CD8+ cytotoxic T-cells.
Mendeliome v0.12151 ADGRV1 Elena Savva Marked gene: ADGRV1 as ready
Mendeliome v0.12149 CASP10 Ain Roesley Marked gene: CASP10 as ready
Mendeliome v0.12148 NUBPL Zornitza Stark Marked gene: NUBPL as ready
Mendeliome v0.12148 NUBPL Zornitza Stark Phenotypes for gene: NUBPL were changed from to Mitochondrial complex I deficiency, nuclear type 21 - MIM#618242
Mendeliome v0.12145 NTRK1 Zornitza Stark Marked gene: NTRK1 as ready
Mendeliome v0.12142 NTF4 Zornitza Stark Marked gene: NTF4 as ready
Mendeliome v0.12139 CASK Ain Roesley Phenotypes for gene: CASK were changed from FG syndrome 4 MIM#300422; Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia MIM#300749; Mental retardation, with or without nystagmus MIM#300422 to FG syndrome 4 MIM#300422; Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia MIM#300749; Mental retardation, with or without nystagmus MIM#300422
Mendeliome v0.12138 CASK Ain Roesley Phenotypes for gene: CASK were changed from to FG syndrome 4 MIM#300422; Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia MIM#300749; Mental retardation, with or without nystagmus MIM#300422
Mendeliome v0.12137 CASK Ain Roesley Marked gene: CASK as ready
Mendeliome v0.12137 CASK Ain Roesley Marked gene: CASK as ready
Mendeliome v0.12135 NSUN2 Zornitza Stark Marked gene: NSUN2 as ready
Mendeliome v0.12135 NSUN2 Zornitza Stark Phenotypes for gene: NSUN2 were changed from to Mental retardation, autosomal recessive 5 - MIM#611091
Mendeliome v0.12134 CASK Ain Roesley reviewed gene: CASK: Rating: GREEN; Mode of pathogenicity: None; Publications: 24278995; Phenotypes: FG syndrome 4 MIM#300422, Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia MIM#300749, Mental retardation, with or without nystagmus MIM#300422; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Mendeliome v0.12132 NSUN2 Zornitza Stark reviewed gene: NSUN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541559, 22541562, 21063731, 22577224, 35126837; Phenotypes: Mental retardation, autosomal recessive 5 - MIM#611091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12132 NRXN1 Zornitza Stark Marked gene: NRXN1 as ready
Mendeliome v0.12129 CARD11 Ain Roesley Phenotypes for gene: CARD11 were changed from Immunodeficiency 11A, autosomal recessive, MIM# 615206; Immunodeficiency 11B with atopic dermatitis, autosomal dominant, MIM# 617638 to Immunodeficiency 11A, autosomal recessive, MIM# 615206; Immunodeficiency 11B with atopic dermatitis, autosomal dominant, MIM# 617638
Mendeliome v0.12128 CARD11 Ain Roesley Phenotypes for gene: CARD11 were changed from to Immunodeficiency 11A, autosomal recessive, MIM# 615206; Immunodeficiency 11B with atopic dermatitis, autosomal dominant, MIM# 617638
Mendeliome v0.12128 CARD11 Ain Roesley Marked gene: CARD11 as ready
Mendeliome v0.12128 CARD11 Ain Roesley Gene: card11 has been classified as Green List (High Evidence).
Mendeliome v0.12128 CARD11 Ain Roesley Publications for gene: CARD11 were set to
Mendeliome v0.12128 CARD11 Ain Roesley Mode of inheritance for gene: CARD11 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12127 CARD11 Ain Roesley reviewed gene: CARD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561803, 12818158, 23374270, 28628108; Phenotypes: Immunodeficiency 11A, autosomal recessive, MIM# 615206, Immunodeficiency 11B with atopic dermatitis, autosomal dominant, MIM# 617638; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12127 CALM3 Ain Roesley Marked gene: CALM3 as ready
Mendeliome v0.12126 CALM2 Ain Roesley Marked gene: CALM2 as ready
Mendeliome v0.12124 CALM1 Ain Roesley Marked gene: CALM1 as ready
Mendeliome v0.12124 CALM1 Ain Roesley Phenotypes for gene: CALM1 were changed from to Long QT syndrome 14 MIM#616247; Ventricular tachycardia, catecholaminergic polymorphic, 4 MIM#614916
Mendeliome v0.12122 CALM1 Ain Roesley reviewed gene: CALM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31170290; Phenotypes: Long QT syndrome 14 MIM#616247, Ventricular tachycardia, catecholaminergic polymorphic, 4 MIM#614916; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.12122 NRL Zornitza Stark Marked gene: NRL as ready
Mendeliome v0.12118 CACNA2D4 Ain Roesley Marked gene: CACNA2D4 as ready
Mendeliome v0.12117 NR2F2 Zornitza Stark Marked gene: NR2F2 as ready
Mendeliome v0.12117 NR2F2 Zornitza Stark Phenotypes for gene: NR2F2 were changed from to 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779
Mendeliome v0.12115 SERAC1 Zornitza Stark Marked gene: SERAC1 as ready
Mendeliome v0.12112 SEMA3A Zornitza Stark Marked gene: SEMA3A as ready
Mendeliome v0.12112 SEMA3A Zornitza Stark Phenotypes for gene: SEMA3A were changed from to Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease; short stature
