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Mendeliome v1.3797 C19orf70 Zornitza Stark Tag new gene name tag was added to gene: C19orf70.
Mendeliome v1.3797 DNAJA3 Zornitza Stark Marked gene: DNAJA3 as ready
Mendeliome v1.3797 DNAJA3 Zornitza Stark Gene: dnaja3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3797 Zornitza Stark Copied gene DNAJA3 from panel Mitochondrial disease
Mendeliome v1.3797 DNAJA3 Zornitza Stark gene: DNAJA3 was added
gene: DNAJA3 was added to Mendeliome. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: DNAJA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJA3 were set to 34750646; 30770860
Phenotypes for gene: DNAJA3 were set to Mitochondrial disease, MONDO:0044970, DNAJA3-related
Mendeliome v1.3796 NDUFA4 Zornitza Stark Tag new gene name tag was added to gene: NDUFA4.
Mendeliome v1.3796 NDUFA4 Zornitza Stark commented on gene: NDUFA4: New HGNC approved name is COXFA4
Mendeliome v1.3796 NHP2 Zornitza Stark Publications for gene: NHP2 were set to 18523010; 31985013
Mendeliome v1.3795 NHP2 Zornitza Stark edited their review of gene: NHP2: Added comment: LIMITED by ClinGen Interstitial Lung Disease panel but note two additional families reported in 2025, albeit with limited additional evidence for pathogenicity.; Changed publications: 18523010, 31985013, 40352450, 40073202
Mendeliome v1.3795 NEB Sangavi Sivagnanasundram edited their review of gene: NEB: Added comment: MOI expansion and upgrade.
The majority (≈140 families) present with recessive nebulin‑associated nemaline myopathy; >4 unrelated families have a dominant distal myopathy caused by large heterozygous deletions with western‑blot confirmation of a truncated protein.

AD - Amber --> green: ClinGen Congenital Myopathies GCEP has still classified the dominant association as moderate.
AR - still green: Classified as Definitive by ClinGen Congenital Myopathy GCEP: https://search.clinicalgenome.org/CCID:005608; Changed rating: GREEN; Changed publications: 39802796, 30679003, 33933294, 40661861, 40517164, 36714460, 27933661; Changed phenotypes: autosomal dominant nebulin-related myopathy MONDO:1010152, nemaline myopathy 2 MONDO:0009725; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3795 HSPB6 Sarah Milton edited their review of gene: HSPB6: Added comment: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. In skeletal muscle HSBP6 is thought to function in promoting smooth muscle relaxation through depolymerising actin cytoskeleton.

PMID: 41294008 describes one individual with adult onset cataract and progressive weakness. His similarly affected mother was not genetically tested. Muscle biopsy demonstrated rimmed vacuoles and accumulation of HSPB6.
Variant was a c terminal extension variant (c.464delC|p.(Pro155Argfs*25) which was thought to result in aggregation of protein and was absent from gnomAD v4.

Other similar extension variants present in gnomAD v4 were transfected into cell models with those that had unstable mRNA transcripts not recapitulating findings however one other demonstrated accumulation of protein in certain settings.

Further literature is required.; Changed publications: 41294008; Changed phenotypes: Myopathy, MONDO:0005336, HSPB6-related
Mendeliome v1.3795 HSPB6 Sarah Milton changed review comment from: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. One of it's roles is in protecting against cellular stress.

PMID 29157081 reports 11 unrelated individuals with a recurrent missense variant c.29C>T|p.( with dilated cardiomyopathy. Supportive mouse models showed transgenic mice with this variant had early death, and cardiac muscle showed decreased contractility and increased cardiomyocyte apoptosis.

This variant is present in gnomAD at a frequency not compatible with rare Mendelian disease with 818 heterozygotes, 2 homozygotes and higher allele frequency in certain subpopulations.
As such further literature is required to establish it's role in disease.
Sources: Literature; to: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. One of it's roles is in protecting against cellular stress.

PMID 29157081 reports 11 unrelated individuals with a recurrent missense variant c.29C>T|p.(Ser10Phe) with dilated cardiomyopathy. Supportive mouse models showed transgenic mice with this variant had early death, and cardiac muscle showed decreased contractility and increased cardiomyocyte apoptosis.

This variant is present in gnomAD at a frequency not compatible with rare Mendelian disease with 818 heterozygotes, 2 homozygotes and higher allele frequency in certain subpopulations.
As such further literature is required to establish it's role in disease.
Sources: Literature
Mendeliome v1.3795 HSPB6 Sarah Milton gene: HSPB6 was added
gene: HSPB6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HSPB6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HSPB6 were set to 29157081
Phenotypes for gene: HSPB6 were set to Dilated cardiomyopathy, MONDO:0005021, HSPB6-related
Review for gene: HSPB6 was set to RED
Added comment: HSPB6 encodes heat shock protein family B [small] member 6 and forms homodimers and heterodimers with other members of it's family. One of it's roles is in protecting against cellular stress.

PMID 29157081 reports 11 unrelated individuals with a recurrent missense variant c.29C>T|p.( with dilated cardiomyopathy. Supportive mouse models showed transgenic mice with this variant had early death, and cardiac muscle showed decreased contractility and increased cardiomyocyte apoptosis.

This variant is present in gnomAD at a frequency not compatible with rare Mendelian disease with 818 heterozygotes, 2 homozygotes and higher allele frequency in certain subpopulations.
As such further literature is required to establish it's role in disease.
Sources: Literature
Mendeliome v1.3794 COPZ1 Zornitza Stark edited their review of gene: COPZ1: Changed phenotypes: Neutropenia, severe congenital, 12, autosomal recessive, MIM# 621439
Mendeliome v1.3794 COPZ1 Zornitza Stark Phenotypes for gene: COPZ1 were changed from Severe congenital neutropenia, autosomal recessive, MONDO:0028226, COPZ1-related to Neutropenia, severe congenital, 12, autosomal recessive MIM# 621439
Mendeliome v1.3793 MT-RNR2 Zornitza Stark Marked gene: MT-RNR2 as ready
Mendeliome v1.3793 MT-RNR2 Zornitza Stark Gene: mt-rnr2 has been classified as Red List (Low Evidence).
Mendeliome v1.3793 Zornitza Stark Copied gene MT-RNR2 from panel Mitochondrial disease
Mendeliome v1.3793 MT-RNR2 Zornitza Stark gene: MT-RNR2 was added
gene: MT-RNR2 was added to Mendeliome. Sources: Expert Review Red,Literature,Expert Review
Mode of inheritance for gene gene: MT-RNR2 was set to MITOCHONDRIAL
Publications for gene: MT-RNR2 were set to 29233888; 17761147; 24367055
Phenotypes for gene: MT-RNR2 were set to mitochondrial disease MONDO:0044970, MT-RNR2-related
Mendeliome v1.3792 IRX4 Lucy Spencer Phenotypes for gene: IRX4 were changed from Ventricular septal defect to Congenital heart disease MONDO:0005453, IRX4-related
Mendeliome v1.3791 IQSEC3 Lucy Spencer Phenotypes for gene: IQSEC3 were changed from Intellectual disability to Intellectual disability MONDO:0001071, IQSEC3-related
Mendeliome v1.3790 IQSEC2 Lucy Spencer Phenotypes for gene: IQSEC2 were changed from Intellectual developmental disorder, X-linked 1 MIM#309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347 to Intellectual developmental disorder, X-linked 1 MIM#309530
Mendeliome v1.3789 IQGAP3 Lucy Spencer Phenotypes for gene: IQGAP3 were changed from Hereditary neuropathy to Hereditary peripheral neuropathy MONDO:0020127, IQGAP3-related
Mendeliome v1.3788 IQCE Lucy Spencer Phenotypes for gene: IQCE were changed from Postaxial polydactyly to Polydactyly, postaxial, type A7 MIM#617642
Mendeliome v1.3787 INSR Lucy Spencer Phenotypes for gene: INSR were changed from Hyperinsulinemic hypoglycemia, familial, 5, MIM# 609968; Leprechaunism, MIM# 246200; Rabson-Mendenhall syndrome, MIM# 262190 to Hyperinsulinemic hypoglycemia, familial, 5, MIM# 609968; Donohue syndrome MIM#246200; Rabson-Mendenhall syndrome, MIM# 262190
Mendeliome v1.3786 IMPDH2 Lucy Spencer Phenotypes for gene: IMPDH2 were changed from Neurodevelopmental disorder with dystonia to Neurodevelopmental disorder (MONDO:0700092), IMPDH2-related
Mendeliome v1.3785 IMPDH1 Lucy Spencer Phenotypes for gene: IMPDH1 were changed from Leber congenital amaurosis 11 (MIM# 613837); Retinitis pigmentosa 10 (MIM# 180105) to IMPDH1-related retinopathy MONDO:1040051; Leber congenital amaurosis 11 (MIM# 613837); Retinitis pigmentosa 10 (MIM# 180105)
Mendeliome v1.3784 IMPDH1 Lucy Spencer commented on gene: IMPDH1
Mendeliome v1.3784 IMMP2L Lucy Spencer Phenotypes for gene: IMMP2L were changed from Autism to Autism MONDO:0005260, IMMP2L-related
Mendeliome v1.3783 ILK Lucy Spencer Phenotypes for gene: ILK were changed from Dilated cardiomyopathy to Dilated cardiomyopathy MONDO:0005021, ILK-related
Mendeliome v1.3782 IL2RG Lucy Spencer commented on gene: IL2RG
Mendeliome v1.3782 IL1RAP Lucy Spencer Phenotypes for gene: IL1RAP were changed from Steroid-sensitive nephrotic syndrome to Nephrotic syndrome of childhood - steroid sensitive MONDO:0044781, IL1RAP-related
Mendeliome v1.3781 IL12RB2 Lucy Spencer Phenotypes for gene: IL12RB2 were changed from Susceptibility to mycobacteria and Salmonella to Immunodeficiency disease MONDO:0021094, IL12RB1-related
Mendeliome v1.3780 IL10 Lucy Spencer Phenotypes for gene: IL10 were changed from Diseases of Immune Dysregulation; Early-onset inflammatory bowel disease to Immune system disorder MONDO:0005046, IL10-related; IL10-related early-onset inflammatory bowel disease MONDO:0016542
Mendeliome v1.3779 IL10 Lucy Spencer commented on gene: IL10
Mendeliome v1.3779 IKBKG Lucy Spencer Phenotypes for gene: IKBKG were changed from Ectodermal dysplasia and immunodeficiency 1, MIM# 300291; Immunodeficiency 33 , MIM#300636; Incontinentia pigmenti, MIM# 308300; Autoinflammatory disease, systemic, X-linked, MIM# 301081 to IKBKG-related immunodeficiency with or without ectodermal dysplasia MONDO:0100162; Ectodermal dysplasia and immunodeficiency 1, MIM# 300291; Immunodeficiency 33 , MIM#300636; Incontinentia pigmenti, MIM# 308300; Autoinflammatory disease, systemic, X-linked, MIM# 301081
Mendeliome v1.3778 IKBKG Lucy Spencer commented on gene: IKBKG
Mendeliome v1.3778 IGHMBP2 Lucy Spencer Phenotypes for gene: IGHMBP2 were changed from Neuronopathy, distal hereditary motor, type VI, MIM# 604320; Charcot-Marie-Tooth disease, axonal, type 2S, MIM# 616155 to Hereditary peripheral neuropathy MONDO:0020127, IGHMBP2-related; Neuronopathy, distal hereditary motor, type VI, MIM# 604320; Charcot-Marie-Tooth disease, axonal, type 2S, MIM# 616155
Mendeliome v1.3777 IGHMBP2 Lucy Spencer commented on gene: IGHMBP2
Mendeliome v1.3777 IFT74 Lucy Spencer Phenotypes for gene: IFT74 were changed from Bardet-Biedl syndrome 20, MIM# 617119; Joubert syndrome 40, MIM# 619582; Spermatogenic failure 58, MIM# 619585 to Ciliopathy MONDO:0005308, IFT74-related; Bardet-Biedl syndrome 20, MIM# 617119; Joubert syndrome 40, MIM# 619582; Spermatogenic failure 58, MIM# 619585
Mendeliome v1.3776 IFT74 Lucy Spencer commented on gene: IFT74
Mendeliome v1.3776 IFT172 Lucy Spencer Phenotypes for gene: IFT172 were changed from Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome 20, MIM# 619471 to Ciliopathy MONDO:0005308, IFT172-related; Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome 20, MIM# 619471
Mendeliome v1.3775 IFT172 Lucy Spencer commented on gene: IFT172
Mendeliome v1.3775 IFT140 Lucy Spencer Phenotypes for gene: IFT140 were changed from Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; Retinitis pigmentosa 80, MIM# 617781; {Polycystic kidney disease 9, susceptibility to} MIM#621164; Cranioectodermal dysplasia 5, MIM# 621180 to IFT140-related recessive ciliopathy MONDO:0100509; Short-rib thoracic dysplasia 9 with or without polydactyly, MIM# 266920; Retinitis pigmentosa 80, MIM# 617781; {Polycystic kidney disease 9, susceptibility to} MIM#621164; Cranioectodermal dysplasia 5, MIM# 621180
Mendeliome v1.3774 IFT140 Lucy Spencer commented on gene: IFT140
Mendeliome v1.3774 IFRD1 Lucy Spencer Phenotypes for gene: IFRD1 were changed from Hereditary spastic paraplegia; peripheral neuropathy; ataxia to Hereditary spastic paraplegia MONDO:0019064, IFRD1-related
Mendeliome v1.3773 PLXNA1 Lucy Spencer Publications for gene: PLXNA1 were set to 34054129
Mendeliome v1.3772 PLXNA1 Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no recent literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic
Mendeliome v1.3772 PLXNA1 Lucy Spencer edited their review of gene: PLXNA1: Changed rating: RED; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.3772 PLXNA1 Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic
Mendeliome v1.3772 PLXNA1 Lucy Spencer Mode of inheritance for gene: PLXNA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3771 PLXNA1 Lucy Spencer commented on gene: PLXNA1
Mendeliome v1.3771 ICE1 Lucy Spencer Phenotypes for gene: ICE1 were changed from Intellectual disability, cerebral atrophy to Intellectual disability (MONDO:0001071), ICE1-related
Mendeliome v1.3770 IBA57 Lucy Spencer commented on gene: IBA57
Mendeliome v1.3770 HUWE1 Lucy Spencer Phenotypes for gene: HUWE1 were changed from Mental retardation, X-linked syndromic, Turner type; Say-Meyer syndrome; Juberg-Marsidi syndrome to Intellectual developmental disorder, X-linked syndromic, Turner type MIM#309590
Mendeliome v1.3769 HTRA1 Lucy Spencer Phenotypes for gene: HTRA1 were changed from {Macular degeneration, age-related, 7}, 6101493; {Macular degeneration, age-related, neovascular type}, 610149; CARASIL syndrome, 600142; Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2, 616779 to Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 2 MIM#616779; Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2 MIM#600142
Mendeliome v1.3768 HSPB1 Lucy Spencer commented on gene: HSPB1
Mendeliome v1.3768 HOXB6 Lucy Spencer Phenotypes for gene: HOXB6 were changed from Hypospadias to Hypospadias MONDO:0005345, HOXB6-related
Mendeliome v1.3767 FAM20B Sangavi Sivagnanasundram reviewed gene: FAM20B: Rating: GREEN; Mode of pathogenicity: None; Publications: 41277483, 30847897; Phenotypes: Desbuquois dysplasia MONDO:0015426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3767 Chirag Patel Added reviews for gene SLC15A4 from panel Pituitary hormone deficiency
Mendeliome v1.3766 Chirag Patel Added reviews for gene HHIP from panel Pituitary hormone deficiency
Mendeliome v1.3765 PRMT9 Lucy Spencer Phenotypes for gene: PRMT9 were changed from Neurodevelopmental disorder, MONDO:0100500, PRMT9-related to Neurodevelopmental disorder, MONDO:0700092, PRMT9-related
Mendeliome v1.3764 PRMT9 Lucy Spencer Publications for gene: PRMT9 were set to PMID: 38561334
Mendeliome v1.3763 PRMT9 Lucy Spencer Classified gene: PRMT9 as Green List (high evidence)
Mendeliome v1.3763 PRMT9 Lucy Spencer Gene: prmt9 has been classified as Green List (High Evidence).
Mendeliome v1.3762 PRMT9 Lucy Spencer reviewed gene: PRMT9: Rating: GREEN; Mode of pathogenicity: None; Publications: 41260215; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, PRMT9-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3762 KCNQ3 Lucy Spencer changed review comment from: From ClinGen:

Definitive for DOMINANT complex neurodevelopmental disorder MONDO:0100038, KCNQ3-related - 24 probands across 7 publications, mostly de novo variants. Mutations are clustered at p.Arg227 and p.Arg230, with a gain of function mechanism PMID: 24851285.

Moderate for DOMINANT self-limited familial neonatal epilepsy (Seizures, benign neonatal, 2 (MIM#121201)) - 15 missense in 18 probands across 16 publications. Variants clustered in the pore region (S5, S6, and intervening loop) and result in loss of function of channel activity PMID: 24851285. Note- there are several NMD predicted variants in this gene with over 10 hets in gnomad.