Mendeliome v0.12109 SCP2 Zornitza Stark Marked gene: SCP2 as ready
Mendeliome v0.12107 CACNA2D2 Ain Roesley Phenotypes for gene: CACNA2D2 were changed from Cerebellar atrophy with seizures and variable developmental delay MIM#618501 to Cerebellar atrophy with seizures and variable developmental delay MIM#618501
Mendeliome v0.12105 CACNA2D2 Ain Roesley Phenotypes for gene: CACNA2D2 were changed from Cerebellar atrophy with seizures and variable developmental delay MIM#618501 to Cerebellar atrophy with seizures and variable developmental delay MIM#618501
Mendeliome v0.12104 CACNA2D2 Ain Roesley Phenotypes for gene: CACNA2D2 were changed from to Cerebellar atrophy with seizures and variable developmental delay MIM#618501
Mendeliome v0.12103 CACNA2D2 Ain Roesley Marked gene: CACNA2D2 as ready
Mendeliome v0.12101 CACNA2D2 Ain Roesley edited their review of gene: CACNA2D2: Changed publications: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Changed phenotypes: Cerebellar atrophy with seizures and variable developmental delay MIM#618501
Mendeliome v0.12100 CACNA2D2 Ain Roesley reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: Cerebellar atrophy with seizures and variable developmental delay MIM#618501; Phenotypes: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12099 CACNA1F Ain Roesley Marked gene: CACNA1F as ready
Mendeliome v0.12099 TUBB1 Zornitza Stark Marked gene: TUBB1 as ready
Mendeliome v0.12099 CACNA1F Ain Roesley Phenotypes for gene: CACNA1F were changed from to Aland Island eye disease MIM#300600; Cone-rod dystrophy, X-linked, 3 MIM#300476; Night blindness, congenital stationary (incomplete), 2A, X-linked MIM#300071
Mendeliome v0.12097 CACNA1F Ain Roesley reviewed gene: CACNA1F: Rating: GREEN; Mode of pathogenicity: None; Publications: 17525176, 16505158, 23776498, 24124559, 26075273, 25999675; Phenotypes: Aland Island eye disease MIM#300600, Cone-rod dystrophy, X-linked, 3 MIM#300476, Night blindness, congenital stationary (incomplete), 2A, X-linked MIM#300071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v0.12096 SCARB2 Zornitza Stark Marked gene: SCARB2 as ready
Mendeliome v0.12096 SCARB2 Zornitza Stark Gene: scarb2 has been classified as Green List (High Evidence).
Mendeliome v0.12096 SCARB2 Zornitza Stark Phenotypes for gene: SCARB2 were changed from to Progressive Myoclonus Epilepsy, MONDO:0020074; Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900
Mendeliome v0.12095 SCARB2 Zornitza Stark Publications for gene: SCARB2 were set to
Mendeliome v0.12094 SCARB2 Zornitza Stark Mode of inheritance for gene: SCARB2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12093 SASH1 Zornitza Stark Marked gene: SASH1 as ready
Mendeliome v0.12093 SASH1 Zornitza Stark Phenotypes for gene: SASH1 were changed from to Dyschromatosis universalis hereditaria 1, MIM #127500; familial generalized lentiginosis MONDO:007891
Mendeliome v0.12090 SASH1 Zornitza Stark reviewed gene: SASH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyschromatosis universalis hereditaria 1, MIM# 127500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12090 CABP2 Ain Roesley Marked gene: CABP2 as ready
Mendeliome v0.12090 TUBB4B Zornitza Stark Marked gene: TUBB4B as ready
Mendeliome v0.12090 TUBB4B Zornitza Stark Phenotypes for gene: TUBB4B were changed from to Leber congenital amaurosis with early onset deafness, LCAEOD, OMIM #617879; MONDO:0060650
Mendeliome v0.12088 TUBB4B Zornitza Stark reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35240325; Phenotypes: Leber congenital amaurosis with early onset deafness, LCAEOD, OMIM #617879, MONDO:0060650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12086 TUFM Zornitza Stark Marked gene: TUFM as ready
Mendeliome v0.12083 CA2 Ain Roesley Marked gene: CA2 as ready
Mendeliome v0.12083 CA2 Ain Roesley reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34624559, 33555497, 12566520, 7627193; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM#259730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12082 CA12 Ain Roesley Marked gene: CA12 as ready
Mendeliome v0.12080 NR2E3 Zornitza Stark Marked gene: NR2E3 as ready
Mendeliome v0.12077 NR0B2 Zornitza Stark Marked gene: NR0B2 as ready
Mendeliome v0.12076 NR0B2 Zornitza Stark Phenotypes for gene: NR0B2 were changed from to Obesity, mild, early-onset, MIM# 601665
Mendeliome v0.12074 NPSR1 Zornitza Stark Marked gene: NPSR1 as ready