Limited for RECESSIVE genetic developmental and epileptic encephalopathy MONDO:0100062, KCNQ3-related - 1 individual and 1 family from 2 publications with homozygous frameshifts PMID: 29852413; 31440727. All have seizures, various brain MRI findings, developmental delay and intellectual disability. The family had 3 similarly affected siblings, all homozygous for an NMD frameshift. The unrelated patient had a mildly affected uncle with learning difficulties and transient neonatal seizures, he was not tested for the variant.

A third recessive patient not reported by ClinGen PMID: 29383681: 7yo girl with seizures, severe neurological impairment, and developmental delay. Compound heterozygous for two missense variants Val359Leu and Asp542Asn. Patch clamp studies showed that expression of either variant alone did not affect current density, but co-expression of both variants lead to a significant current reduction.; to: From ClinGen:

Definitive for DOMINANT complex neurodevelopmental disorder MONDO:0100038, KCNQ3-related - 24 probands across 7 publications, mostly de novo variants. Mutations are clustered at p.Arg227 and p.Arg230, with a gain of function mechanism PMID: 24851285.

Moderate for DOMINANT self-limited familial neonatal epilepsy (Seizures, benign neonatal, 2 (MIM#121201)) - 15 missense in 18 probands across 16 publications. Variants clustered in the pore region (S5, S6, and intervening loop) and result in loss of function of channel activity PMID: 24851285. Note- there are several NMD predicted variants in this gene with over 10 hets in gnomad.

Limited for RECESSIVE genetic developmental and epileptic encephalopathy MONDO:0100062, KCNQ3-related - 1 individual and 1 family from 2 publications with homozygous frameshifts PMID: 29852413; 31440727. All have seizures, various brain MRI findings, developmental delay and intellectual disability. The family had 3 similarly affected siblings, all homozygous for an NMD frameshift. The unrelated patient had a mildly affected uncle with learning difficulties and transient neonatal seizures, he was not tested for the variant.

A third recessive patient not reported by ClinGen PMID: 29383681: 7yo girl with seizures, severe neurological impairment, and developmental delay. Compound heterozygous for two missense variants Val359Leu and Asp542Asn. Patch clamp studies showed that expression of either variant alone did not affect current density, but co-expression of both variants lead to a significant current reduction.

borderline amber/green for recessive
Mendeliome v1.3762 KCNQ3 Lucy Spencer Mode of inheritance for gene: KCNQ3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3761 KCNQ3 Lucy Spencer Publications for gene: KCNQ3 were set to 33337327
Mendeliome v1.3760 KCNQ3 Lucy Spencer Phenotypes for gene: KCNQ3 were changed from Seizures, benign neonatal, 2, MIM# 121201 to Complex neurodevelopmental disorder MONDO:0100038, KCNQ3-related; Seizures, benign neonatal, 2 MIM#121201; genetic developmental and epileptic encephalopathy MONDO:0100062, KCNQ3-related
Mendeliome v1.3759 KCNQ3 Lucy Spencer reviewed gene: KCNQ3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24851285, 29852413, 31440727; Phenotypes: Complex neurodevelopmental disorder MONDO:0100038, KCNQ3-related, Seizures, benign neonatal, 2 MIM#121201, genetic developmental and epileptic encephalopathy MONDO:0100062, KCNQ3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3759 SLC39A8 Zornitza Stark Phenotypes for gene: SLC39A8 were changed from Congenital disorder of glycosylation, type IIn , MIM#16721 to Congenital disorder of glycosylation, type IIn , MIM#616721
Mendeliome v1.3758 SLC39A8 Zornitza Stark edited their review of gene: SLC39A8: Changed phenotypes: Congenital disorder of glycosylation, type IIn , MIM#616721
Mendeliome v1.3758 SLC12A6 Zornitza Stark Phenotypes for gene: SLC12A6 were changed from Andermann syndrome; Agenesis of the corpus callosum with peripheral neuropathy, MIM#21800; Charcot-Marie-Tooth disease, axonal, type 2II , MIM#620068 to Andermann syndrome; Agenesis of the corpus callosum with peripheral neuropathy, MIM#218000; Charcot-Marie-Tooth disease, axonal, type 2II , MIM#620068
Mendeliome v1.3757 RSPRY1 Zornitza Stark Phenotypes for gene: RSPRY1 were changed from Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585 to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, MIM# 616723
Mendeliome v1.3756 RSPRY1 Zornitza Stark edited their review of gene: RSPRY1: Changed phenotypes: Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, MIM# 616723
Mendeliome v1.3756 POPDC2 Zornitza Stark Phenotypes for gene: POPDC2 were changed from Sinoatrial node disorder, MONDO:0000469, POPDC2-related to Cardiac conduction disease with or without cardiomyopathy 2, MIM# 621367
Mendeliome v1.3755 POPDC2 Zornitza Stark Publications for gene: POPDC2 were set to
Mendeliome v1.3754 POPDC2 Zornitza Stark reviewed gene: POPDC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiac conduction disease with or without cardiomyopathy 2, MIM# 621367; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3754 ESRRG Zornitza Stark Marked gene: ESRRG as ready
Mendeliome v1.3754 ESRRG Zornitza Stark Gene: esrrg has been classified as Green List (High Evidence).
Mendeliome v1.3754 ESRRG Zornitza Stark Classified gene: ESRRG as Green List (high evidence)
Mendeliome v1.3754 ESRRG Zornitza Stark Gene: esrrg has been classified as Green List (High Evidence).
Mendeliome v1.3753 ESRRG Zornitza Stark gene: ESRRG was added
gene: ESRRG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ESRRG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ESRRG were set to 41265451
Phenotypes for gene: ESRRG were set to Movement disorder, MONDO:0005395, ESRRG-related
Review for gene: ESRRG was set to GREEN
Added comment: Eight individuals from seven unrelated families reported with heterozygous, mostly de novo variants in ESRRG: c.410G>A (p.Gly137Glu), c.446A>G (p.Lys149Arg), c.539G>A (p.Cys180Tyr), c.550C>T (p.Arg184Cys), c.1346T>G (p.Leu449Arg), and c.1352dup (p.Leu451Phefs∗38). All individuals had motor developmental delay, muscular hypotonia, and eye movement disorders, as well as congenital ataxia or gait imbalance. Other symptoms included joint hyperflexibility, dysarthria, myopia, and growth delay. Supportive functional data.
Sources: Literature
Mendeliome v1.3752 ELMSAN1 Zornitza Stark Marked gene: ELMSAN1 as ready
Mendeliome v1.3752 ELMSAN1 Zornitza Stark Gene: elmsan1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3752 ELMSAN1 Zornitza Stark Classified gene: ELMSAN1 as Amber List (moderate evidence)
Mendeliome v1.3752 ELMSAN1 Zornitza Stark Gene: elmsan1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3751 ELMSAN1 Zornitza Stark gene: ELMSAN1 was added
gene: ELMSAN1 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: ELMSAN1.
Mode of inheritance for gene: ELMSAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ELMSAN1 were set to Neurodevelopmental disorder, MONDO:0700092, ELMSAN1-related
Review for gene: ELMSAN1 was set to AMBER
Added comment: PMID 41290615 reports 2 individuals from 2 unrelated families with the same heterozygous de novo missense variant p.Tyr654Ser presenting with a neurodevelopmental disorder characterized by speech delay, joint contractures, dysmorphic facial features, and gastrointestinal dysmotility. Functional studies demonstrated that the Y654S variant lies in an auto‑inhibitory loop of the MiDAC HDAC complex, causes a 3‑5‑fold increase in deacetylase activity, shows increased phosphorylation, and leads to reciprocal gene‑expression changes in patient fibroblasts versus loss‑of‑function models.

New HGNC approved name is MIDEAS.
Sources: Literature
Mendeliome v1.3750 SUCO Zornitza Stark Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta, MONDO:0019019, SUCO-related to Syndromic disease (MONDO:0002254), SUCO-related
Mendeliome v1.3749 SUCO Zornitza Stark Publications for gene: SUCO were set to 29620724; 20440000
Mendeliome v1.3748 SUCO Zornitza Stark Classified gene: SUCO as Green List (high evidence)
Mendeliome v1.3748 SUCO Zornitza Stark Gene: suco has been classified as Green List (High Evidence).
Mendeliome v1.3747 SUCO Zornitza Stark edited their review of gene: SUCO: Added comment: PMID 41282771: 13 individuals from 6 families reported with bi-allelic variants in this gene and features of spastic CP and OI. Identified variants included 2 truncating, 3 missense, and 3 canonical splice site variants. SUCO knockout (KO) (Opt −/−) mice display impaired bone formation and spontaneous fractures but also have evidence of a neurological phenotype with imbalanced gait and an impaired righting response. Drosophila model system using nervous system-specific RNAi knockdown of the SUCO ortholog (CG31678) showed neurological impairments occur independent of skeletal phenotypes.; Changed rating: GREEN; Changed publications: 20440000, 41282771; Changed phenotypes: Syndromic disease (MONDO:0002254), SUCO-related; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3747 KCTD1 Zornitza Stark Phenotypes for gene: KCTD1 were changed from Scalp-ear-nipple syndrome MIM#181270 to Scalp-ear-nipple syndrome MIM#181270; Dental radicular dysplasia, MIM# 621434
Mendeliome v1.3746 KCTD1 Zornitza Stark Publications for gene: KCTD1 were set to 23541344; 31324836
Mendeliome v1.3745 KCTD1 Zornitza Stark reviewed gene: KCTD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 38791218; Phenotypes: Dental radicular dysplasia, MIM# 621434; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3745 GTF2H4 Zornitza Stark Marked gene: GTF2H4 as ready
Mendeliome v1.3745 GTF2H4 Zornitza Stark Gene: gtf2h4 has been classified as Red List (Low Evidence).
Mendeliome v1.3745 Zornitza Stark Copied gene GTF2H4 from panel Photosensitivity Syndromes
Mendeliome v1.3745 GTF2H4 Zornitza Stark gene: GTF2H4 was added
gene: GTF2H4 was added to Mendeliome. Sources: Expert Review Red,Literature
Mode of inheritance for gene: GTF2H4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF2H4 were set to 40924495; 40924475
Phenotypes for gene: GTF2H4 were set to Xeroderma pigmentosum, complementation group J, MIM# 621435
Mendeliome v1.3744 OPA1 Zornitza Stark Phenotypes for gene: OPA1 were changed from Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type)MIM# 616896; Behr syndrome MIM#210000, AR; Optic atrophy 1, MIM#165500; Optic atrophy plus syndrome, MIM# 125250 to OPA1-related optic atrophy with or without extraocular features, MONDO:0800181
Mendeliome v1.3743 OPA1 Zornitza Stark Publications for gene: OPA1 were set to 30165240
Mendeliome v1.3743 OPA1 Zornitza Stark Publications for gene: OPA1 were set to
Mendeliome v1.3743 Zornitza Stark Added reviews for gene OPA1 from panel Mitochondrial disease
Mendeliome v1.3742 Zornitza Stark Added reviews for gene PPM1K from panel Aminoacidopathy
Mendeliome v1.3741 HSPA9 Zornitza Stark edited their review of gene: HSPA9: Added comment: PMID 39196378: another three individuals reported albeit with little supportive data.; Changed rating: GREEN; Changed publications: 26491070, 39196378
Mendeliome v1.3741 FGD5 Zornitza Stark Marked gene: FGD5 as ready
Mendeliome v1.3741 FGD5 Zornitza Stark Gene: fgd5 has been classified as Red List (Low Evidence).
Mendeliome v1.3741 Chirag Patel Added reviews for gene ARNT2 from panel Mendeliome
Mendeliome v1.3740 ESRP2 Chirag Patel Classified gene: ESRP2 as Amber List (moderate evidence)
Mendeliome v1.3740 ESRP2 Chirag Patel Gene: esrp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3740 ESRP2 Chirag Patel Classified gene: ESRP2 as Amber List (moderate evidence)
Mendeliome v1.3740 ESRP2 Chirag Patel Gene: esrp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3739 MT-ND2 Zornitza Stark Tag mtDNA tag was added to gene: MT-ND2.
Mendeliome v1.3739 MT-CO3 Zornitza Stark Marked gene: MT-CO3 as ready
Mendeliome v1.3739 MT-CO3 Zornitza Stark Gene: mt-co3 has been classified as Green List (High Evidence).
Mendeliome v1.3739 MT-CO3 Zornitza Stark Publications for gene: MT-CO3 were set to 11063732; 33863631; 34054915; 8630495; 9634511; 12414820; 21163656; 16288875; 8630495; 9634511
Mendeliome v1.3738 MT-CO3 Zornitza Stark Tag mtDNA tag was added to gene: MT-CO3.
Mendeliome v1.3738 Zornitza Stark Copied gene MT-CO3 from panel Mitochondrial disease
Mendeliome v1.3738 MT-CO3 Zornitza Stark gene: MT-CO3 was added
gene: MT-CO3 was added to Mendeliome. Sources: Expert Review Green,Literature
Mode of inheritance for gene gene: MT-CO3 was set to MITOCHONDRIAL
Publications for gene: MT-CO3 were set to 11063732; 33863631; 34054915; 8630495; 9634511; 12414820; 21163656; 16288875; 8630495; 9634511
Phenotypes for gene: MT-CO3 were set to Mitochondrial disease MONDO:0044970, MT-CO3-related
Mendeliome v1.3737 HMGCS1 Zornitza Stark Phenotypes for gene: HMGCS1 were changed from Rigid spine syndrome, MONDO:0019951, HMGCS1-related to Congenital myopathy 28 with rigid spine, MIM# 621433
Mendeliome v1.3736 HMGCS1 Zornitza Stark edited their review of gene: HMGCS1: Changed phenotypes: Congenital myopathy 28 with rigid spine, MIM# 621433
Mendeliome v1.3736 MT-ATP8 Zornitza Stark Classified gene: MT-ATP8 as Amber List (moderate evidence)
Mendeliome v1.3736 MT-ATP8 Zornitza Stark Gene: mt-atp8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3735 MT-ATP8 Zornitza Stark edited their review of gene: MT-ATP8: Changed publications: 40112238, 24153443, 20207608, 32858252, 33340416, 32858252, 19759059, 22919063
Mendeliome v1.3735 MT-ATP8 Zornitza Stark edited their review of gene: MT-ATP8: Changed rating: AMBER
Mendeliome v1.3735 MT-ATP8 Zornitza Stark Deleted their comment
Mendeliome v1.3735 MT-ATP8 Zornitza Stark commented on gene: MT-ATP8: LIMITED by ClinGen. Three variants (m.8403T>C, m.8411A>G, m.8424T>C) have been reported in three individuals. Age of onset varied from birth to the 30s. Clinical features included muscle weakness, wasting, and cramping; dysarthria, headache, periodic paralysis, seizures, mood disorder, neuropathy, pancreatitis, diarrhoea, and weight loss. Brain imaging revealed cerebellar atrophy; lactate was elevated. The gene-disease relationship is also supported by a biochemical function (complex V subunit) shared with other genes associated with primary mitochondrial disease, functional alteration in non-patient cells, and model organisms.
Mendeliome v1.3735 FASTKD5 Zornitza Stark Phenotypes for gene: FASTKD5 were changed from Leigh syndrome MONDO:0009723, FASTKD5-related to Mitochondrial complex IV deficiency, nuclear type 24, MIM# 621431
Mendeliome v1.3734 FASTKD5 Zornitza Stark reviewed gene: FASTKD5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 24, MIM# 621431; Mode of inheritance: None
Mendeliome v1.3734 COL10A1 Zornitza Stark Publications for gene: COL10A1 were set to 15880705; 31633898
Mendeliome v1.3733 COL10A1 Zornitza Stark edited their review of gene: COL10A1: Changed publications: 15880705, 31633898, 31348255, 25542771
Mendeliome v1.3733 COL10A1 Zornitza Stark changed review comment from: Note: Gene reviews also notes severe lethal phenotypes in recessive inheritance where parents were only mildly affected, however only 2 unrelated families reported to date (PMID: 31633898). Both haploinsufficiency and dominant-negative mechanisms have been suggested to cause disease (OMIM, PMID: 15880705, PMID: 31633898). “Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].” -> from Gene Reviews (PMID: 31633898). Some pathogenic missense also reported in the N-terminal signal peptide (Decipher), however please note that to date, no Gly-X-Y substitutions in the collagen triple helix repeats have yet been reported, pathogenic or otherwise.; to: Note: Gene reviews also notes severe lethal phenotypes in recessive inheritance where parents were only mildly affected, however only 2 unrelated families reported to date (PMID: 31633898). Both haploinsufficiency and dominant-negative mechanisms have been suggested to cause disease (OMIM, PMID: 15880705, PMID: 31633898). “Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].” -> from Gene Reviews (PMID: 31633898). Some pathogenic missense also reported in the N-terminal signal peptide (Decipher).

Note that unlike with other collagens, Gly-X-Y substitutions in the collagen triple helix repeats are very rarely reported as disease-causing, and may result in a milder phenotype (PMID 31348255; 25542771). These should be interpreted with caution.
Mendeliome v1.3733 TBXAS1 Zornitza Stark Publications for gene: TBXAS1 were set to
Mendeliome v1.3732 TBXAS1 Zornitza Stark edited their review of gene: TBXAS1: Added comment: PMID 27156553, 28868793, 33244729, 33595912, 36786374, 39220787 and 39277773 together report 10 individuals from 8 unrelated families with biallelic loss‑of‑function variants in TBXAS1. Clinical features include anemia/pancytopenia, thrombocytopenia, bone‑marrow fibrosis, splenomegaly and markedly increased diaphyseal bone density, often responding to steroids.; Changed publications: 18264100, 27156553, 28868793, 33244729, 33595912, 36786374, 39220787, 39277773
Mendeliome v1.3732 ADAMTSL2 Zornitza Stark Phenotypes for gene: ADAMTSL2 were changed from Geleophysic dysplasia 1, MIM# 231050; Dermatosparaxic Ehlers Danlos syndrome to Geleophysic dysplasia 1, MIM# 231050; Dermatosparaxic Ehlers Danlos syndrome; Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356)
Mendeliome v1.3731 ADAMTSL2 Zornitza Stark edited their review of gene: ADAMTSL2: Added comment: PMID 36896612: 12 individuals reported with the severe end of the spectrum of ADAMTSL2-related skeletal dysplasia. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly.; Changed publications: 33369194, 26879370, 21415077, 36896612; Changed phenotypes: Geleophysic dysplasia 1, MIM# 231050, Dermatosparaxic Ehlers Danlos syndrome, Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356)
Mendeliome v1.3731 MED16 Lucy Spencer Phenotypes for gene: MED16 were changed from complex neurodevelopmental disorder MONDO:0100038 to Guillouet-Gordon syndrome MIM#621220
Mendeliome v1.3730 MED16 Lucy Spencer reviewed gene: MED16: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Guillouet-Gordon syndrome MIM#621220; Mode of inheritance: None
Mendeliome v1.3730 CSNK1G1 Zornitza Stark edited their review of gene: CSNK1G1: Changed rating: AMBER
Mendeliome v1.3730 CSNK1G1 Zornitza Stark commented on gene: CSNK1G1: Gene-disease relationship reviewed again. No new literature in last 5 years. Only one LP assertion in ClinVar by 3billion. LoF variants in population. Downgrade to Amber.
Mendeliome v1.3730 CSNK1G1 Zornitza Stark Classified gene: CSNK1G1 as Amber List (moderate evidence)
Mendeliome v1.3730 CSNK1G1 Zornitza Stark Gene: csnk1g1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3729 Bryony Thompson Added reviews for gene COQ7 from panel Hereditary Spastic Paraplegia
Mendeliome v1.3728 ABI2 Zornitza Stark Marked gene: ABI2 as ready
Mendeliome v1.3728 ABI2 Zornitza Stark Gene: abi2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3728 Zornitza Stark Copied gene ABI2 from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3728 ABI2 Zornitza Stark gene: ABI2 was added
gene: ABI2 was added to Mendeliome. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: ABI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABI2 were set to 40475134
Phenotypes for gene: ABI2 were set to Neurodevelopmental disorder, MONDO:0700092, ABI2-related
Mendeliome v1.3727 Bryony Thompson Added reviews for gene PLD3 from panel Ataxia
Mendeliome v1.3726 HOXA4 Lucy Spencer Phenotypes for gene: HOXA4 were changed from Microtia-Atresia; CAKUT to Microtia with meatal atresia and conductive deafness MONDO:0009634, HOXA4-related
Mendeliome v1.3725 HNRNPD Lucy Spencer Phenotypes for gene: HNRNPD were changed from Neurodevelopmental disorder to Complex neurodevelopmental disorder MONDO:0100038, HNRNPD-related
Mendeliome v1.3724 HMBS Lucy Spencer commented on gene: HMBS
Mendeliome v1.3724 HIRA Lucy Spencer Phenotypes for gene: HIRA were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, HIRA-related
Mendeliome v1.3723 HID1 Lucy Spencer Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Developmental and epileptic encephalopathy 105 with hypopituitarism MIM#619983
Mendeliome v1.3722 HIBADH Lucy Spencer Phenotypes for gene: HIBADH were changed from Organic aciduria to 3-hydroxyisobutyric aciduria MONDO:0009371, HIBADH-related
Mendeliome v1.3721 HIBADH Lucy Spencer Classified gene: HIBADH as Green List (high evidence)
Mendeliome v1.3721 HIBADH Lucy Spencer Gene: hibadh has been classified as Green List (High Evidence).
Mendeliome v1.3720 HIBADH Lucy Spencer reviewed gene: HIBADH: Rating: GREEN; Mode of pathogenicity: None; Publications: 35174513, 34176136; Phenotypes: 3-hydroxyisobutyric aciduria MONDO:0009371, HIBADH-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3720 HELQ Lucy Spencer Phenotypes for gene: HELQ were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, HELQ-related
Mendeliome v1.3719 HEATR5B Lucy Spencer Phenotypes for gene: HEATR5B were changed from pontocerebellar hypoplasia; intellectual disability; seizures to Pontocerebellar hypoplasia MONDO:0020135, HEATR5B-related
Mendeliome v1.3718 HDAC4 Lucy Spencer Phenotypes for gene: HDAC4 were changed from Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability; Intellectual disability syndrome to Neurodevelopmental disorder with central hypotonia and dysmorphic facies MIM#619797; Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability; Intellectual disability syndrome
Mendeliome v1.3717 HCN1 Lucy Spencer commented on gene: HCN1
Mendeliome v1.3717 H3F3B Lucy Spencer Phenotypes for gene: H3F3B were changed from Intellectual disability; regression; seizures to Bryant-Li-Bhoj neurodevelopmental syndrome 2 MIM#619721
Mendeliome v1.3716 H3F3A Lucy Spencer Phenotypes for gene: H3F3A were changed from Intellectual disability; regression; seizures to Bryant-Li-Bhoj neurodevelopmental syndrome 1 MIM#619720
Mendeliome v1.3715 GUCY2D Lucy Spencer Phenotypes for gene: GUCY2D were changed from Cone-rod dystrophy 6, MIM# 601777; Leber congenital amaurosis 1, MIM# 204000; Night blindness, congenital stationary, type 1I, MIM# 618555 to GUCY2D-related dominant retinopathy MONDO:0100441; GUCY2D-related recessive retinopathy MONDO:0100453
Mendeliome v1.3714 GUCY2D Lucy Spencer reviewed gene: GUCY2D: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: GUCY2D-related dominant retinopathy MONDO:0100441, GUCY2D-related recessive retinopathy MONDO:0100453; Mode of inheritance: None
Mendeliome v1.3714 GSS Lucy Spencer Phenotypes for gene: GSS were changed from Glutathione synthetase deficiency MIM#266130; Hemolytic anemia due to glutathione synthetase deficiency MIM#231900; Disorders of the gamma-glutamyl cycle to inherited glutathione synthetase deficiency MONDO:0017909; Glutathione synthetase deficiency MIM#266130; Hemolytic anemia due to glutathione synthetase deficiency MIM#231900
Mendeliome v1.3713 GSPT2 Lucy Spencer Phenotypes for gene: GSPT2 were changed from Intellectual disability to Intellectual disability MONDO:0001071, GSPT2-related
Mendeliome v1.3712 GRIN2B Lucy Spencer Phenotypes for gene: GRIN2B were changed from Mental retardation, autosomal dominant 6, MIM# 613970; Epileptic encephalopathy, early infantile, 27, MIM# 616139 to GRIN2B-related complex neurodevelopmental disorder MONDO:0700350; Developmental and epileptic encephalopathy 27 MIM#616139; Intellectual developmental disorder, autosomal dominant 6, with or without seizures MIM#613970
Mendeliome v1.3711 GRIN2B Lucy Spencer reviewed gene: GRIN2B: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: GRIN2B-related complex neurodevelopmental disorder MONDO:0700350; Mode of inheritance: None
Mendeliome v1.3711 GRIN1 Lucy Spencer Phenotypes for gene: GRIN1 were changed from Developmental and epileptic encephalopathy 101, MIM# 619814; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820 to GRIN1-related complex neurodevelopmental disorder MONDO:1060123; Developmental and epileptic encephalopathy 101, MIM# 619814; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Mendeliome v1.3710 GRIN1 Lucy Spencer reviewed gene: GRIN1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: GRIN1-related complex neurodevelopmental disorder MONDO:1060123; Mode of inheritance: None
Mendeliome v1.3710 GRIK2 Lucy Spencer Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6 MIM# 611092; Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580 to Intellectual developmental disorder, autosomal recessive 6 MIM#611092; Neurodevelopmental disorder with impaired language and ataxia and with or without seizures MIM#619580
Mendeliome v1.3709 GPR161 Lucy Spencer Phenotypes for gene: GPR161 were changed from Predisposition to paediatric medulloblastoma to Medulloblastoma predisposition syndrome MIM#155255
Mendeliome v1.3708 GPR143 Lucy Spencer Phenotypes for gene: GPR143 were changed from GPR143-related foveal hypoplasia MONDO:0700230; congenital nystagmus 6, MIM 300814; type I ocular albinism, Nettleship-Falls type, MIM 300500 to GPR143-related foveal hypoplasia MONDO:0700230; congenital nystagmus 6, MIM# 300814; Ocular albinism, type I, Nettleship-Falls type, MIM# 300500
Mendeliome v1.3707 GPR143 Lucy Spencer Phenotypes for gene: GPR143 were changed from congenital nystagmus 6, MIM 300814; type I ocular albinism, Nettleship-Falls type, MIM 300500 to GPR143-related foveal hypoplasia MONDO:0700230; congenital nystagmus 6, MIM 300814; type I ocular albinism, Nettleship-Falls type, MIM 300500
Mendeliome v1.3706 GPR143 Lucy Spencer reviewed gene: GPR143: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: GPR143-related foveal hypoplasia MONDO:0700230; Mode of inheritance: None
Mendeliome v1.3706 GOLGA3 Lucy Spencer Phenotypes for gene: GOLGA3 were changed from Primary ciliary dyskinesia to Primary ciliary dyskinesia MONDO:0016575, GOLGA3-related
Mendeliome v1.3705 GNPTAB Lucy Spencer Phenotypes for gene: GNPTAB were changed from GNPTAB-mucolipidosis MONDO:0100122; Mucolipidosis II alpha/beta, MIM# 252500; MONDO:0009650; Mucolipidosis III alpha/beta, MIM# 252600; MONDO:0018931 to GNPTAB-mucolipidosis MONDO:0100122; Mucolipidosis II alpha/beta, MIM# 252500; Mucolipidosis III alpha/beta, MIM# 252600
Mendeliome v1.3704 GNPTAB Lucy Spencer Phenotypes for gene: GNPTAB were changed from Mucolipidosis II alpha/beta, MIM# 252500; MONDO:0009650; Mucolipidosis III alpha/beta, MIM# 252600; MONDO:0018931 to GNPTAB-mucolipidosis MONDO:0100122; Mucolipidosis II alpha/beta, MIM# 252500; MONDO:0009650; Mucolipidosis III alpha/beta, MIM# 252600; MONDO:0018931
Mendeliome v1.3703 GNPTAB Lucy Spencer reviewed gene: GNPTAB: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: GNPTAB-mucolipidosis MONDO:0100122; Mode of inheritance: None
Mendeliome v1.3703 GNB5 Lucy Spencer Phenotypes for gene: GNB5 were changed from Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Early infantile epileptic encephalopathy (EIEE) to gnb5-related intellectual disability-cardiac arrhythmia syndrome MONDO:0014953; Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia (MIM#617173); Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia (MIM#617182)
Mendeliome v1.3702 GNB5 Lucy Spencer reviewed gene: GNB5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: gnb5-related intellectual disability-cardiac arrhythmia syndrome MONDO:0014953; Mode of inheritance: None
Mendeliome v1.3702 GMPPB Lucy Spencer Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 (MIM# 615350); Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 (MIM# 615351); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 (MIM# 615352) to Myopathy caused by variation in GMPPB MONDO:0700084; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 (MIM# 615350); Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 (MIM# 615351); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 (MIM# 615352)
Mendeliome v1.3701 FDFT1 Bryony Thompson Phenotypes for gene: FDFT1 were changed from squalene synthase deficiency MONDO:0032566 to squalene synthase deficiency MONDO:0032566; porokeratosis MONDO:0006602, FDFT1-related
Mendeliome v1.3700 FDFT1 Bryony Thompson Publications for gene: FDFT1 were set to 29909962
Mendeliome v1.3699 FDFT1 Bryony Thompson Mode of inheritance for gene: FDFT1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3698 FDFT1 Bryony Thompson edited their review of gene: FDFT1: Added comment: PMID: 38653249 - Skin lesions of 2 individuals with generalised porokeratosis had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis. Whereas, lesions of the solitary or linearly arranged localised form in 6 individuals had somatic biallelic promoter hypermethylation or monoallelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis - gene-specific somatic epigenetic mosaicism. Porokeratosis is characterised as an autoinflammatory keratinisation disease; Changed publications: 29909962, 38653249; Changed phenotypes: squalene synthase deficiency MONDO:0032566, porokeratosis MONDO:0006602, FDFT1-related; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3698 FDPS Bryony Thompson Marked gene: FDPS as ready
Mendeliome v1.3698 FDPS Bryony Thompson Gene: fdps has been classified as Green List (High Evidence).
Mendeliome v1.3698 FDPS Bryony Thompson Classified gene: FDPS as Green List (high evidence)
Mendeliome v1.3698 FDPS Bryony Thompson Gene: fdps has been classified as Green List (High Evidence).
Mendeliome v1.3697 FDPS Bryony Thompson gene: FDPS was added
gene: FDPS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FDPS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FDPS were set to 26202976; 30561051; 38283795; 41240373
Phenotypes for gene: FDPS were set to porokeratosis 9, multiple types MONDO:0014713
Review for gene: FDPS was set to GREEN
Added comment: PMID 26202976 reports 4 individuals from 4 families with autosomal dominant loss‑of‑function FDPS variants causing extensive porokeratosis; PMID 30561051 adds 2 affected individuals from 1 family with disseminated superficial actinic porokeratosis; PMID 38283795 describes a single case of disseminated superficial porokeratosis; and PMID 41240373 reviews 22 individuals from the literature and an additional 3 families, with disseminated superficial actinic porokeratosis / disseminated superficial porokeratosis and genital porokeratosis.
Sources: Literature
Mendeliome v1.3696 HELB Zornitza Stark Marked gene: HELB as ready
Mendeliome v1.3696 HELB Zornitza Stark Gene: helb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3696 HELB Rylee Peters Classified gene: HELB as Amber List (moderate evidence)
Mendeliome v1.3696 HELB Rylee Peters Gene: helb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3695 HELB Rylee Peters gene: HELB was added
gene: HELB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HELB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HELB were set to 41212051
Phenotypes for gene: HELB were set to Premature ovarian failure, MONDO:0019852, HELB-related
Review for gene: HELB was set to AMBER
Added comment: PMID: 41212051 reports three individuals from a single family with a heterozygous missense HELB c.349G>T (p.Asp117Tyr) presenting with premature ovarian insufficiency and early menopause. The variant co-segregates with disease across three generations and is absent from population databases. A mouse knock-in model recapitulates the POI phenotype; RNA-seq and transcriptomic analysis showed dysregulation of genes associated with ovarian function in Helb-mutated mice.
Sources: Literature
Mendeliome v1.3694 NOS1 Chirag Patel Marked gene: NOS1 as ready
Mendeliome v1.3694 NOS1 Chirag Patel Gene: nos1 has been classified as Green List (High Evidence).
Mendeliome v1.3694 NOS1 Chirag Patel Classified gene: NOS1 as Green List (high evidence)
Mendeliome v1.3694 NOS1 Chirag Patel Gene: nos1 has been classified as Green List (High Evidence).
Mendeliome v1.3693 Chirag Patel Copied gene NOS1 from panel Pituitary hormone deficiency
Mendeliome v1.3693 NOS1 Chirag Patel gene: NOS1 was added
gene: NOS1 was added to Mendeliome. Sources: Expert Review Red,Literature
Mode of inheritance for gene: NOS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOS1 were set to 36197968
Phenotypes for gene: NOS1 were set to Hypogonadotropic hypogonadism, MONDO:0018555
Mendeliome v1.3692 COX4I1 Lucy Spencer Classified gene: COX4I1 as Green List (high evidence)
Mendeliome v1.3692 COX4I1 Lucy Spencer Gene: cox4i1 has been classified as Green List (High Evidence).
Mendeliome v1.3691 SLC6A9 Zornitza Stark Phenotypes for gene: SLC6A9 were changed from Glycine encephalopathy with normal serum glycine, MIM# 617301 to Glycine encephalopathy with normal serum glycine, MIM# 617301; Scoliosis, isolated, susceptibility to, 6, MIM# 621428
Mendeliome v1.3690 SLC6A9 Zornitza Stark Mode of inheritance for gene: SLC6A9 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3689 SLC6A9 Zornitza Stark edited their review of gene: SLC6A9: Added comment: 26 patients from 5 families with adolescent idiopathic scoliosis. Plasma glycine concentration measured in 15 patients was elevated compared to that in 36 unaffected controls. In addition, surface electromyography in 2 affected children showed aberrant paraspinal muscle activity, which was not observed in affected adults, suggesting an etiology for the spinal curvature occurring during the developmental period.