Mendeliome v0.12071 ACER3 Zornitza Stark edited their review of gene: ACER3: Added comment: Additional publication (Dehvani et al., 2021; PMID: 34281620) detailing three further unrelated cases, each with novel homozygous variants in the ACER3 gene. All individuals displayed features of progressive leukoencephalopathy, developmental delay, hypotonia, appendicular spasticity, and dystonia. Early development is apparently normal followed by symptoms of stagnation and neurologic regression (onset within first year of life).; Changed rating: GREEN; Changed publications: 32816236, 26792856, 34281620; Changed phenotypes: Leukodystrophy, progressive, early childhood-onset, MIM:617762
Mendeliome v0.12071 LIAS Alison Yeung Marked gene: LIAS as ready
Mendeliome v0.12068 LHX4 Alison Yeung Phenotypes for gene: LHX4 were changed from to Pituitary hormone deficiency, combined, 4, MIM# 262700
Mendeliome v0.12067 LHX4 Alison Yeung Marked gene: LHX4 as ready
Mendeliome v0.12066 LHX4 Alison Yeung reviewed gene: LHX4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 4, MIM# 262700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.12066 SEMA3A Samantha Ayres reviewed gene: SEMA3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28075028, 33369061, 20301509, 21059704, 24124006, 22927827; Phenotypes: Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897, congenital heart disease, short stature; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.12066 LHX3 Alison Yeung Marked gene: LHX3 as ready
Mendeliome v0.12066 LHX3 Alison Yeung Phenotypes for gene: LHX3 were changed from to Pituitary hormone deficiency, combined, 3, MIM# 221750
Mendeliome v0.12064 LHX3 Alison Yeung reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 3, MIM# 221750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.12064 LHB Alison Yeung Marked gene: LHB as ready
Mendeliome v0.12062 SCARB2 Samantha Ayres reviewed gene: SCARB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18308289, 18424452, 23659519, 19847901, 18022370, 19933215; Phenotypes: Progressive Myoclonus Epilepsy, MONDO:0020074, Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12062 SASH1 Samantha Ayres reviewed gene: SASH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23333244, 27885802, 32981204; Phenotypes: Dyschromatosis universalis hereditaria 1, MIM #127500, familial generalized lentiginosis MONDO:007891; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.12062 NUBPL Krithika Murali reviewed gene: NUBPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 20818383, 32518176, 23553477, 31917109, 32518176, 31787496, 30897263, 22826544; Phenotypes: Mitochondrial complex I deficiency, nuclear type 21 - MIM#618242; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12062 TUBB4B Manny Jacobs reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29198720; Phenotypes: Leber congenital amaurosis with early onset deafness, LCAEOD, OMIM #617879, MONDO:0060650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12062 LGI1 Alison Yeung Marked gene: LGI1 as ready
Mendeliome v0.12059 LEMD3 Alison Yeung Marked gene: LEMD3 as ready
Mendeliome v0.12056 LDLRAP1 Alison Yeung Marked gene: LDLRAP1 as ready
Mendeliome v0.12053 LDHB Alison Yeung Marked gene: LDHB as ready
Mendeliome v0.12049 LCAT Alison Yeung Marked gene: LCAT as ready
Mendeliome v0.12046 LCA5 Alison Yeung Marked gene: LCA5 as ready
Mendeliome v0.12043 NR2F2 Krithika Murali reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24702954, 29478779, 31687637, 27363585, 29222010, 29663647; Phenotypes: 46,XX sex reversal 5 - MIM#618901, Congenital heart defects, multiple types, 4 - MIM#615779; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12043 MSMB Zornitza Stark Marked gene: MSMB as ready
Mendeliome v0.12043 MSMB Zornitza Stark Phenotypes for gene: MSMB were changed from to {Prostate cancer, hereditary, 13} 611928
Mendeliome v0.12040 MSMB Zornitza Stark reviewed gene: MSMB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Prostate cancer, hereditary, 13} 611928; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12040 SON Zornitza Stark Marked gene: SON as ready
Mendeliome v0.12037 SNX3 Zornitza Stark Marked gene: SNX3 as ready
Mendeliome v0.12036 SMARCE1 Zornitza Stark Phenotypes for gene: SMARCE1 were changed from Coffin-Siris syndrome 5, MIM# 616938 to Coffin-Siris syndrome 5, MIM# 616938; {Meningioma, familial, susceptibility to} 607174
Mendeliome v0.12035 SMARCE1 Zornitza Stark changed review comment from: Coffin-Siris syndrome is a rare congenital disorder characterized by delayed psychomotor development, intellectual disability, coarse facial features, and hypoplasia of the distal phalanges, particularly the fifth digit. Other features may also be observed, including congenital heart defects, hypoplasia of the corpus callosum, and poor overall growth with short stature and microcephaly.