Two different missense variants reported. Functional studies indicated a dominant negative effect. In zebrafish, mutant glyt1 protein was shown to exhibit dominant-negative effects over the wildtype protein. All slc6A9 hmz m/m fish died by 18 days postfertilization (dpf), whereas about half of the slc6A9 het m/+ fish survived to 30 dpf. Glycine levels were elevated in the slc6A9 m/m fish, and at 7 dpf the majority of the mutant fish had a lateral axial curvature. In addition, some of the slc6A9 m/+ fish also had a lateral axial curvature, which persisted through day 100 dpf. The spinal curvature was rescued by expression of wildtype SLC6A9 but not with expression of SLC6A9 with a Y206F or R662W mutation. Treatment of the slc6A9 m/m fish with benzoate, a glycine neutralizer, moderately improved the curvature phenotype; Changed publications: 27481395, 27773429, 14622582, 33269555, 37962965; Changed phenotypes: Glycine encephalopathy with normal serum glycine, MIM# 617301, Scoliosis, isolated, susceptibility to, 6, MIM# 621428; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3689 Chirag Patel Added reviews for gene GJA5 from panel Congenital Heart Defect
Mendeliome v1.3688 Chirag Patel Copied gene HDAC1 from panel Congenital Heart Defect
Mendeliome v1.3688 HDAC1 Chirag Patel gene: HDAC1 was added
gene: HDAC1 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: HDAC1.
Mode of inheritance for gene: HDAC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HDAC1 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3687 TRA2B Zornitza Stark Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092 to Ramond-Elliott neurodevelopmental syndrome, MIM# 621421
Mendeliome v1.3686 TRA2B Zornitza Stark reviewed gene: TRA2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ramond-Elliott neurodevelopmental syndrome, MIM# 621421; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3686 Chirag Patel Added reviews for gene DAND5 from panel Heterotaxy
Mendeliome v1.3685 Chirag Patel Added reviews for gene UGDH from panel Congenital Heart Defect
Mendeliome v1.3684 Chirag Patel Added reviews for gene NFATC2 from panel Congenital Heart Defect
Mendeliome v1.3684 Chirag Patel Copied gene PROX1 from panel Congenital Heart Defect
Mendeliome v1.3684 PROX1 Chirag Patel gene: PROX1 was added
gene: PROX1 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: PROX1.
Mode of inheritance for gene: PROX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PROX1 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3683 Chirag Patel Copied gene RAI2 from panel Congenital Heart Defect
Mendeliome v1.3683 RAI2 Chirag Patel gene: RAI2 was added
gene: RAI2 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: RAI2.
Mode of inheritance for gene: RAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAI2 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3682 Chirag Patel Added reviews for gene NFATC1 from panel Congenital Heart Defect
Mendeliome v1.3681 Chirag Patel Added reviews for gene CTNNA3 from panel Congenital Heart Defect
Mendeliome v1.3680 Chirag Patel Copied gene NTRK3 from panel Congenital Heart Defect
Mendeliome v1.3680 NTRK3 Chirag Patel gene: NTRK3 was added
gene: NTRK3 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: NTRK3.
Mode of inheritance for gene: NTRK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NTRK3 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3680 Chirag Patel Copied gene HEY1 from panel Congenital Heart Defect
Mendeliome v1.3680 HEY1 Chirag Patel gene: HEY1 was added
gene: HEY1 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: HEY1.
Mode of inheritance for gene: HEY1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HEY1 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3679 OSR1 Chirag Patel changed review comment from: ClinGen DISPUTED - Aug 2024; to: ClinGen DISPUTED - Apr 2024
Mendeliome v1.3679 OSR1 Chirag Patel reviewed gene: OSR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3679 OSR1 Chirag Patel Mode of inheritance for gene: OSR1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3679 OSR1 Chirag Patel Phenotypes for gene: OSR1 were changed from to Congenital heart disease, MONDO:0005453
Mendeliome v1.3678 Chirag Patel Added reviews for gene LEFTY2 from panel Congenital Heart Defect
Mendeliome v1.3677 Chirag Patel Copied gene CSRP1 from panel Congenital Heart Defect
Mendeliome v1.3677 CSRP1 Chirag Patel gene: CSRP1 was added
gene: CSRP1 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: CSRP1.
Mode of inheritance for gene: CSRP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CSRP1 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3677 Chirag Patel Copied gene ATE1 from panel Congenital Heart Defect
Mendeliome v1.3677 ATE1 Chirag Patel gene: ATE1 was added
gene: ATE1 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: ATE1.
Mode of inheritance for gene: ATE1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATE1 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3676 FOXL1 Chirag Patel Phenotypes for gene: FOXL1 were changed from Otosclerosis 11 #MIM620576 to Otosclerosis 11 #MIM620576; Congenital heart disease, MONDO:0005453
Mendeliome v1.3675 Chirag Patel Added reviews for gene FOXL1 from panel Congenital Heart Defect
Mendeliome v1.3674 Chirag Patel Copied gene FMO5 from panel Congenital Heart Defect
Mendeliome v1.3674 FMO5 Chirag Patel gene: FMO5 was added
gene: FMO5 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: FMO5.
Mode of inheritance for gene: FMO5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FMO5 were set to Congenital heart disease, MONDO:0005453
Mendeliome v1.3673 Chirag Patel Added reviews for gene DTNA from panel Congenital Heart Defect
Mendeliome v1.3672 Chirag Patel Added reviews for gene DTNA from panel Congenital Heart Defect
Mendeliome v1.3671 CLIC2 Chirag Patel Tag disputed tag was added to gene: CLIC2.
Mendeliome v1.3671 Chirag Patel Copied gene EN2 from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3671 EN2 Chirag Patel gene: EN2 was added
gene: EN2 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: EN2.
Mode of inheritance for gene: EN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EN2 were set to Complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3670 CNTN4 Chirag Patel Mode of inheritance for gene: CNTN4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3670 CNTN4 Chirag Patel Mode of inheritance for gene: CNTN4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3669 KIRREL3 Chirag Patel reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3669 KIRREL3 Chirag Patel Tag refuted was removed from gene: KIRREL3.
Tag disputed tag was added to gene: KIRREL3.
Mendeliome v1.3669 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3669 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3669 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3669 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3669 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3669 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3669 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3668 CNTN4 Chirag Patel Phenotypes for gene: CNTN4 were changed from to complex neurodevelopmental disorder, MONDO:0100038
Mendeliome v1.3667 CNTN4 Chirag Patel Tag disputed tag was added to gene: CNTN4.
Mendeliome v1.3667 Chirag Patel Added reviews for gene CNTN4 from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3666 CNTNAP5 Chirag Patel Marked gene: CNTNAP5 as ready
Mendeliome v1.3666 CNTNAP5 Chirag Patel Gene: cntnap5 has been classified as Red List (Low Evidence).
Mendeliome v1.3666 Chirag Patel Copied gene CNTNAP5 from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3666 CNTNAP5 Chirag Patel gene: CNTNAP5 was added
gene: CNTNAP5 was added to Mendeliome. Sources: Expert Review Red,Genetic Health Queensland
disputed tags were added to gene: CNTNAP5.
Mode of inheritance for gene: CNTNAP5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNTNAP5 were set to 20346443
Phenotypes for gene: CNTNAP5 were set to Autism
Mendeliome v1.3665 TMLHE Chirag Patel Tag disputed tag was added to gene: TMLHE.
Mendeliome v1.3665 SLC9A9 Chirag Patel Tag disputed tag was added to gene: SLC9A9.
Mendeliome v1.3665 SLC6A4 Chirag Patel Phenotypes for gene: SLC6A4 were changed from Autism spectrum disorder MONDO:0005258 to Autism spectrum disorder MONDO:0005258
Mendeliome v1.3665 SLC6A4 Chirag Patel Phenotypes for gene: SLC6A4 were changed from {Obsessive-compulsive disorder}, MIM# 164230; depression; alcohol dependence to Autism spectrum disorder MONDO:0005258
Mendeliome v1.3664 SLC6A4 Chirag Patel Tag disputed tag was added to gene: SLC6A4.
Mendeliome v1.3664 SLC6A4 Chirag Patel commented on gene: SLC6A4: ClinGen DISPUTED - Jan 2021
Mendeliome v1.3664 SLC6A4 Chirag Patel reviewed gene: SLC6A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Autism spectrum disorder MONDO:0005258; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3664 COX4I1 Lucy Spencer Publications for gene: COX4I1 were set to 28766551; 22592081; 31290619
Mendeliome v1.3663 COX4I1 Lucy Spencer reviewed gene: COX4I1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28766551, 31290619, 40095452, 41203052; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 16 MIM#619060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3663 COQ5 Zornitza Stark Classified gene: COQ5 as Green List (high evidence)
Mendeliome v1.3663 COQ5 Zornitza Stark Gene: coq5 has been classified as Green List (High Evidence).
Mendeliome v1.3662 COQ5 Lucy Spencer Phenotypes for gene: COQ5 were changed from Coenzyme Q10 deficiency, primary 9, MIM#619028; Cerebellar ataxia; encephalopathy; generalized tonic-clonic seizures; intellectual disability to Coenzyme Q10 deficiency, primary 9, MIM#619028
Mendeliome v1.3661 COQ5 Lucy Spencer Publications for gene: COQ5 were set to 29044765
Mendeliome v1.3660 COQ5 Lucy Spencer reviewed gene: COQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29044765, 37599337, 21937992, 41199775, 36266294; Phenotypes: Coenzyme Q10 deficiency, primary, 9 MIM#619028; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3660 LAMB1 Zornitza Stark Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, MIM# 615191; Cystic leukoencephalopathy; Adult-onset leukoencephalopathy to Lissencephaly 5, MIM# 615191; Leukoencephalopathy, adult-onset, MIM# 621424
Mendeliome v1.3659 LAMB1 Zornitza Stark edited their review of gene: LAMB1: Changed phenotypes: Lissencephaly 5, MIM# 615191, Leukoencephalopathy, adult-onset, MIM# 621424
Mendeliome v1.3659 FGD5 Sangavi Sivagnanasundram gene: FGD5 was added
gene: FGD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGD5 were set to 32037394; 30232381
Phenotypes for gene: FGD5 were set to tetralogy of fallot MONDO:0008542
Review for gene: FGD5 was set to RED
Added comment: Appears to be two separate families reported with different nonsense variants in FGD5 associated with TOF. There is some author and recruitment overlap however there is no compelling evidence to state the two probands are related.

32037394 - one family reported with a nonsense variant in an individual with pulmonary stenosis and dysplastic valve, ASD - Glu322* (variant is absent in gnomAD v4.1)
30232381 (missed this publication) - individual reported with TOF, ASD, AF, hypertension, aortic dilation Arg1225* - present in gnomADv4.1 singleton in EAS population.

There is no clear evidence that LoF is the mechanism of disease. No pathogenic variants have been reported in ClinVar at this stage thus the gene should remain as Red till further evidence is provided.
Sources: Literature
Mendeliome v1.3658 CUL1 Zornitza Stark Marked gene: CUL1 as ready
Mendeliome v1.3658 CUL1 Zornitza Stark Gene: cul1 has been classified as Green List (High Evidence).
Mendeliome v1.3658 CUL1 Zornitza Stark Classified gene: CUL1 as Green List (high evidence)
Mendeliome v1.3658 CUL1 Zornitza Stark Gene: cul1 has been classified as Green List (High Evidence).
Mendeliome v1.3657 PDE11A Zornitza Stark Tag disputed was removed from gene: PDE11A.
Mendeliome v1.3657 KLF13 Krithika Murali Marked gene: KLF13 as ready
Mendeliome v1.3657 KLF13 Krithika Murali Gene: klf13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3657 KLF13 Krithika Murali Classified gene: KLF13 as Amber List (moderate evidence)
Mendeliome v1.3657 KLF13 Krithika Murali Gene: klf13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3656 KLF13 Krithika Murali gene: KLF13 was added
gene: KLF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLF13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KLF13 were set to Congenital heart disease MONDO:0005453 - KLF13-related; Dilated cardiomyopathy - MONDO:0005021, KLF13-related
Review for gene: KLF13 was set to AMBER
Added comment: Curated by ClinGen as Moderate for association with congenital heart disease (12/2/2024)

PMID: 33215447 Wang et al 2020 - novel heterozygous variation, NM_015995.3: c.370G>T; p.(Glu124*), co-segregating with congenital heart disease in a 3-generation Chinese family. Supportive functional evidence.

PMID: 35369534 Abhinav et al 2022 - NM_015995.3: c.430G>T; p.(Glu144*) co-segregated with congenital heart disease in a Han Chinese family. Supportive functional evidence.

PMID: 32293321 Li et al 2020 - Two heterozygous missense variants in two unrelated patients with congenital heart disease. However, they have much higher gnomAD frequencies - c.487C > T (P163S) (11 hets gnomAD v4) and c.467G > A (S156N)(22 hets gnomAD v4). No segregation information and the functional evidence was not convincing. This paper was included as genetic evidence in the ClinGen curation.

Monoallelic variants have also been reported in association with adult-onset DCM.

PMID 36346048 Guo et al 2022 – Identified heterozygous KLF13 gene variants co-segregating with adult-onset DCM in 3 unrelated families - c.430G>T (p.E144X); c.580G>T (p.E194X) and c.595T>C (p.C199R). Functional studies support disrupted synergistic transactivation between mutant KLF13 and target genes ACTC1, MYH7 and GATA4. Monoallelic variants in KLF13 have also been associated with congenital heart disease. Of note, 2 individuals from Family 1 and 1 individual from Family 2 also had an atrial septal defect.

PMID 41201692 Tang et al 2025 – report a novel heterozygous truncating KLF13 mutation, i.e., NM_015995.3:c.534 C>G;p.(Tyr178) in two unrelated patients with adult onset DCM (42-year-old male patient and a 51-year old female case 51 years old). Variant was absent in healthy controls. No segregation evidence. Supportive functional evidence.

More evidence including segregation information, genotype-phenotype correlation between DCM and/or congenital heart disease and ascertainment from diverse ancestries required.
Sources: Literature
Mendeliome v1.3655 CUL1 Sarah Milton gene: CUL1 was added
gene: CUL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CUL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CUL1 were set to PMID: 41189326
Phenotypes for gene: CUL1 were set to Neurodevelopmental disorder, MONDO:0700092, CUL1-related
Review for gene: CUL1 was set to GREEN
Added comment: CUL1 encodes Cullin 1 and is part of the SCF ubiquitin ligase complex which is involved in protein degradation and cell cycle progression.

Other Cullin proteins have previously been implicated in neurodevelopmental disorders e.g. CUL3

PMID: 41189326 describes 4 probands with microcephaly (postnatal in 3 out of 4), severe ID, seizures (2/4) and variable dysmorphic features. Variant types include nonsense, missense and splice with proposed LOF mechanism.
One individual inherited the variant from an affected mother with a slightly milder phenotype.
All variants were very rare (1 het) or absent from gnomAD v4.

CUL1 is under LOF constraint with very few NMD predicted variants in the population.

The paper described supportive zebrafish studies showing knockout models had reduced forebrain proportion and abnormal growth.
Sources: Literature
Mendeliome v1.3654 SEC31A Zornitza Stark Phenotypes for gene: SEC31A were changed from Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MIM# 618651; congenital neurodevelopmental syndrome; spastic paraplegia; multiple contractures; profound developmental delay; epilepsy; failure to thrive to Halperin-Birk syndrome, MIM# 618651
Mendeliome v1.3653 SEC31A Zornitza Stark Publications for gene: SEC31A were set to PMID: 30464055
Mendeliome v1.3652 Zornitza Stark Added reviews for gene SEC31A from panel Arthrogryposis
Mendeliome v1.3651 KCTD19 Zornitza Stark Marked gene: KCTD19 as ready
Mendeliome v1.3651 KCTD19 Zornitza Stark Gene: kctd19 has been classified as Green List (High Evidence).
Mendeliome v1.3651 Zornitza Stark Copied gene KCTD19 from panel Infertility and Recurrent Pregnancy Loss
Mendeliome v1.3651 KCTD19 Zornitza Stark gene: KCTD19 was added
gene: KCTD19 was added to Mendeliome. Sources: Expert Review Green,Literature
Mode of inheritance for gene: KCTD19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCTD19 were set to 37192818; 37485353; 39318590; 40410542; 41221840
Phenotypes for gene: KCTD19 were set to Infertility disorder, MONDO:0005047, KCTD19-related
Mendeliome v1.3650 MAFA Zornitza Stark Marked gene: MAFA as ready
Mendeliome v1.3650 MAFA Zornitza Stark Gene: mafa has been classified as Green List (High Evidence).
Mendeliome v1.3650 MAFA Zornitza Stark Classified gene: MAFA as Green List (high evidence)
Mendeliome v1.3650 MAFA Zornitza Stark Gene: mafa has been classified as Green List (High Evidence).
Mendeliome v1.3649 Zornitza Stark Added reviews for gene C1GALT1C1 from panel Atypical Haemolytic Uraemic Syndrome_MPGN
Mendeliome v1.3648 DHX38 Zornitza Stark Marked gene: DHX38 as ready
Mendeliome v1.3648 DHX38 Zornitza Stark Added comment: Comment when marking as ready: Maintain Amber rating after reviewing PMID 35719279, another homozygous ?synonymous variant with little supportive data.
Mendeliome v1.3648 DHX38 Zornitza Stark Gene: dhx38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3648 DHX38 Zornitza Stark Publications for gene: DHX38 were set to 24737827; 30208423
Mendeliome v1.3647 ASIC5 Zornitza Stark Marked gene: ASIC5 as ready
Mendeliome v1.3647 ASIC5 Zornitza Stark Gene: asic5 has been classified as Red List (Low Evidence).
Mendeliome v1.3647 Zornitza Stark Copied gene ASIC5 from panel Infertility and Recurrent Pregnancy Loss
Mendeliome v1.3647 ASIC5 Zornitza Stark gene: ASIC5 was added
gene: ASIC5 was added to Mendeliome. Sources: Expert Review Red,Literature
Mode of inheritance for gene: ASIC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASIC5 were set to PMID: 34395479
Phenotypes for gene: ASIC5 were set to Unexplained recurrent pregnancy loss
Mendeliome v1.3646 A4GALT Zornitza Stark Phenotypes for gene: A4GALT were changed from [Blood group, P1Pk system, p phenotype], MIM# 111400 to A4GALT-congenital disorder of glycosylation MONDO:0100587
Mendeliome v1.3645 A4GALT Zornitza Stark Publications for gene: A4GALT were set to
Mendeliome v1.3644 A4GALT Zornitza Stark Mode of inheritance for gene: A4GALT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3643 A4GALT Zornitza Stark Classified gene: A4GALT as Green List (high evidence)
Mendeliome v1.3643 A4GALT Zornitza Stark Gene: a4galt has been classified as Green List (High Evidence).
Mendeliome v1.3642 ZNF334 Zornitza Stark Marked gene: ZNF334 as ready
Mendeliome v1.3642 ZNF334 Zornitza Stark Gene: znf334 has been classified as Red List (Low Evidence).
Mendeliome v1.3642 GPKOW Zornitza Stark Publications for gene: GPKOW were set to 28612833; 40221893
Mendeliome v1.3641 GPKOW Zornitza Stark changed review comment from: Possible additional report in PMID 32426895, adult proband, extreme short stature and microcephaly, severe ID. De novo missense p.Gly427Arg.; to: Possible additional report in PMID 32426895, adult proband, extreme short stature and microcephaly, severe ID. De novo missense p.Gly427Arg.