Accounts for ~2% of Coffin Siris syndrome.; to: Coffin-Siris syndrome is a rare congenital disorder characterized by delayed psychomotor development, intellectual disability, coarse facial features, and hypoplasia of the distal phalanges, particularly the fifth digit. Other features may also be observed, including congenital heart defects, hypoplasia of the corpus callosum, and poor overall growth with short stature and microcephaly.

Accounts for ~2% of Coffin Siris syndrome.

Germline LoF variants also linked to familial meningioma.
Mendeliome v0.12035 SMARCE1 Zornitza Stark edited their review of gene: SMARCE1: Changed publications: 23377182, 22426308, 23906836, 23929686, 32732226, 32436246, 32410215, 34205270; Changed phenotypes: Coffin-Siris syndrome 5, MIM# 616938, {Meningioma, familial, susceptibility to} 607174
Mendeliome v0.12035 SMARCE1 Zornitza Stark Publications for gene: SMARCE1 were set to 22426308; 23906836; 23929686; 32732226; 32436246; 32410215; 34205270
Mendeliome v0.12034 SMARCE1 Zornitza Stark Marked gene: SMARCE1 as ready
Mendeliome v0.12034 SMARCE1 Zornitza Stark Gene: smarce1 has been classified as Green List (High Evidence).
Mendeliome v0.12034 SMARCE1 Zornitza Stark Phenotypes for gene: SMARCE1 were changed from to Coffin-Siris syndrome 5, MIM# 616938
Mendeliome v0.12033 SMARCE1 Zornitza Stark Publications for gene: SMARCE1 were set to
Mendeliome v0.12032 SMARCE1 Zornitza Stark Mode of inheritance for gene: SMARCE1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12031 SMARCE1 Zornitza Stark reviewed gene: SMARCE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22426308, 23906836, 23929686, 32732226, 32436246, 32410215, 34205270; Phenotypes: Coffin-Siris syndrome 5, MIM# 616938; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.12031 MAX Zornitza Stark Marked gene: MAX as ready
Mendeliome v0.12028 MAT1A Zornitza Stark Marked gene: MAT1A as ready
Mendeliome v0.12025 SNX14 Zornitza Stark Marked gene: SNX14 as ready
Mendeliome v0.12025 SNX14 Zornitza Stark Phenotypes for gene: SNX14 were changed from to Spinocerebellar ataxia, autosomal recessive 20 (MIM#616354)
Mendeliome v0.12022 SNX14 Zornitza Stark reviewed gene: SNX14: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439728, 25848753, 27913285; Phenotypes: Spinocerebellar ataxia, autosomal recessive 20 (MIM#616354); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12022 SNORD118 Zornitza Stark Marked gene: SNORD118 as ready
Mendeliome v0.12019 SNAP29 Zornitza Stark Marked gene: SNAP29 as ready
Mendeliome v0.12019 SNAP29 Zornitza Stark Phenotypes for gene: SNAP29 were changed from to Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome, MIM#609528
Mendeliome v0.12016 SNAP29 Zornitza Stark reviewed gene: SNAP29: Rating: GREEN; Mode of pathogenicity: None; Publications: 29051910, 21073448, 30793783; Phenotypes: Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome, MIM#609528; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.12016 SNAP25 Zornitza Stark Marked gene: SNAP25 as ready
Mendeliome v0.12013 SNAI2 Zornitza Stark Marked gene: SNAI2 as ready
Mendeliome v0.12013 SNAI2 Zornitza Stark Phenotypes for gene: SNAI2 were changed from to Waardenburg syndrome, type 2D, MIM# 608890; Piebaldism, MIM# 172800
Mendeliome v0.12009 SNAI2 Zornitza Stark reviewed gene: SNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 12444107, 30936914, 12955764, 24443330; Phenotypes: Waardenburg syndrome, type 2D, MIM# 608890, Piebaldism, MIM# 172800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.12009 SMS Zornitza Stark Marked gene: SMS as ready
Mendeliome v0.12005 RPS10 Zornitza Stark Marked gene: RPS10 as ready
Mendeliome v0.12002 ROBO3 Zornitza Stark Marked gene: ROBO3 as ready
Mendeliome v0.11999 ROBO2 Zornitza Stark Marked gene: ROBO2 as ready
Mendeliome v0.11996 RNF216 Zornitza Stark Marked gene: RNF216 as ready
Mendeliome v0.11996 RNF216 Zornitza Stark Phenotypes for gene: RNF216 were changed from to Cerebellar ataxia and hypogonadotropic hypogonadism MIM#212840
Mendeliome v0.11993 ATP2B2 Zornitza Stark Marked gene: ATP2B2 as ready
Mendeliome v0.11991 TFAP2B Zornitza Stark Marked gene: TFAP2B as ready
Mendeliome v0.11990 TFAP2B Zornitza Stark changed review comment from: Well established association with syndromic and non-syndromic PDA.; to: Well established association with syndromic and non-syndromic PDA.

Four individuals reported in PMID: 31292255 (Correction in PMID: 31405973) as part of a craniosynostosis cohort: 2 de novo and 2 inherited. There is evidence for reduced penetrance as in one case the variant was inherited from an unaffected parent (affected parent for the other inherited variant).
Mendeliome v0.11990 TFAP2B Zornitza Stark edited their review of gene: TFAP2B: Changed publications: 31292255, 11505339, 15684060, 18752453, 21643846; Changed phenotypes: Char syndrome, MIM# 169100, Patent ductus arteriosus 2, MIM# 617035, Syndromic craniosynostosis
Mendeliome v0.11990 TFAP2B Zornitza Stark Phenotypes for gene: TFAP2B were changed from Char syndrome, MIM# 169100; Patent ductus arteriosus 2, MIM# 617035 to Char syndrome, MIM# 169100; Patent ductus arteriosus 2, MIM# 617035; Syndromic craniosynostosis
Mendeliome v0.11989 TFAP2B Zornitza Stark Phenotypes for gene: TFAP2B were changed from to Char syndrome, MIM# 169100; Patent ductus arteriosus 2, MIM# 617035
Mendeliome v0.11986 TFAP2B Zornitza Stark reviewed gene: TFAP2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 11505339, 15684060, 18752453, 21643846; Phenotypes: Char syndrome, MIM# 169100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11986 TERT Zornitza Stark Marked gene: TERT as ready
Mendeliome v0.11986 TERT Zornitza Stark Phenotypes for gene: TERT were changed from to Dyskeratosis congenita, MIM# 613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, MIM# 614742
Mendeliome v0.11983 TERT Zornitza Stark reviewed gene: TERT: Rating: GREEN; Mode of pathogenicity: None; Publications: 16247010, 15814878; Phenotypes: Dyskeratosis congenita, MIM# 613989, Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, MIM# 614742; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.11983 TERC Zornitza Stark Marked gene: TERC as ready
Mendeliome v0.11980 TEK Zornitza Stark Marked gene: TEK as ready
Mendeliome v0.11980 TEK Zornitza Stark Phenotypes for gene: TEK were changed from to Glaucoma 3, primary congenital, E, MIM# 617272; Venous malformations, multiple cutaneous and mucosal, MIM# 600195
Mendeliome v0.11977 TEK Zornitza Stark reviewed gene: TEK: Rating: GREEN; Mode of pathogenicity: None; Publications: 27270174, 19888299; Phenotypes: Glaucoma 3, primary congenital, E, MIM# 617272, Venous malformations, multiple cutaneous and mucosal, MIM# 600195; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11977 TEAD1 Zornitza Stark Marked gene: TEAD1 as ready
Mendeliome v0.11975 TEAD1 Zornitza Stark changed review comment from: Sveinsson chorioretinal atrophy (SCRA) is characterized by bilateral, well-defined, tongue-shaped strips of atrophic retina and choroid that extend from the optic nerve into the peripheral ocular fundus. The lesions may be evident at birth and usually progress at a variable rate, sometimes leading to central visual loss. Separate small distinct circular atrophic lesions are observed in the peripheral ocular fundus in some patients. Congenital anterior polar cataracts are found in approximately 25% of affected individuals.

The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA is also described in patients of non-Icelandic descent. The variant reported in the Icelanding population is (c.1261T>C, p.Tyr421His), another variant at same position c.1261T>A, p.Tyr421Asn also reported in non-Icelandic family.

Functional data supports gene-disease association.; to: Sveinsson chorioretinal atrophy (SCRA) is characterized by bilateral, well-defined, tongue-shaped strips of atrophic retina and choroid that extend from the optic nerve into the peripheral ocular fundus. The lesions may be evident at birth and usually progress at a variable rate, sometimes leading to central visual loss. Separate small distinct circular atrophic lesions are observed in the peripheral ocular fundus in some patients. Congenital anterior polar cataracts are found in approximately 25% of affected individuals.

The vast majority of reported cases were of Icelandic origin but the characteristic clinical picture of SCRA is also described in patients of non-Icelandic descent. The variant reported in the Icelanding population is (c.1261T>C, p.Tyr421His), another variant at same position c.1261T>A, p.Tyr421Asn also reported in non-Icelandic family.