MODERATE by ClinGen.
Mendeliome v1.3641 GPKOW Zornitza Stark reviewed gene: GPKOW: Rating: GREEN; Mode of pathogenicity: None; Publications: 32426895; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.3641 ARFGEF1 Zornitza Stark commented on gene: ARFGEF1: DEFINITIVE by ClinGen.
Mendeliome v1.3641 COL4A2 Zornitza Stark Phenotypes for gene: COL4A2 were changed from Cerebral Palsy MONDO#0006497, COL4A2-related; Brain small vessel disease 2 MIM# 614483 to Cerebral Palsy MONDO#0006497, COL4A2-related; Brain small vessel disease 2A, autosomal dominant MIM# 614483; Brain small vessel disease 2B, autosomal recessive, MIM# 621414
Mendeliome v1.3640 COL4A2 Zornitza Stark reviewed gene: COL4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 2B, autosomal recessive, MIM# 621414; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3640 GLB1 Zornitza Stark Phenotypes for gene: GLB1 were changed from GM1 gangliosidosis MONDO:0018149; GM1-gangliosidosis, type I MIM#230500; GM1-gangliosidosis, type II MIM# 230600; GM1-gangliosidosis, type III MIM#230650; Mucopolysaccharidosis type IVB (Morquio) MIM#253010 to GM1 gangliosidosis MONDO:0018149; Mucopolysaccharidosis type IVB (Morquio) MIM#253010
Mendeliome v1.3639 GBE1 Zornitza Stark Phenotypes for gene: GBE1 were changed from Glycogen storage disease due to glycogen branching enzyme deficiency MONDO:0009292; Glycogen storage disease IV, MIM# 232500; Polyglucosan body disease, adult form MIM#263570 to Glycogen storage disease due to glycogen branching enzyme deficiency MONDO:0009292
Mendeliome v1.3638 GATA6 Zornitza Stark Phenotypes for gene: GATA6 were changed from GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540; Pancreatic agenesis and congenital heart defects, 600001; Atrial septal defect 9, 614475; Atrioventricular septal defect 5, 614474; Tetralogy of Fallot, 187500; Persistent truncus arteriosus, 217095 to GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540
Mendeliome v1.3637 GATA4 Zornitza Stark Phenotypes for gene: GATA4 were changed from Structural congenital heart disease, multiple types - GATA4 MONDO:0100009; Atrial septal defect 2 MIM#607941; Atrioventricular septal defect 4 MIM#614430; Ventricular septal defect 1 MIM#614429 to Structural congenital heart disease, multiple types - GATA4 MONDO:0100009
Mendeliome v1.3636 GATA2 Zornitza Stark Phenotypes for gene: GATA2 were changed from Immunodeficiency 21, MIM# 614172; GATA2 deficiency with susceptibility to MDS/AML MONDO:0042982; Emberger syndrome, MIM# 614038; Deafness-lymphoedema-leukaemia syndrome MONDO:0013540 to GATA2 deficiency with susceptibility to MDS/AML MONDO:0042982
Mendeliome v1.3635 GLS Lucy Spencer Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328; Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412; Cataract to Epileptic encephalopathy, early infantile, 71, MIM#618328; Global developmental delay, progressive ataxia, and elevated glutamine, MIM#618412; CASGID syndrome MIM#618339
Mendeliome v1.3634 GLS Lucy Spencer reviewed gene: GLS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: CASGID syndrome MIM#618339; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3634 GLI1 Lucy Spencer Phenotypes for gene: GLI1 were changed from Polydactyly, postaxial, type A8 MIM#618123; Polydactyly, preaxial I MIM#174400 to Postaxial polydactyly MONDO:0020927, GLI1-related; Polydactyly, postaxial, type A8 MIM#618123; Polydactyly, preaxial I MIM#174400
Mendeliome v1.3633 GLI1 Lucy Spencer reviewed gene: GLI1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Postaxial polydactyly MONDO:0020927, GLI1-related; Mode of inheritance: None
Mendeliome v1.3633 CACNA1A Zornitza Stark Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2 MIM#108500 to Developmental and epileptic encephalopathy 42, MIM# 617106
Mendeliome v1.3632 GLB1 Lucy Spencer Phenotypes for gene: GLB1 were changed from GM1-gangliosidosis, type I MIM#230500; GM1-gangliosidosis, type II MIM# 230600; GM1-gangliosidosis, type III MIM#230650; Mucopolysaccharidosis type IVB (Morquio) MIM#253010 to GM1 gangliosidosis MONDO:0018149; GM1-gangliosidosis, type I MIM#230500; GM1-gangliosidosis, type II MIM# 230600; GM1-gangliosidosis, type III MIM#230650; Mucopolysaccharidosis type IVB (Morquio) MIM#253010
Mendeliome v1.3631 GLB1 Lucy Spencer reviewed gene: GLB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GM1 gangliosidosis MONDO:0018149; Mode of inheritance: None
Mendeliome v1.3631 GJC2 Lucy Spencer commented on gene: GJC2
Mendeliome v1.3631 GBE1 Lucy Spencer Phenotypes for gene: GBE1 were changed from Glycogen storage disease IV, MIM# 232500; Polyglucosan body disease, adult form MIM#263570 to Glycogen storage disease due to glycogen branching enzyme deficiency MONDO:0009292; Glycogen storage disease IV, MIM# 232500; Polyglucosan body disease, adult form MIM#263570
Mendeliome v1.3630 GBE1 Lucy Spencer reviewed gene: GBE1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycogen storage disease due to glycogen branching enzyme deficiency MONDO:0009292; Mode of inheritance: None
Mendeliome v1.3630 GATA6 Lucy Spencer Phenotypes for gene: GATA6 were changed from Pancreatic agenesis and congenital heart defects, 600001; Atrial septal defect 9, 614475; Atrioventricular septal defect 5, 614474; Tetralogy of Fallot, 187500; Persistent truncus arteriosus, 217095 to GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540; Pancreatic agenesis and congenital heart defects, 600001; Atrial septal defect 9, 614475; Atrioventricular septal defect 5, 614474; Tetralogy of Fallot, 187500; Persistent truncus arteriosus, 217095
Mendeliome v1.3629 GATA6 Lucy Spencer reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes MONDO:0100540; Mode of inheritance: None
Mendeliome v1.3629 GATA4 Lucy Spencer Phenotypes for gene: GATA4 were changed from Atrial septal defect 2 MIM#607941; Atrioventricular septal defect 4 MIM#614430; Ventricular septal defect 1 MIM#614429 to Structural congenital heart disease, multiple types - GATA4 MONDO:0100009; Atrial septal defect 2 MIM#607941; Atrioventricular septal defect 4 MIM#614430; Ventricular septal defect 1 MIM#614429
Mendeliome v1.3628 GATA4 Lucy Spencer reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Structural congenital heart disease, multiple types - GATA4 MONDO:0100009; Mode of inheritance: None
Mendeliome v1.3628 GATA2 Lucy Spencer reviewed gene: GATA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GATA2 deficiency with susceptibility to MDS/AML MONDO:0042982; Mode of inheritance: None
Mendeliome v1.3628 GAD1 Lucy Spencer Phenotypes for gene: GAD1 were changed from Cerebral palsy, spastic quadriplegic, 1, MIM#603513; Developmental and epileptic encephalopathy 89, MIM# 619124 to Developmental and epileptic encephalopathy 89, MIM# 619124
Mendeliome v1.3627 GAD1 Lucy Spencer commented on gene: GAD1
Mendeliome v1.3627 CACNA1A Zornitza Stark Mode of inheritance for gene: CACNA1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3626 CACNA1A Zornitza Stark reviewed gene: CACNA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476654, 36063114; Phenotypes: Developmental and epileptic encephalopathy 42, MIM# 617106; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3626 EXOSC10 Zornitza Stark Marked gene: EXOSC10 as ready
Mendeliome v1.3626 EXOSC10 Zornitza Stark Gene: exosc10 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3626 EXOSC10 Zornitza Stark Classified gene: EXOSC10 as Amber List (moderate evidence)
Mendeliome v1.3626 EXOSC10 Zornitza Stark Gene: exosc10 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3625 Bryony Thompson Copied gene SPP2 from panel Retinitis pigmentosa_Autosomal Dominant
Mendeliome v1.3625 SPP2 Bryony Thompson gene: SPP2 was added
gene: SPP2 was added to Mendeliome. Sources: Expert Review Red,Royal Melbourne Hospital
Mode of inheritance for gene: SPP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPP2 were set to 26459573
Phenotypes for gene: SPP2 were set to Autosomal dominant retinitis pigmentosa
Mendeliome v1.3624 Bryony Thompson Added reviews for gene CRB1 from panel Retinitis pigmentosa_Autosomal Dominant
Mendeliome v1.3623 PCSK5 Chirag Patel Marked gene: PCSK5 as ready
Mendeliome v1.3623 PCSK5 Chirag Patel Gene: pcsk5 has been classified as Red List (Low Evidence).
Mendeliome v1.3623 Chirag Patel Copied gene PCSK5 from panel Congenital Heart Defect
Mendeliome v1.3623 PCSK5 Chirag Patel gene: PCSK5 was added
gene: PCSK5 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: PCSK5.
Mode of inheritance for gene: PCSK5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PCSK5 were set to Syndromic congenital heart disease, MONDO:0100614
Mendeliome v1.3622 SCN2B Chirag Patel Marked gene: SCN2B as ready
Mendeliome v1.3622 SCN2B Chirag Patel Gene: scn2b has been classified as Red List (Low Evidence).
Mendeliome v1.3622 SCN2B Chirag Patel Marked gene: SCN2B as ready
Mendeliome v1.3622 SCN2B Chirag Patel Gene: scn2b has been classified as Red List (Low Evidence).
Mendeliome v1.3622 SLMAP Chirag Patel Marked gene: SLMAP as ready
Mendeliome v1.3622 SLMAP Chirag Patel Gene: slmap has been classified as Red List (Low Evidence).
Mendeliome v1.3622 Chirag Patel Copied gene SCN2B from panel Brugada syndrome
Mendeliome v1.3622 SCN2B Chirag Patel gene: SCN2B was added
gene: SCN2B was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: SCN2B.
Mode of inheritance for gene: SCN2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SCN2B were set to Brugada syndrome, MONDO:0015263
Mendeliome v1.3621 Chirag Patel Copied gene SLMAP from panel Brugada syndrome
Mendeliome v1.3621 SLMAP Chirag Patel gene: SLMAP was added
gene: SLMAP was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: SLMAP.
Mode of inheritance for gene: SLMAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SLMAP were set to Brugada syndrome, MONDO:0015263
Mendeliome v1.3620 KCNE5 Chirag Patel Tag disputed tag was added to gene: KCNE5.
Mendeliome v1.3620 KCNE5 Chirag Patel Phenotypes for gene: KCNE5 were changed from Atrial fibrillation to Atrial fibrillation; Brugada syndrome, MONDO:0015263
Mendeliome v1.3619 Chirag Patel Added reviews for gene KCNE5 from panel Brugada syndrome
Mendeliome v1.3618 PLAT Chirag Patel Marked gene: PLAT as ready
Mendeliome v1.3618 PLAT Chirag Patel Gene: plat has been classified as Red List (Low Evidence).
Mendeliome v1.3618 TP53BP2 Chirag Patel Marked gene: TP53BP2 as ready
Mendeliome v1.3618 TP53BP2 Chirag Patel Gene: tp53bp2 has been classified as Red List (Low Evidence).
Mendeliome v1.3618 TP53BP2 Chirag Patel gene: TP53BP2 was added
gene: TP53BP2 was added to Mendeliome. Sources: ClinGen
disputed tags were added to gene: TP53BP2.
Mode of inheritance for gene: TP53BP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53BP2 were set to Open-angle glaucoma MONDO:0005338
Review for gene: TP53BP2 was set to RED
Added comment: ClinGen DISPUTED - May 2023
Sources: ClinGen
Mendeliome v1.3617 Chirag Patel Copied gene PLAT from panel Bleeding and Platelet Disorders
Mendeliome v1.3617 PLAT Chirag Patel gene: PLAT was added
gene: PLAT was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: PLAT.
Mode of inheritance for gene: PLAT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PLAT were set to Thrombophilia, familial, due to decreased release of tissue plasminogen activator MONDO:0012872
Mendeliome v1.3616 ACADL Chirag Patel Phenotypes for gene: ACADL were changed from Hereditary pulmonary alveoral proteinosis, MONDO:0012580, ACADL-related to Long chain acyl-CoA dehydrogenase deficiency MONDO:0020531
Mendeliome v1.3615 Chirag Patel Added reviews for gene ACADL from panel Fatty Acid Oxidation Defects
Mendeliome v1.3614 STEAP3 Chirag Patel Phenotypes for gene: STEAP3 were changed from Severe congenital hypochromic anemia with ringed sideroblasts, MONDO:0014094 to Severe congenital hypochromic anemia with ringed sideroblasts, MONDO:0014094
Mendeliome v1.3614 STEAP3 Chirag Patel Phenotypes for gene: STEAP3 were changed from Anaemia, hypochromic microcytic, with iron overload 2, MIM# 615234 to Severe congenital hypochromic anemia with ringed sideroblasts, MONDO:0014094
Mendeliome v1.3613 STEAP3 Chirag Patel Tag disputed tag was added to gene: STEAP3.
Mendeliome v1.3613 Chirag Patel Added reviews for gene STEAP3 from panel Metal Metabolism Disorders
Mendeliome v1.3612 FOXD3 Chirag Patel Phenotypes for gene: FOXD3 were changed from Autoimmune disease, susceptibility to, 1 MONDO:0011919 to Autoimmune disease, susceptibility to, 1 MONDO:0011919; Aniridia, MONDO:0019172
Mendeliome v1.3611 FOXD3 Chirag Patel Deleted their review
Mendeliome v1.3611 Chirag Patel Added reviews for gene FOXD3 from panel Eye Anterior Segment Abnormalities
Mendeliome v1.3610 Chirag Patel Added reviews for gene PRKACG from panel Bleeding and Platelet Disorders
Mendeliome v1.3609 PRKACG Chirag Patel Tag disputed tag was added to gene: PRKACG.
Mendeliome v1.3609 MYOZ2 Chirag Patel Phenotypes for gene: MYOZ2 were changed from Hypertrophic cardiomyopathy, MONDO:0005045 to Hypertrophic cardiomyopathy, MONDO:0005045
Mendeliome v1.3609 MYOZ2 Chirag Patel Phenotypes for gene: MYOZ2 were changed from Cardiomyopathy, hypertrophic, 16 MIM#613838 to Hypertrophic cardiomyopathy, MONDO:0005045
Mendeliome v1.3608 MYOZ2 Chirag Patel Tag disputed tag was added to gene: MYOZ2.
Mendeliome v1.3608 Chirag Patel Added reviews for gene MYOZ2 from panel Hypertrophic cardiomyopathy_HCM
Mendeliome v1.3607 MYOM1 Chirag Patel Tag disputed tag was added to gene: MYOM1.
Mendeliome v1.3607 Chirag Patel Added reviews for gene MYOM1 from panel Hypertrophic cardiomyopathy_HCM
Mendeliome v1.3606 MYLK2 Chirag Patel Tag disputed tag was added to gene: MYLK2.
Mendeliome v1.3606 Chirag Patel Added reviews for gene MYLK2 from panel Hypertrophic cardiomyopathy_HCM
Mendeliome v1.3605 CALR3 Chirag Patel Phenotypes for gene: CALR3 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, MONDO:0005045
Mendeliome v1.3604 CALR3 Chirag Patel Tag refuted was removed from gene: CALR3.
Tag disputed tag was added to gene: CALR3.
Mendeliome v1.3604 Chirag Patel Added reviews for gene CALR3 from panel Hypertrophic cardiomyopathy_HCM
Mendeliome v1.3603 ANKRD1 Chirag Patel Tag disputed tag was added to gene: ANKRD1.
Mendeliome v1.3603 ANKRD1 Chirag Patel reviewed gene: ANKRD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: None
Mendeliome v1.3603 Chirag Patel Copied gene KCNE2 from panel Long QT Syndrome
Mendeliome v1.3603 KCNE2 Chirag Patel gene: KCNE2 was added
gene: KCNE2 was added to Mendeliome. Sources: Expert Review Red,Victorian Clinical Genetics Services
disputed tags were added to gene: KCNE2.
Mode of inheritance for gene: KCNE2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNE2 were set to 31983240; 28794082
Phenotypes for gene: KCNE2 were set to Long QT syndrome
Mendeliome v1.3602 Chirag Patel Copied gene AKAP9 from panel Long QT Syndrome
Mendeliome v1.3602 AKAP9 Chirag Patel gene: AKAP9 was added
gene: AKAP9 was added to Mendeliome. Sources: Expert Review Red,Victorian Clinical Genetics Services
disputed tags were added to gene: AKAP9.
Mode of inheritance for gene: AKAP9 was set to Unknown
Publications for gene: AKAP9 were set to 31983240
Phenotypes for gene: AKAP9 were set to long QT syndrome
Mendeliome v1.3601 TUBA8 Chirag Patel Deleted their review
Mendeliome v1.3601 TUBA8 Chirag Patel Deleted their comment
Mendeliome v1.3601 Chirag Patel Added reviews for gene TUBA8 from panel Polymicrogyria and Schizencephaly
Mendeliome v1.3600 Chirag Patel Copied gene TEKT1 from panel Ciliary Dyskinesia
Mendeliome v1.3600 TEKT1 Chirag Patel gene: TEKT1 was added
gene: TEKT1 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: TEKT1.
Mode of inheritance for gene: TEKT1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TEKT1 were set to Primary ciliary dyskinesia, MONDO:0016575
Mendeliome v1.3599 DNAH14 Chirag Patel changed review comment from: ClinGen DISPUTED - May 2025
Sources: ClinGen; to: PCD - ClinGen DISPUTED - May 2025
Sources: ClinGen
Mendeliome v1.3599 Chirag Patel Added reviews for gene DNAH14 from panel Ciliary Dyskinesia
Mendeliome v1.3598 AK7 Chirag Patel Marked gene: AK7 as ready
Mendeliome v1.3598 AK7 Chirag Patel Gene: ak7 has been classified as Red List (Low Evidence).
Mendeliome v1.3598 Chirag Patel Copied gene AK7 from panel Ciliary Dyskinesia
Mendeliome v1.3598 AK7 Chirag Patel gene: AK7 was added
gene: AK7 was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: AK7.
Mode of inheritance for gene: AK7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AK7 were set to Primary ciliary dyskinesia, MONDO:0016575
Mendeliome v1.3597 IGBP1 Chirag Patel Tag disputed tag was added to gene: IGBP1.
Mendeliome v1.3597 IGBP1 Chirag Patel reviewed gene: IGBP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3597 ARHGEF6 Chirag Patel Tag disputed tag was added to gene: ARHGEF6.
Mendeliome v1.3597 Chirag Patel Added reviews for gene ARHGEF6 from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3596 ANK2 Chirag Patel changed review comment from: ClinGen DISPUTED for catecholaminergic polymorphic ventricular tachycardia - Jan 2021
Sources: ClinGen; to: CPVT - ClinGen DISPUTED - Jan 2021
Sources: ClinGen
Mendeliome v1.3596 PKP2 Chirag Patel edited their review of gene: PKP2: Added comment: CPVT - ClinGen DISPUTED - Jan 2021; Changed phenotypes: Catecholaminergic polymorphic ventricular tachycardia, MONDO:0017990
Mendeliome v1.3596 ANK2 Chirag Patel changed review comment from: ClinGen DISPUTED - Jan 2021
Sources: ClinGen; to: ClinGen DISPUTED for catecholaminergic polymorphic ventricular tachycardia - Jan 2021
Sources: ClinGen
Mendeliome v1.3596 Chirag Patel Added reviews for gene ANK2 from panel Catecholaminergic Polymorphic Ventricular Tachycardia
Mendeliome v1.3595 Chirag Patel Added reviews for gene PKP2 from panel Catecholaminergic Polymorphic Ventricular Tachycardia
Mendeliome v1.3594 EWSR1 Chirag Patel Tag disputed tag was added to gene: EWSR1.
Mendeliome v1.3594 UPK3A Chirag Patel commented on gene: UPK3A: ClinGen DISPUTED - Jan 2023
Mendeliome v1.3594 UPK3A Chirag Patel Phenotypes for gene: UPK3A were changed from CAKUT to Congenital anomaly of kidney and urinary tract, MONDO:0019719
Mendeliome v1.3593 UPK3A Chirag Patel Tag disputed tag was added to gene: UPK3A.
Mendeliome v1.3593 Chirag Patel Added reviews for gene UPK3A from panel Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic
Mendeliome v1.3592 Chirag Patel Added reviews for gene ZFYVE27 from panel Hereditary Spastic Paraplegia - adult onset
Mendeliome v1.3591 ZFYVE27 Chirag Patel Tag disputed tag was added to gene: ZFYVE27.
Mendeliome v1.3590 PIK3R5 Chirag Patel Tag disputed tag was added to gene: PIK3R5.
Mendeliome v1.3591 Chirag Patel Added reviews for gene PIK3R5 from panel Cerebellar and Pontocerebellar Hypoplasia
Mendeliome v1.3590 CFAP47 Chirag Patel changed review comment from: 3 Japanese individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts, infertility, or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation.; to: 3 Japanese individuals with bilateral kidney cysts with mild enlargement of kidneys (mean age at Dx ~70yrs). They were all undergoing treatment for hypertension, had mean eGFR of ~31, None of them had any liver cysts, infertility, or any family history of cystic kidney disease. WGS after negative clinical diagnostic testing, identified 3 missense variants in CFAP47 gene [p.(Arg870Gln), p.(Phe516Cys), and p.(Gly6Asp)]. The variants were rare in gnomAD but had equivocal in silico prediction scores, and would be reported as VUS using ACMG criteria. Segregation was not possible as their mothers were deceased. CFAP47 encodes cilia and flagella associated protein 47 a protein that plays a role in the formation and function of cilia and flagella. It is is expressed in primary cilia of human kidney tubules. Knockout (KO) mice exhibited larger kidneys with vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation.

ClinGen DISPUTED - Feb 2025
Mendeliome v1.3590 MYO1F Chirag Patel Marked gene: MYO1F as ready
Mendeliome v1.3590 MYO1F Chirag Patel Gene: myo1f has been classified as Red List (Low Evidence).
Mendeliome v1.3590 MYO1F Chirag Patel gene: MYO1F was added
gene: MYO1F was added to Mendeliome. Sources: ClinGen
disputed tags were added to gene: MYO1F.
Mode of inheritance for gene: MYO1F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MYO1F were set to Nonsyndromic genetic hearing loss, MONDO:0019497
Review for gene: MYO1F was set to RED
Added comment: ClinGen DISPUTED - Oct 2024
Sources: ClinGen
Mendeliome v1.3589 CEMIP Chirag Patel Marked gene: CEMIP as ready
Mendeliome v1.3589 CEMIP Chirag Patel Gene: cemip has been classified as Red List (Low Evidence).
Mendeliome v1.3589 Chirag Patel Copied gene CEMIP from panel Deafness_IsolatedAndComplex
Mendeliome v1.3589 CEMIP Chirag Patel gene: CEMIP was added
gene: CEMIP was added to Mendeliome. Sources: Expert Review Red,ClinGen
disputed tags were added to gene: CEMIP.
Mode of inheritance for gene: CEMIP was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEMIP were set to Nonsyndromic genetic hearing loss, MONDO:0019497
Mendeliome v1.3588 MYO1C Chirag Patel Marked gene: MYO1C as ready
Mendeliome v1.3588 MYO1C Chirag Patel Gene: myo1c has been classified as Red List (Low Evidence).
Mendeliome v1.3588 Chirag Patel Copied gene MYO1C from panel Deafness_IsolatedAndComplex
Mendeliome v1.3588 MYO1C Chirag Patel gene: MYO1C was added
gene: MYO1C was added to Mendeliome. Sources: ClinGen
disputed tags were added to gene: MYO1C.
Mode of inheritance for gene: MYO1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MYO1C were set to Nonsyndromic genetic hearing loss, MONDO:0019497
Mendeliome v1.3587 PDLIM3 Chirag Patel Tag disputed tag was added to gene: PDLIM3.
Mendeliome v1.3587 PDLIM3 Chirag Patel Phenotypes for gene: PDLIM3 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy; Dilated cardiomyopathy, MONDO:0005021
Mendeliome v1.3586 Chirag Patel Added reviews for gene PDLIM3 from panel Dilated Cardiomyopathy
Mendeliome v1.3585 Chirag Patel Copied gene PKP2 from panel Dilated Cardiomyopathy
Mendeliome v1.3585 PKP2 Chirag Patel gene: PKP2 was added
gene: PKP2 was added to Mendeliome. Sources: Expert Review Green,Literature
Mode of inheritance for gene: PKP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKP2 were set to 15489853; 16567567; 30562116; 35059364; 38050058
Phenotypes for gene: PKP2 were set to Arrhythmogenic right ventricular dysplasia 9 (MIM#609040); Dilated cardiomyopathy, MONDO:0005021, PKP2-related; hypoplastic left heart syndrome; hydrops fetalis; ventricular septal defect; left ventricular non-compaction
Mendeliome v1.3584 PRICKLE1 Chirag Patel Tag disputed tag was added to gene: PRICKLE1.
Mendeliome v1.3584 CPA6 Chirag Patel Source Victorian Clinical Genetics Services was removed from CPA6.
Source ClinGen was added to CPA6.
Mode of inheritance for gene CPA6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3583 FAAP24 Chirag Patel Tag disputed tag was added to gene: FAAP24.
Mendeliome v1.3583 FAAP24 Chirag Patel reviewed gene: FAAP24: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3583 LIMS2 Chirag Patel Tag disputed tag was added to gene: LIMS2.
Mendeliome v1.3583 Chirag Patel Added reviews for gene LIMS2 from panel Myopathy - paediatric onset
Mendeliome v1.3582 TMPO Chirag Patel Tag refuted tag was added to gene: TMPO.
Mendeliome v1.3582 SRPX2 Chirag Patel reviewed gene: SRPX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3582 SRPX2 Chirag Patel Tag refuted tag was added to gene: SRPX2.
Mendeliome v1.3582 Chirag Patel Copied gene RANGRF from panel Brugada syndrome
Mendeliome v1.3582 RANGRF Chirag Patel gene: RANGRF was added
gene: RANGRF was added to Mendeliome. Sources: Expert Review Red,ClinGen
refuted tags were added to gene: RANGRF.
Mode of inheritance for gene: RANGRF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RANGRF were set to Brugada syndrome, MONDO:0015263
Mendeliome v1.3581 Chirag Patel Copied gene RAB40AL from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3581 RAB40AL Chirag Patel gene: RAB40AL was added
gene: RAB40AL was added to Mendeliome. Sources: Expert Review Red,Genetic Health Queensland
refuted tags were added to gene: RAB40AL.
Mode of inheritance for gene: RAB40AL was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RAB40AL were set to 25044830
Phenotypes for gene: RAB40AL were set to MENTAL RETARDATION, X-LINKED, SYNDROMIC, MARTIN-PROBST TYPE
Mendeliome v1.3580 MYO1A Chirag Patel Classified gene: MYO1A as Red List (low evidence)
Mendeliome v1.3580 MYO1A Chirag Patel Gene: myo1a has been classified as Red List (Low Evidence).
Mendeliome v1.3579 MYO1A Chirag Patel reviewed gene: MYO1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital diarrhea, MONDO:0000824; Mode of inheritance: None
Mendeliome v1.3579 KLF11 Chirag Patel Tag refuted tag was added to gene: KLF11.
Mendeliome v1.3579 GEN1 Chirag Patel Marked gene: GEN1 as ready
Mendeliome v1.3579 GEN1 Chirag Patel Gene: gen1 has been classified as Red List (Low Evidence).
Mendeliome v1.3579 Chirag Patel Copied gene GEN1 from panel Breast Cancer
Mendeliome v1.3579 GEN1 Chirag Patel gene: GEN1 was added
gene: GEN1 was added to Mendeliome. Sources: ClinGen
refuted tags were added to gene: GEN1.
Mode of inheritance for gene: GEN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GEN1 were set to Hereditary breast carcinoma, MONDO:0016419
Mendeliome v1.3578 EFHC1 Chirag Patel commented on gene: EFHC1
Mendeliome v1.3578 EFHC1 Chirag Patel Tag disputed was removed from gene: EFHC1.
Tag refuted tag was added to gene: EFHC1.
Mendeliome v1.3578 CHRNA7 Chirag Patel Tag refuted tag was added to gene: CHRNA7.
Mendeliome v1.3578 CRH Chirag Patel Marked gene: CRH as ready
Mendeliome v1.3578 CRH Chirag Patel Gene: crh has been classified as Red List (Low Evidence).
Mendeliome v1.3578 Chirag Patel Copied gene CRH from panel Genetic Epilepsy
Mendeliome v1.3578 CRH Chirag Patel gene: CRH was added
gene: CRH was added to Mendeliome. Sources: Expert Review Red,ClinGen
refuted tags were added to gene: CRH.
Mode of inheritance for gene: CRH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CRH were set to Epilepsy, MONDO:0005027
Mendeliome v1.3577 ADRA2B Chirag Patel Tag refuted tag was added to gene: ADRA2B.
Mendeliome v1.3577 EXOSC10 Rylee Peters changed review comment from: PMID: 41132091 | Article describes four unrelated individuals with heterozygous de novo EXOSC10 variants (1x missense and 4x microdeletions within the 1p36 region) presenting with primary microcephaly, anomalies of cortical structures, intellectual disability and global developmental delay. Exosc10 heterozygous knockout mice exhibited reduced cortical size resembling microcephaly, with a more severe phenotype observed in homozygous knockout mice.

However, these microdeletions occur within the 1p36 region, which is associated with chromosome 1p36 deletion syndrome (green in panelapp), and encompass many genes.
Sources: Literature; to: PMID: 41132091 | Article describes four unrelated individuals with heterozygous de novo EXOSC10 variants (1x missense and 4x microdeletions within the 1p36 region) presenting with primary microcephaly, anomalies of cortical structures, intellectual disability and global developmental delay. Exosc10 heterozygous knockout mice exhibited reduced cortical size resembling microcephaly, with a more severe phenotype observed in homozygous knockout mice.

However, these microdeletions occur within the 1p36 region, which is associated with chromosome 1p36 deletion syndrome (green in Panelapp), and encompass many genes.
Sources: Literature
Mendeliome v1.3577 EXOSC10 Rylee Peters gene: EXOSC10 was added
gene: EXOSC10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EXOSC10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EXOSC10 were set to 41132091
Phenotypes for gene: EXOSC10 were set to Microcephaly, MONDO:0001149, EXOSC10-related
Review for gene: EXOSC10 was set to AMBER
Added comment: PMID: 41132091 | Article describes four unrelated individuals with heterozygous de novo EXOSC10 variants (1x missense and 4x microdeletions within the 1p36 region) presenting with primary microcephaly, anomalies of cortical structures, intellectual disability and global developmental delay. Exosc10 heterozygous knockout mice exhibited reduced cortical size resembling microcephaly, with a more severe phenotype observed in homozygous knockout mice.

However, these microdeletions occur within the 1p36 region, which is associated with chromosome 1p36 deletion syndrome (green in panelapp), and encompass many genes.
Sources: Literature
Mendeliome v1.3576 RPS6KC1 Zornitza Stark Marked gene: RPS6KC1 as ready
Mendeliome v1.3576 RPS6KC1 Zornitza Stark Gene: rps6kc1 has been classified as Green List (High Evidence).
Mendeliome v1.3576 STARD9 Zornitza Stark Marked gene: STARD9 as ready
Mendeliome v1.3576 STARD9 Zornitza Stark Gene: stard9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3576 STARD9 Rylee Peters Classified gene: STARD9 as Amber List (moderate evidence)
Mendeliome v1.3576 STARD9 Rylee Peters Gene: stard9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3575 RPS6KC1 Rylee Peters Classified gene: RPS6KC1 as Green List (high evidence)
Mendeliome v1.3575 RPS6KC1 Rylee Peters Gene: rps6kc1 has been classified as Green List (High Evidence).
Mendeliome v1.3574 RPS6KC1 Rylee Peters gene: RPS6KC1 was added
gene: RPS6KC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to Complex neurodevelopmental disorder, MONDO:0100038, RPS6KC1-related
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID: 41130203 | Bi-allelic RPS6KC1 variants identified in 13 individuals from 8 independent families. Phenotypic manifestations included neurodevelopmental delay, epilepsy, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features.
Functional studies including a HAP1 cellular model and a Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.
Sources: Literature
Mendeliome v1.3573 DOCK4 Zornitza Stark Phenotypes for gene: DOCK4 were changed from DOCK4-related neurodevelopmental disorder (MONDO:0060490) to Neurodevelopmental disorder, MONDO:0700092, DOCK4-related
Mendeliome v1.3572 DOCK4 Zornitza Stark reviewed gene: DOCK4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, DOCK4-related; Mode of inheritance: None
Mendeliome v1.3572 STARD9 Rylee Peters gene: STARD9 was added
gene: STARD9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STARD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STARD9 were set to 41137852; 28777490
Phenotypes for gene: STARD9 were set to Syndromic disorder (MONDO:0002254), STARD9-related
Review for gene: STARD9 was set to AMBER
Added comment: STARD9 enables microtubule binding activity, motor activity and is involved in spindle assembly.