A de novo nonsense variant has also been reported in a case with Aicardi syndrome with infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae.
Mendeliome v0.11973 TDP1 Zornitza Stark Phenotypes for gene: TDP1 were changed from to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 , MIM# 607250
Mendeliome v0.11969 TDP1 Zornitza Stark reviewed gene: TDP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31182267, 12244316; Phenotypes: Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 , MIM# 607250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11969 TCIRG1 Zornitza Stark Marked gene: TCIRG1 as ready
Mendeliome v0.11966 TCF4 Zornitza Stark Marked gene: TCF4 as ready
Mendeliome v0.11963 TCAP Zornitza Stark Marked gene: TCAP as ready
Mendeliome v0.11963 TCAP Zornitza Stark Phenotypes for gene: TCAP were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 7, MIM# 601954
Mendeliome v0.11961 TCAP Zornitza Stark reviewed gene: TCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 7, MIM# 601954; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11961 TBX5 Zornitza Stark Marked gene: TBX5 as ready
Mendeliome v0.11958 TBX20 Zornitza Stark Marked gene: TBX20 as ready
Mendeliome v0.11955 TBL1XR1 Zornitza Stark Marked gene: TBL1XR1 as ready
Mendeliome v0.11955 TBL1XR1 Zornitza Stark Phenotypes for gene: TBL1XR1 were changed from to Mental retardation, autosomal dominant 41, MIM# 616944; Pierpont syndrome, MIM# 602342
Mendeliome v0.11952 TBL1XR1 Zornitza Stark reviewed gene: TBL1XR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26769062, 30365874, 25425123, 9450851, 23160955, 28687524, 23176139, 16007632; Phenotypes: Mental retardation, autosomal dominant 41, MIM# 616944, Pierpont syndrome, MIM# 602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11952 TBCK Zornitza Stark Marked gene: TBCK as ready
Mendeliome v0.11952 TBCK Zornitza Stark Phenotypes for gene: TBCK were changed from to Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900
Mendeliome v0.11949 TBCK Zornitza Stark reviewed gene: TBCK: Rating: GREEN; Mode of pathogenicity: None; Publications: 27040692, 30103036, 27040691; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11949 TBC1D23 Zornitza Stark Marked gene: TBC1D23 as ready
Mendeliome v0.11949 TBC1D23 Zornitza Stark Phenotypes for gene: TBC1D23 were changed from to Pontocerebellar hypoplasia, type 11, MIM# 617695
Mendeliome v0.11946 TBC1D1 Zornitza Stark Marked gene: TBC1D1 as ready
Mendeliome v0.11946 TBC1D1 Zornitza Stark Phenotypes for gene: TBC1D1 were changed from to CAKUT; Non-syndromic renal or urinary tract malformation, MONDO:0019720
Mendeliome v0.11943 TBC1D1 Zornitza Stark reviewed gene: TBC1D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26572137; Phenotypes: CAKUT, Non-syndromic renal or urinary tract malformation, MONDO:0019720; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11943 TAZ Zornitza Stark Marked gene: TAZ as ready
Mendeliome v0.11943 TAZ Zornitza Stark Phenotypes for gene: TAZ were changed from to Barth syndrome, MIM# 302060
Mendeliome v0.11941 TAZ Zornitza Stark reviewed gene: TAZ: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Barth syndrome, MIM# 302060; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.11940 TAT Zornitza Stark Marked gene: TAT as ready
Mendeliome v0.11938 TAS2R38 Zornitza Stark Marked gene: TAS2R38 as ready
Mendeliome v0.11938 TAS2R38 Zornitza Stark Phenotypes for gene: TAS2R38 were changed from to [Phenylthiocarbamide tasting] 171200
Mendeliome v0.11935 TAS2R38 Zornitza Stark reviewed gene: TAS2R38: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: [Phenylthiocarbamide tasting] 171200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11935 TAS2R16 Zornitza Stark Marked gene: TAS2R16 as ready
Mendeliome v0.11932 TANGO2 Zornitza Stark Marked gene: TANGO2 as ready
Mendeliome v0.11932 TANGO2 Zornitza Stark Phenotypes for gene: TANGO2 were changed from to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878