PMID: 41137852 | 1x cHet individual with early-onset febrile seizures followed by atypical absence seizures. The two missense identified, p.(Leu694Phe) and p.(Met3409Val), have 5 hets and 125 hets respectively in gnomAD v4.

PMID: 28777490 | 1x hom individual with a frameshift variant, p.(L3920fs*38). Patient had severe intellectual disability, epilepsy, dysmorphic features, acquired microcephaly, and blindness. Patient cells showed mitotic spindle assembly defects.
Sources: Literature
Mendeliome v1.3571 LRRC7 Zornitza Stark Phenotypes for gene: LRRC7 were changed from neurodevelopmental disorder (MONDO:0700092), LRRC7-related to Intellectual developmental disorder, autosomal dominant 77, MIM# 621415
Mendeliome v1.3570 LRRC7 Zornitza Stark edited their review of gene: LRRC7: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 77, MIM# 621415
Mendeliome v1.3570 PEX11B Zornitza Stark changed review comment from: Comment when marking as ready: Two published families and one International.; to: Comment when marking as ready: Two published families and one internal.
Mendeliome v1.3570 KLHL13 Krithika Murali Phenotypes for gene: KLHL13 were changed from HMSN to Neurodevelopmental disorder, MONDO:0700092, KLHL13-related
Mendeliome v1.3569 KLHL13 Krithika Murali Publications for gene: KLHL13 were set to 24627108
Mendeliome v1.3568 KLHL13 Krithika Murali Classified gene: KLHL13 as Green List (high evidence)
Mendeliome v1.3568 KLHL13 Krithika Murali Gene: klhl13 has been classified as Green List (High Evidence).
Mendeliome v1.3567 Krithika Murali Added reviews for gene KLHL13 from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3566 NOL10 Zornitza Stark Marked gene: NOL10 as ready
Mendeliome v1.3566 NOL10 Zornitza Stark Gene: nol10 has been classified as Red List (Low Evidence).
Mendeliome v1.3566 CASP1 Zornitza Stark Phenotypes for gene: CASP1 were changed from Absent IL18 and lymphopenia but no clinical disease to Inborn error of immunity, MONDO:0003778, CASP1-related; Absent IL18 and lymphopenia but no clinical disease
Mendeliome v1.3565 UNC119 Zornitza Stark Publications for gene: UNC119 were set to 11006213; 23563732; 27079236; 22184408
Mendeliome v1.3564 UNC119 Zornitza Stark edited their review of gene: UNC119: Added comment: PMID 41107067: another mouse model to support the association with cone-rod dystrophy.; Changed publications: 22184408, 41107067
Mendeliome v1.3564 TXNIP Zornitza Stark Marked gene: TXNIP as ready
Mendeliome v1.3564 TXNIP Zornitza Stark Gene: txnip has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3564 HDAC6 Bryony Thompson Marked gene: HDAC6 as ready
Mendeliome v1.3564 HDAC6 Bryony Thompson Gene: hdac6 has been classified as Red List (Low Evidence).
Mendeliome v1.3564 HDAC6 Bryony Thompson gene: HDAC6 was added
gene: HDAC6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HDAC6 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: HDAC6 were set to 20181727
Phenotypes for gene: HDAC6 were set to chondrodysplasia MONDO:0022723
Review for gene: HDAC6 was set to RED
Added comment: PMID 20181727 reports eight individuals from a single unrelated family with X-linked dominant chondrodysplasia caused by a 3′‑UTR HDAC6 variant (c.*281A>T) that abolishes miR‑433 regulation, leading to HDAC6 overexpression; severe skeletal anomalies are seen in males and a milder asymmetric short‑limb phenotype in heterozygous females. Functional assays in MG63 cells and fetal tissues confirm loss of miRNA‑mediated repression.
Sources: Literature
Mendeliome v1.3563 NAA16 Zornitza Stark Marked gene: NAA16 as ready
Mendeliome v1.3563 NAA16 Zornitza Stark Gene: naa16 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3563 OAS2 Zornitza Stark Phenotypes for gene: OAS2 were changed from Multisystem inflammatory syndrome, MONDO:0035375, OAS2-related to Autoinflammation and autoimmunity, systemic, with immune dysregulation 2, MIM# 621409
Mendeliome v1.3562 OAS2 Zornitza Stark edited their review of gene: OAS2: Changed phenotypes: Autoinflammation and autoimmunity, systemic, with immune dysregulation 2, MIM# 621409
Mendeliome v1.3562 BAIAP2 Bryony Thompson Marked gene: BAIAP2 as ready
Mendeliome v1.3562 BAIAP2 Bryony Thompson Gene: baiap2 has been classified as Green List (High Evidence).
Mendeliome v1.3562 BAIAP2 Bryony Thompson Classified gene: BAIAP2 as Green List (high evidence)
Mendeliome v1.3562 BAIAP2 Bryony Thompson Gene: baiap2 has been classified as Green List (High Evidence).
Mendeliome v1.3561 BAIAP2 Bryony Thompson gene: BAIAP2 was added
gene: BAIAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAIAP2 were set to 41133935; 38149472
Phenotypes for gene: BAIAP2 were set to BAIAP2-related complex neurodevelopmental disorder MONDO:0100038
Review for gene: BAIAP2 was set to GREEN
Added comment: The protein encoded by this gene has been identified as a brain-specific angiogenesis inhibitor (BAI1)-binding protein.
6 individuals with de novo GoF missense variants with DEE. Only 1 individual reported with a LoF missense variant & lissencephaly.
PMID: 41133935 - Reports 6 individuals from 6 unrelated families with heterozygous de novo missense BAIAP2 variants presenting with developmental and epileptic encephalopathy (DEE). Core phenotype: infantile/early‑childhood onset refractory seizures, severe language and motor delay, intellectual disability. All patients have detailed clinical descriptions; variants cluster in the phosphorylation‑rich autoinhibited region. Functional assays (HeLa cell spreading, primary hippocampal neuron electrophysiology, zebrafish overexpression) demonstrate gain‑of‑function effects. No benign variants reported; variants absent from gnomAD.
PMID: 38149472 - Reports 1 individual from 1 family with a de novo heterozygous BAIAP2 missense variant p.Arg29Trp (4 hets in gnomAD v4.1) presenting with classical lissencephaly (posterior>anterior gradient), severe global developmental delay and refractory epilepsy. Mouse Baiap2 knockdown reproduces neuronal migration defects; the p.Arg29Trp variant fails to rescue and shows reduced membrane localization, indicating a loss‑of‑function effect.
Sources: Literature
Mendeliome v1.3560 TXNIP Lucy Spencer Classified gene: TXNIP as Amber List (moderate evidence)
Mendeliome v1.3560 TXNIP Lucy Spencer Gene: txnip has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3559 TXNIP Lucy Spencer gene: TXNIP was added
gene: TXNIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TXNIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TXNIP were set to 41116060; 30755400
Phenotypes for gene: TXNIP were set to Metabolic disease MONDO:0005066, TXNIP-related
Review for gene: TXNIP was set to AMBER
Added comment: TXNIP binds and inhibits TXN, controlling its activity. The TXN system is a major cellular system for control of redox state, antioxidant defense, and several signaling pathways. TXNIP can also activate the NLRP3 inflammasome and suppress of the activities of the
nuclear factor (erythroid-derived 2)–like 2 (Nrf2) transcription factor.

PMID 30755400 reports three affected siblings from a consanguineous Libyan family with autosomal recessive congenital lactic acidosis and low serum methionine. 2 of the three siblings have developed normally and appear to be mostly asymptomatic apart from variable hypoglycaemia, while the third had failure the thrive as an infant, slow development, ?autism, and slight muscular hypotonus. All three siblings were homozygous for TXNIP c.174_175delinsTT which creates a stopgain at p.Gly59* (and a missense at p.58). Patient‑derived fibroblasts and myoblasts show impaired pyruvate‑driven mitochondrial respiration that is rescued by TXNIP re‑constitution. However, patient cells showed no difference in cell growth or morphology, and had normal downstream TXN activity while Nrf2 target gene transcripts were upregulated.

PMID 41116060 describes an additional individual with a severe metabolic disease; lactic acidosis, recurrent hypoglycaemia, significant developmental delay, epileptic seizures, and hypotonia. Homozygous for c.642_643insT p.(Ile215Tyrfs*59). Functional studies showed it disrupts SLC7A5-SLC3A2 endocytosis and cellular glucose uptake.
Sources: Literature
Mendeliome v1.3558 ESRP2 Chirag Patel Classified gene: ESRP2 as Green List (high evidence)
Mendeliome v1.3558 ESRP2 Chirag Patel Gene: esrp2 has been classified as Green List (High Evidence).
Mendeliome v1.3557 Chirag Patel Added reviews for gene ESRP2 from panel Clefting disorders
Mendeliome v1.3556 NAA16 Lucy Spencer Classified gene: NAA16 as Amber List (moderate evidence)
Mendeliome v1.3556 NAA16 Lucy Spencer Gene: naa16 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3555 NAA16 Lucy Spencer gene: NAA16 was added
gene: NAA16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAA16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NAA16 were set to 41148812; 23665959; 28991257
Phenotypes for gene: NAA16 were set to Congenital heart disease, MONDO:0005453, NAA16-related
Review for gene: NAA16 was set to AMBER
Added comment: NAA16 is part of the auxiliary subunit of the NatA complex along with NAA15. this complex is responsible for acetylating a broad range of proteins following initiator methionine removal. NAA15 and NAA10 which is part of the catalytic subunit of the complex have previously been associated with neurodevelopmental disorders, including CHD for NAA15.

PMID 41148812 3 individuals from 3 unrelated families with heterozygous NAA16 variants (p.R70C missense de novo; p.L765fs and p.E630fs frameshifts unclear inheritance) presenting with congenital heart disease (atrial septal defect, Tetralogy of Fallot, conotruncal defects). These 3 families were identified in a large cohort from the Paediatric Cardiac Genomic Consortium (PMID: 23665959, PMID: 28991257). One of the individuals with a frameshift is also listed as having a neurodevelopmental phenotype PMID: 28991257. Arg70Cys has 24 hets in gnomad and the gene is not very constrained for LOF.

PMID 41148812 Drosophila cardiac‑specific rescue assay shows loss‑of‑function for the missense variant (unable to rescue the phenotype), supporting pathogenicity.
Sources: Literature
Mendeliome v1.3554 NMNAT3 Chirag Patel Marked gene: NMNAT3 as ready
Mendeliome v1.3554 NMNAT3 Chirag Patel Gene: nmnat3 has been classified as Red List (Low Evidence).
Mendeliome v1.3554 Chirag Patel Copied gene NMNAT3 from panel Red cell disorders
Mendeliome v1.3554 NMNAT3 Chirag Patel gene: NMNAT3 was added
gene: NMNAT3 was added to Mendeliome. Sources: Expert Review Red,Literature
Mode of inheritance for gene: NMNAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT3 were set to 41100733, 24739386
Phenotypes for gene: NMNAT3 were set to Familial hemolytic anemia, MONDO:0003689
Mendeliome v1.3553 CASP1 Chirag Patel Marked gene: CASP1 as ready
Mendeliome v1.3553 CASP1 Chirag Patel Gene: casp1 has been classified as Red List (Low Evidence).
Mendeliome v1.3553 Chirag Patel Copied gene CASP1 from panel Defects of intrinsic and innate immunity
Mendeliome v1.3553 CASP1 Chirag Patel gene: CASP1 was added
gene: CASP1 was added to Mendeliome. Sources: Expert Review Red,Literature
Mode of inheritance for gene: CASP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP1 were set to 41101739
Phenotypes for gene: CASP1 were set to Absent IL18 and lymphopenia but no clinical disease
Mendeliome v1.3552 NOL10 Sangavi Sivagnanasundram gene: NOL10 was added
gene: NOL10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOL10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOL10 were set to 41093997
Phenotypes for gene: NOL10 were set to NOL10-related neurological disorder MONDO:0100545
Review for gene: NOL10 was set to RED
Added comment: 12yr F with recurrent focal seizures, progressive memory impairment and atrophy and parietal gliosis on MRI. Homozygous missense variant was identified (NM_024894.4: c.682 A > C; p.Asn228His). The variant is absent in gnomAD v4.1

Functional study using patient-derived fibroblasts was conducted and showed defective ribosome biogenesis. As this is a new gene disease association, it is unclear if that is the mechanism of disease. Need more evidence to promote the gene to Amber.
Sources: Literature
Mendeliome v1.3551 AP1B1 Chirag Patel Phenotypes for gene: AP1B1 were changed from Ichthyosiform erythroderma, corneal involvement, and hearing loss MONDO:0009440 to Ichthyosiform erythroderma, corneal involvement, and hearing loss MONDO:0009440
Mendeliome v1.3551 AP1B1 Chirag Patel Phenotypes for gene: AP1B1 were changed from Keratitis-ichthyosis-deafness syndrome, autosomal recessive, MIM# 242150 to Ichthyosiform erythroderma, corneal involvement, and hearing loss MONDO:0009440
Mendeliome v1.3550 AP1B1 Chirag Patel Publications for gene: AP1B1 were set to 31630791, 31630788, 33452671, 33349978, 35144013, 37657632, 32969855
Mendeliome v1.3550 AP1B1 Chirag Patel Publications for gene: AP1B1 were set to 31630788; 31630791
Mendeliome v1.3549 AP1B1 Chirag Patel reviewed gene: AP1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31630791, 31630788, 33452671, 33349978, 35144013, 37657632, 32969855; Phenotypes: Ichthyosiform erythroderma, corneal involvement, and hearing loss MONDO:0009440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3549 AP1S1 Chirag Patel reviewed gene: AP1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19057675, 23423674, 30244301, 32306098, 24754424, 39541497; Phenotypes: MEDNIK syndrome, MONDO:0012251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3549 ZNF334 Sarah Milton gene: ZNF334 was added
gene: ZNF334 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF334 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF334 were set to PIMD: 41168503
Phenotypes for gene: ZNF334 were set to Familial cold autoinflammatory syndrome, MONDO:0018768, ZNF334-related
Review for gene: ZNF334 was set to RED
Added comment: ZNF334 encodes zinc finger protein 334 and function is not clearly defined.

PMID: 41168503 describes 1 individual with late onset cold induced autoinflammatory disease (urticaria, fever, arthralgia, lymphadenopathy, onset 40 yo) and progressive SNHL.

Functional studies indicated reduced interaction ZNF334 and HSP90 (a cold stress regulator protein), monocytic cells lines with truncated ZNF344 showed enhanced cold induced TNF/NFKB1/NLRP3/STAT3 signalling.

This variant was truncating NMD escape, however the gene has pLI = 0.
Further literature is required.
Sources: Literature
Mendeliome v1.3548 NUDT6 Zornitza Stark Phenotypes for gene: NUDT6 were changed from Osteogenesis imperfecta to Osteogenesis imperfecta, MONDO:0019019, NUDT6-related
Mendeliome v1.3547 NUDT6 Zornitza Stark Marked gene: NUDT6 as ready
Mendeliome v1.3547 NUDT6 Zornitza Stark Gene: nudt6 has been classified as Red List (Low Evidence).
Mendeliome v1.3547 QSER1 Zornitza Stark Marked gene: QSER1 as ready
Mendeliome v1.3547 QSER1 Zornitza Stark Gene: qser1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3547 QSER1 Zornitza Stark Classified gene: QSER1 as Amber List (moderate evidence)
Mendeliome v1.3547 QSER1 Zornitza Stark Gene: qser1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3546 WRAP73 Zornitza Stark Phenotypes for gene: WRAP73 were changed from Microsperophakia to Anterior segment dysgenesis, MONDO:0019503, WRAP73-related
Mendeliome v1.3545 WRAP73 Rylee Peters reviewed gene: WRAP73: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Anterior segment dysgenesis, MONDO:0019503, WRAP73-related; Mode of inheritance: None
Mendeliome v1.3545 QSER1 Sarah Milton gene: QSER1 was added
gene: QSER1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: QSER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: QSER1 were set to PMID: 41139957
Phenotypes for gene: QSER1 were set to Neurodevelopmental disorder, MONDO:0700092, QSER1-related
Review for gene: QSER1 was set to AMBER
Added comment: QSER1 encodes glutamine and serine rich protein 1 of which the function is not clearly defined however is thought to have a role in methylation.