Mendeliome v0.11929 TANGO2 Zornitza Stark reviewed gene: TANGO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26805782, 30245509; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11929 TACR3 Zornitza Stark Marked gene: TACR3 as ready
Mendeliome v0.11926 TAC3 Zornitza Stark Marked gene: TAC3 as ready
Mendeliome v0.11923 T Zornitza Stark Marked gene: T as ready
Mendeliome v0.11916 LARGE1 Zornitza Stark Publications for gene: LARGE1 were set to
Mendeliome v0.11915 LARGE1 Zornitza Stark Mode of inheritance for gene: LARGE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11910 LBR Alison Yeung Marked gene: LBR as ready
Mendeliome v0.11908 LAT Alison Yeung Marked gene: LAT as ready
Mendeliome v0.11906 LAMB2 Zornitza Stark Phenotypes for gene: LAMB2 were changed from to Pierson syndrome, MIM# 609049; Nephrotic syndrome, type 5, with or without ocular abnormalities, MIM# 614199
Mendeliome v0.11903 L1CAM Zornitza Stark Phenotypes for gene: L1CAM were changed from Hydrocephalus due to aqueductal stenosis, MIM# 307000; MASA syndrome, MIM# 303350; L1 syndrome, MONDO:0017140 to Hydrocephalus due to aqueductal stenosis, MIM# 307000; MASA syndrome, MIM# 303350; L1 syndrome, MONDO:0017140; Corpus callosum, partial agenesis of, MIM# 304100
Mendeliome v0.11902 L1CAM Zornitza Stark reviewed gene: L1CAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrocephalus due to aqueductal stenosis, MIM# 307000, Corpus callosum, partial agenesis of, MIM# 304100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.11900 NPRL3 Zornitza Stark Marked gene: NPRL3 as ready
Mendeliome v0.11900 NPRL3 Zornitza Stark Phenotypes for gene: NPRL3 were changed from to Epilepsy, familial focal, with variable foci 3- MIM#617118
Mendeliome v0.11897 NPPC Zornitza Stark Marked gene: NPPC as ready
Mendeliome v0.11893 NOTCH2 Zornitza Stark Marked gene: NOTCH2 as ready
Mendeliome v0.11890 NOTCH1 Zornitza Stark Marked gene: NOTCH1 as ready
Mendeliome v0.11887 NONO Zornitza Stark Marked gene: NONO as ready
Mendeliome v0.11884 NOL3 Zornitza Stark Marked gene: NOL3 as ready
Mendeliome v0.11880 NOG Zornitza Stark Marked gene: NOG as ready
Mendeliome v0.11880 NOG Zornitza Stark Phenotypes for gene: NOG were changed from to Brachydactyly, type B2 - MIM#611377; Multiple synostoses syndrome 1 (MIM#186500); Stapes ankylosis with broad thumbs and toes (MIM#184460); Symphalangism, proximal, 1A (MIM#185800); Tarsal-carpal coalition syndrome (MIM#186570)
Mendeliome v0.11877 NNT Zornitza Stark Marked gene: NNT as ready
Mendeliome v0.11874 NLRP7 Zornitza Stark Marked gene: NLRP7 as ready
Mendeliome v0.11871 NLRP12 Zornitza Stark Marked gene: NLRP12 as ready
Mendeliome v0.11868 TCF20 Elena Savva reviewed gene: TCF20: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 34904221, 30739909, 30819258, 25228304; Phenotypes: Developmental delay with variable intellectual impairment and behavioral abnormalities MIM#618430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.11868 LAS1L Alison Yeung Marked gene: LAS1L as ready
Mendeliome v0.11865 LARGE1 Alison Yeung Phenotypes for gene: LARGE1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, MIM# 613154; Muscular dystrophy-dystroglycanopathy type B6, MIM# 608840
Mendeliome v0.11864 LARGE1 Alison Yeung Marked gene: LARGE1 as ready
Mendeliome v0.11864 LARGE1 Alison Yeung Gene: large1 has been classified as Green List (High Evidence).
Mendeliome v0.11864 LARGE1 Alison Yeung reviewed gene: LARGE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12966029, 19067344, 17436019, 21248746; Phenotypes: Muscular dystrophy-dystroglycanopathy type A6, MIM# 613154, Muscular dystrophy-dystroglycanopathy type B6, MIM# 608840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.11864 LAMC3 Alison Yeung Marked gene: LAMC3 as ready
Mendeliome v0.11864 LAMB2 Alison Yeung Marked gene: LAMB2 as ready
Mendeliome v0.11864 LAMB2 Alison Yeung changed review comment from: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss.

Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus.

The two disorders are likely part of a spectrum. More than 5 unrelated families reported. ; to: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss.

Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus.

More than 5 unrelated families reported.
Mendeliome v0.11864 LAMB2 Alison Yeung changed review comment from: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss.

Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus.; to: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss.

Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus.

The two disorders are likely part of a spectrum. More than 5 unrelated families reported.
Mendeliome v0.11864 LAMB2 Alison Yeung reviewed gene: LAMB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 14136829, 15372515, 17256789; Phenotypes: Pierson syndrome, MIM# 609049, Nephrotic syndrome, type 5, with or without ocular abnormalities, MIM# 614199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11864 L1CAM Alison Yeung Marked gene: L1CAM as ready
Mendeliome v0.11863 TRIM63 Zornitza Stark Phenotypes for gene: TRIM63 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, MONDO:0005045
Mendeliome v0.11862 TRIM63 Zornitza Stark edited their review of gene: TRIM63: Changed rating: GREEN; Changed phenotypes: Hypertrophic cardiomyopathy, MONDO:0005045; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11862 MYOM1 Zornitza Stark Phenotypes for gene: MYOM1 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, MONDO:0005045
Mendeliome v0.11860 MYOM1 Zornitza Stark edited their review of gene: MYOM1: Changed rating: RED; Changed phenotypes: Hypertrophic cardiomyopathy, MONDO:0005045
Mendeliome v0.11860 NPRL3 Krithika Murali reviewed gene: NPRL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27173016, 26285051, 33461085; Phenotypes: Epilepsy, familial focal, with variable foci 3- MIM#617118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11860 NOG Krithika Murali reviewed gene: NOG: Rating: GREEN; Mode of pathogenicity: None; Publications: 11846737, 18440889, 12089654, 10080184, 15066478, 22088931, 17381491; Phenotypes: Brachydactyly, type B2 - MIM#611377, Multiple synostoses syndrome 1 (MIM#186500), Stapes ankylosis with broad thumbs and toes (MIM#184460), Symphalangism, proximal, 1A (MIM#185800), Tarsal-carpal coalition syndrome (MIM#186570); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11860 STAG1 Zornitza Stark Marked gene: STAG1 as ready
Mendeliome v0.11860 STAG1 Zornitza Stark Phenotypes for gene: STAG1 were changed from to Mental retardation, autosomal dominant 47, MIM# 617635
Mendeliome v0.11857 STAG1 Zornitza Stark reviewed gene: STAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28119487, 34440290; Phenotypes: Mental retardation, autosomal dominant 47, MIM# 617635; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11857 STAR Zornitza Stark Marked gene: STAR as ready
Mendeliome v0.11857 STAR Zornitza Stark Gene: star has been classified as Green List (High Evidence).
Mendeliome v0.11857 STAR Zornitza Stark Phenotypes for gene: STAR were changed from to Lipoid adrenal hyperplasia (MIM#201710)
Mendeliome v0.11856 STAR Zornitza Stark Publications for gene: STAR were set to
Mendeliome v0.11855 STAR Zornitza Stark Mode of inheritance for gene: STAR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11854 STAR Zornitza Stark reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7892608, 8634702; Phenotypes: Lipoid adrenal hyperplasia (MIM#201710); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11854 STAT1 Zornitza Stark Marked gene: STAT1 as ready
Mendeliome v0.11851 STAT2 Zornitza Stark Marked gene: STAT2 as ready
Mendeliome v0.11848 STS Zornitza Stark Marked gene: STS as ready
Mendeliome v0.11846 STUB1 Zornitza Stark Marked gene: STUB1 as ready
Mendeliome v0.11846 STUB1 Zornitza Stark Phenotypes for gene: STUB1 were changed from to Spinocerebellar ataxia, autosomal recessive 16, MIM# 615768; Spinocerebellar ataxia 48, MIM#618093
Mendeliome v0.11843 STUB1 Zornitza Stark changed review comment from: Onset is typically in adolescence but onset in childhood also reported.
Sources: Expert list; to: Multiple families reported with mono-allelic and bi-allelic disease, variable age of onset.
Sources: Expert list
Mendeliome v0.11843 STUB1 Zornitza Stark edited their review of gene: STUB1: Changed publications: 25258038, 24742043, 32337344, 30381368, 31126790; Changed phenotypes: Spinocerebellar ataxia, autosomal recessive 16, MIM# 615768, Spinocerebellar ataxia 48, MIM#618093; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.11843 STX11 Zornitza Stark Marked gene: STX11 as ready
Mendeliome v0.11840 NLRC4 Zornitza Stark Marked gene: NLRC4 as ready
Mendeliome v0.11836 NLGN3 Zornitza Stark Marked gene: NLGN3 as ready
Mendeliome v0.11834 NKX3-2 Zornitza Stark Marked gene: NKX3-2 as ready
Mendeliome v0.11831 NIPAL4 Zornitza Stark Marked gene: NIPAL4 as ready
Mendeliome v0.11828 NHS Zornitza Stark Marked gene: NHS as ready
Mendeliome v0.11828 NHS Zornitza Stark Phenotypes for gene: NHS were changed from to Nance-Horan syndrome - MIM#302350; Cataract 40, X-linked - MIM#302200
Mendeliome v0.11825 NFKBIL1 Zornitza Stark Marked gene: NFKBIL1 as ready
Mendeliome v0.11825 NFKBIL1 Zornitza Stark Phenotypes for gene: NFKBIL1 were changed from to {Rheumatoid arthritis, susceptibility to} - MIM#180300
Mendeliome v0.11823 NFIA Zornitza Stark Marked gene: NFIA as ready
Mendeliome v0.11823 NFIA Zornitza Stark Phenotypes for gene: NFIA were changed from to Brain malformations with or without urinary tract defects - MIM#613735
Mendeliome v0.11819 NEXN Zornitza Stark Marked gene: NEXN as ready
Mendeliome v0.11819 NEXN Zornitza Stark Phenotypes for gene: NEXN were changed from to Lethal fetal cardiomyopathy; Hydrops fetalis; Cardiomyopathy, dilated 1CC - MIM#613122
Mendeliome v0.11816 STX1B Zornitza Stark Marked gene: STX1B as ready
Mendeliome v0.11813 STX2 Zornitza Stark Marked gene: STX2 as ready
Mendeliome v0.11812 STX4 Zornitza Stark Marked gene: STX4 as ready
Mendeliome v0.11811 STXBP2 Zornitza Stark Marked gene: STXBP2 as ready
Mendeliome v0.11808 SULT2B1 Zornitza Stark Marked gene: SULT2B1 as ready
Mendeliome v0.11805 SUMF1 Zornitza Stark Marked gene: SUMF1 as ready
Mendeliome v0.11802 SUMO4 Zornitza Stark Marked gene: SUMO4 as ready
Mendeliome v0.11798 SURF1 Zornitza Stark Marked gene: SURF1 as ready
Mendeliome v0.11798 SURF1 Zornitza Stark Phenotypes for gene: SURF1 were changed from to Charcot-Marie-Tooth disease, type 4K MIM#616684; Mitochondrial complex IV deficiency, nuclear type 1 MIM#220110
Mendeliome v0.11795 SURF1 Zornitza Stark reviewed gene: SURF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843204, 9837813; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 1, MIM# 220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11795 SUZ12 Zornitza Stark Marked gene: SUZ12 as ready
Mendeliome v0.11792 NHS Krithika Murali reviewed gene: NHS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31755796, 25266737; Phenotypes: Nance-Horan syndrome - MIM#302350, Cataract 40, X-linked - MIM#302200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.11792 NFKBIL1 Krithika Murali reviewed gene: NFKBIL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Rheumatoid arthritis, susceptibility to} - MIM#180300; Mode of inheritance: None
Mendeliome v0.11792 NFIA Krithika Murali reviewed gene: NFIA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35018717, 33973697, 32926563; Phenotypes: Brain malformations with or without urinary tract defects - MIM#613735; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.11792 NEXN Krithika Murali reviewed gene: NEXN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33947203, 33949776, 35166435, 32058062; Phenotypes: Lethal fetal cardiomyopathy, Hydrops fetalis, Cardiomyopathy, dilated 1CC - MIM#613122; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.11792 NEK2 Zornitza Stark Marked gene: NEK2 as ready
Mendeliome v0.11788 SYCP3 Zornitza Stark Marked gene: SYCP3 as ready