PMID: 41139957 describes 3 individuals with de novo heterozygous variants in QSER1 without clear consistent phenotypes.
2 individuals were born at less than 26 weeks with developmental delay with the individual that was born at term found to have normal development. Other associated features noted were ophthalmologic abnormalities (2), genitourinary abnormalities (2), congenital cardiac abnormalities (2), hemiparesis/gait abnormalities (1), preaxial polydactyly (1).

Variant types included frameshift and splice site.
One variant was present in 3 hets in gnomAD v4 with the others absent.

Functional studies demonstrated widespread expression of the protein in zebrafish without further experiments to examine molecular mechanism of variants or downstream effects.
Sources: Literature
Mendeliome v1.3544 SOX3 Chirag Patel Classified gene: SOX3 as Green List (high evidence)
Mendeliome v1.3544 SOX3 Chirag Patel Gene: sox3 has been classified as Green List (High Evidence).
Mendeliome v1.3543 Chirag Patel Added reviews for gene SOX3 from panel Pituitary hormone deficiency
Mendeliome v1.3542 CCNK Sangavi Sivagnanasundram Marked gene: CCNK as ready
Mendeliome v1.3542 CCNK Sangavi Sivagnanasundram Gene: ccnk has been classified as Green List (High Evidence).
Mendeliome v1.3542 CCNK Sangavi Sivagnanasundram Classified gene: CCNK as Green List (high evidence)
Mendeliome v1.3542 CCNK Sangavi Sivagnanasundram Gene: ccnk has been classified as Green List (High Evidence).
Mendeliome v1.3541 CCNK Sangavi Sivagnanasundram changed review comment from: CCNK encodes a regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases.
Reported affected individuals presented with a syndromic neurodevelopmental disorder (i.e. DD, ID, language impairment and various dysmorphic features)
7 unrelated families with different de novo variants (missense and CNV, deletion). All variants were either rare for AD gene or absent in gnomAD v4.1.
Supportive functional studies (knockdown zebrafish and mouse model) showed recapitulation of human phenotype and was supportive of LoF as the mechanism of disease
Sources: Literature; to: CCNK encodes a regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases.
Reported affected individuals presented with a syndromic neurodevelopmental disorder (i.e. DD, ID, language impairment and various dysmorphic features)
7 unrelated families with different de novo variants (missense and CNV, deletion). All variants were absent in gnomAD v4.1.
Supportive functional studies (knockdown zebrafish and mouse model) showed recapitulation of human phenotype and was supportive of LoF as the mechanism of disease
Sources: Literature
Mendeliome v1.3541 CCNK Sangavi Sivagnanasundram gene: CCNK was added
gene: CCNK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCNK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCNK were set to 41101726; 37597256; 30122539
Phenotypes for gene: CCNK were set to CCNK-related neurodevelopmental disorder-severe intellectual disability-facial dysmorphism syndrome MONDO:0035775
Review for gene: CCNK was set to GREEN
Added comment: CCNK encodes a regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases.
Reported affected individuals presented with a syndromic neurodevelopmental disorder (i.e. DD, ID, language impairment and various dysmorphic features)
7 unrelated families with different de novo variants (missense and CNV, deletion). All variants were either rare for AD gene or absent in gnomAD v4.1.
Supportive functional studies (knockdown zebrafish and mouse model) showed recapitulation of human phenotype and was supportive of LoF as the mechanism of disease
Sources: Literature
Mendeliome v1.3540 FOXA2 Chirag Patel Phenotypes for gene: FOXA2 were changed from Hyperinsulinism MONDO:0002177 to Hyperinsulinism MONDO:0002177; Hypopituitarism, MONDO:0005152
Publications for gene FOXA2 were changed from 29329447; 28973288; 11445544; 33999151; 30414530; 33729509; 31294511 to 29329447; 28973288; 11445544; 33999151; 30414530; 33729509; 31294511
Mendeliome v1.3539 Chirag Patel Added reviews for gene FOXA2 from panel Pituitary hormone deficiency
Mendeliome v1.3538 Chirag Patel Copied gene NUDT6 from panel Osteogenesis Imperfecta and Osteoporosis
Mendeliome v1.3538 NUDT6 Chirag Patel gene: NUDT6 was added
gene: NUDT6 was added to Mendeliome. Sources: Expert List
Mode of inheritance for gene: NUDT6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NUDT6 were set to Osteogenesis imperfecta
Mendeliome v1.3537 TAPT1 Chirag Patel Classified gene: TAPT1 as Green List (high evidence)
Mendeliome v1.3537 TAPT1 Chirag Patel Gene: tapt1 has been classified as Green List (High Evidence).
Mendeliome v1.3536 Chirag Patel Added reviews for gene TAPT1 from panel Osteogenesis Imperfecta and Osteoporosis
Mendeliome v1.3535 SRRM1 Zornitza Stark Marked gene: SRRM1 as ready
Mendeliome v1.3535 SRRM1 Zornitza Stark Gene: srrm1 has been classified as Green List (High Evidence).
Mendeliome v1.3535 Zornitza Stark Copied gene SRRM1 from panel Intellectual disability syndromic and non-syndromic
Mendeliome v1.3535 SRRM1 Zornitza Stark gene: SRRM1 was added
gene: SRRM1 was added to Mendeliome. Sources: Expert Review Green,Literature
Mode of inheritance for gene: SRRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM1 were set to 41145827
Phenotypes for gene: SRRM1 were set to Neurodevelopmental disorder, MONDO:0700092, SRRM1-related
Mendeliome v1.3534 ZNF81 Rylee Peters Tag disputed tag was added to gene: ZNF81.
Mendeliome v1.3534 SGSM3 Zornitza Stark Phenotypes for gene: SGSM3 were changed from Neurodevelopmental disorder (MONDO:0700092), SGSM3-related to Intellectual developmental disorder, autosomal recessive 84, MIM# 620401
Mendeliome v1.3533 SGSM3 Zornitza Stark reviewed gene: SGSM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 84, MIM# 620401; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3533 EPB41 Bryony Thompson Mode of inheritance for gene: EPB41 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3532 KHDC3L Bryony Thompson Added comment: Comment on mode of inheritance: No evidence of monoallelic association in the literature
Mendeliome v1.3532 KHDC3L Bryony Thompson Mode of inheritance for gene: KHDC3L was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3531 EIF4A2 Bryony Thompson Mode of inheritance for gene: EIF4A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3530 EGR2 Bryony Thompson Mode of inheritance for gene: EGR2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3529 PHGDH Sangavi Sivagnanasundram reviewed gene: PHGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005786; Phenotypes: Neurometabolic disorder due to serine deficiency MONDO:0018162; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3529 RHOA Zornitza Stark Phenotypes for gene: RHOA were changed from normal cognition; leukoencephalopathy; micro-ophthalmia; strabismus; linear hypopigmentation; malar hypoplasia; downslanting palpebral fissures; microstomia; dental anomalies; body asymmetry; limb length discrepancy to Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic, MIM# 618727
Mendeliome v1.3528 RHOA Zornitza Stark Publications for gene: RHOA were set to 31570889; 31821646
Mendeliome v1.3527 RHOA Zornitza Stark edited their review of gene: RHOA: Changed phenotypes: Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic, MIM# 618727
Mendeliome v1.3527 RHOA Zornitza Stark edited their review of gene: RHOA: Added comment: PMID 40414526: non-mosaic individual reported.; Changed publications: 31821646, 40414526
Mendeliome v1.3527 CARS Zornitza Stark Tag new gene name tag was added to gene: CARS.
Mendeliome v1.3527 CARS Zornitza Stark Phenotypes for gene: CARS were changed from Intellectual disability; microcephaly; brittle hair and nails to Microcephaly, developmental delay, and brittle hair syndrome, MIM# 618891
Mendeliome v1.3526 CARS Zornitza Stark Publications for gene: CARS were set to PMID: 30824121
Mendeliome v1.3525 CARS Zornitza Stark reviewed gene: CARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 41121266, 39963003, 30824121; Phenotypes: Microcephaly, developmental delay, and brittle hair syndrome, MIM# 618891; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3525 PAN2 Zornitza Stark Phenotypes for gene: PAN2 were changed from Syndromic disease MONDO:0002254, PAN2-related to Developmental delay with variable cardiac and renal congenital anomalies and dysmoprhic facies, MIM# 621384
Mendeliome v1.3524 PAN2 Zornitza Stark edited their review of gene: PAN2: Changed phenotypes: Developmental delay with variable cardiac and renal congenital anomalies and dysmoprhic facies, MIM# 621384
Mendeliome v1.3524 IL27RA Zornitza Stark Phenotypes for gene: IL27RA were changed from Epstein-Barr virus infection MONDO:0005111 , IL27RA-related to Immunodeficiency 134 (Epstein-Barr virus-specific), MIM# 621405
Mendeliome v1.3523 IL27RA Zornitza Stark reviewed gene: IL27RA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 134 (Epstein-Barr virus-specific), MIM# 621405; Mode of inheritance: None
Mendeliome v1.3523 RRP12 Zornitza Stark Marked gene: RRP12 as ready
Mendeliome v1.3523 RRP12 Zornitza Stark Gene: rrp12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3523 RRP12 Zornitza Stark Phenotypes for gene: RRP12 were changed from Brain calcifications to Syndromic disease, MONDO:0002254, RRP12-related; Brain calcifications
Mendeliome v1.3522 RRP12 Zornitza Stark Mode of pathogenicity for gene: RRP12 was changed from Other to None
Mendeliome v1.3521 RRP12 Zornitza Stark Classified gene: RRP12 as Amber List (moderate evidence)
Mendeliome v1.3521 RRP12 Zornitza Stark Gene: rrp12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3520 RRP12 Catherine Dalzell gene: RRP12 was added
gene: RRP12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRP12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRP12 were set to PMID: 41059649
Phenotypes for gene: RRP12 were set to Brain calcifications
Penetrance for gene: RRP12 were set to unknown
Mode of pathogenicity for gene: RRP12 was set to Other
Review for gene: RRP12 was set to AMBER
Added comment: Variants: 5 individuals from 3 unrelated families with homozygous RRP12 variants (3 different variants, 2 consanguineous families with same variant, 2 siblings with same variant).

Phenotype: all individuals had brain calcifications (varying distribution, severity and age of onset). The patients from the two consanguineous families both had infantile-onset generalised dystonia, spasticity and severe speech impairment with widespread brain calcifications. One also had microcephaly, seizures and a cataract whilst the other had mild thrombocytopenia. The two siblings had psychiatric symptoms (one bipolar disease and one anxiety) with marked, bilateral symmetric calcifications. One also had cerebellar ataxia, choreic movements, cognitive impairment and subtle Parkinsonism whilst the other had chronic tinnitus. The final individual had dizziness and only faint bilateral lenticular calcifications.

Functional data: a statistically significant reduction in RRP12 protein levels in probands’ fibroblasts compared to controls was demonstrated. rrp12 knockdown in zebrafish embryos demonstrated reduced survival (50% survival at 2 days and maximum survival of 6 days compared to 100% survival at 6 days in controls). Phenotype abnormalities (delayed development and crimping) were also seen in the rrp12 knockdown embryos. Functional studies support a possible LoF mechanism.
Sources: Literature
Mendeliome v1.3520 TAF2 Zornitza Stark Phenotypes for gene: TAF2 were changed from Mental retardation, autosomal recessive 40, MIM# 615599 to Intellectual development disorder, autosomal recessive 40, MIM# 615599
Mendeliome v1.3519 TAF2 Zornitza Stark edited their review of gene: TAF2: Changed phenotypes: Intellectual development disorder, autosomal recessive 40, MIM# 615599
Mendeliome v1.3519 OSBPL2 Zornitza Stark Publications for gene: OSBPL2 were set to 25077649; 25759012; 31451425; 30894143
Mendeliome v1.3518 OSBPL2 Zornitza Stark reviewed gene: OSBPL2: Rating: RED; Mode of pathogenicity: None; Publications: 38701954; Phenotypes: Dyschromatosis, ichthyosis, deafness, and atopic disease, MIM# 621400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3518 CTSA Zornitza Stark Phenotypes for gene: CTSA were changed from Galactosialidosis, MIM# 256540; Cathepsin A-related arteriopathy with strokes and leukoencephalopathy to Galactosialidosis, MIM# 256540; Brain small vessel disease 6 with leukoencephalopathy, MIM# 621394
Mendeliome v1.3517 CTSA Zornitza Stark edited their review of gene: CTSA: Changed phenotypes: Galactosialidosis, MIM# 256540, Brain small vessel disease 6 with leukoencephalopathy, MIM# 621394
Mendeliome v1.3517 EPO Zornitza Stark Phenotypes for gene: EPO were changed from erythrocytosis, familial, 5 MONDO:0033483 to Erythrocytosis, familial, 5, MIM# 617907; Diamond-Blackfan anaemia-like, MIM# 617911
Mendeliome v1.3516 EPO Zornitza Stark Publications for gene: EPO were set to 27651169; 29514032; 25985138; 28283061
Mendeliome v1.3515 EPO Zornitza Stark Mode of pathogenicity for gene: EPO was changed from Other to None
Mendeliome v1.3514 EPO Zornitza Stark Mode of inheritance for gene: EPO was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3513 EPO Zornitza Stark reviewed gene: EPO: Rating: GREEN; Mode of pathogenicity: None; Publications: 27651169, 29514032, 32130275, 20700488, 30507031, 28283061, 41137542; Phenotypes: Erythrocytosis, familial, 5, MIM# 617907, Diamond-Blackfan anaemia-like, MIM# 617911; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3513 IRF3 Bryony Thompson Publications for gene: IRF3 were set to 26513235
Mendeliome v1.3512 IRF3 Bryony Thompson reviewed gene: IRF3: Rating: AMBER; Mode of pathogenicity: None; Publications: 32972995, 38665565, 33386334, 41065760, 26216125, 26513235; Phenotypes: Inborn error of immunity MONDO:0003778; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3512 IFNGR2 Zornitza Stark Deleted their comment
Mendeliome v1.3512 IFNGR2 Zornitza Stark edited their review of gene: IFNGR2: Added comment: PMID 23161749: some evidence that haploinsufficiency causes mono-allelic disease. Amber for this association.; Changed publications: 15924140, 18625743, 31222290, 23161749, 23161749; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3512 NLRP12 Zornitza Stark reviewed gene: NLRP12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3512 CXorf56 Zornitza Stark Marked gene: CXorf56 as ready
Mendeliome v1.3512 CXorf56 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is STEEP1
Mendeliome v1.3512 CXorf56 Zornitza Stark Gene: cxorf56 has been classified as Green List (High Evidence).
Mendeliome v1.3512 CXorf56 Zornitza Stark Publications for gene: CXorf56 were set to 29374277
Mendeliome v1.3511 CXorf56 Zornitza Stark Phenotypes for gene: CXorf56 were changed from Mental retardation, X-linked 107, MIM# 301013 to Intellectual developmental disorder, X-linked 107, MIM# 301013
Mendeliome v1.3510 CXorf56 Zornitza Stark Tag new gene name tag was added to gene: CXorf56.
Mendeliome v1.3510 SKOR2 Zornitza Stark Phenotypes for gene: SKOR2 were changed from complex neurodevelopmental disorder with motor features MONDO:0100516 to Valence-Farazi cerebellar ataxia syndrome, MIM# 621386
Mendeliome v1.3509 SKOR2 Zornitza Stark reviewed gene: SKOR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Valence-Farazi cerebellar ataxia syndrome, MIM# 621386; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3509 TBX19 Chirag Patel Source Victorian Clinical Genetics Services was removed from TBX19.
Source Expert List was added to TBX19.
Publications for gene TBX19 were changed from 15613420, 31998673, 11290323, 15476446, 22170728 to 15613420, 31998673, 11290323, 15476446, 22170728
Mendeliome v1.3508 LCP1 Zornitza Stark Phenotypes for gene: LCP1 were changed from Bone marrow failure syndrome, MONDO:0000159, LCP1-related to Combined immunodeficiency, MONDO:0015131, LCP1-related
Mendeliome v1.3507 LCP1 Zornitza Stark Publications for gene: LCP1 were set to 38710235
Mendeliome v1.3506 LCP1 Zornitza Stark Classified gene: LCP1 as Green List (high evidence)
Mendeliome v1.3506 LCP1 Zornitza Stark Gene: lcp1 has been classified as Green List (High Evidence).
Mendeliome v1.3505 LCP1 Sarah Milton changed review comment from: LCP1 encodes lymphocyte cytosolic protein and has a role in actin cross-linking in haematopoietic cells.

PMID: 41056520 describes 4 families with 10 affected individuals who presented with neutropenia +/- lymphopenia and hypogammaglobulinemia. 2 individuals developed acute leukemia.

Variant type included missense, splice and inframe del. Appears there is some genotype phenotype correlation in regards to severity of disease.
All variants appropriately rare in gnomAD v4.

Supportive functional studies with IPSC produced with variant seen in affected individuals, these haematopoietic progenitors failed to produce CFU-G colonies with rescue upon introduction of gene corrected cells.

PMID: 41056520 describes additional family with 5 affected individuals who also had neutropenia +/- lymphopenia, hypogammaglobulinemia as well as deafness.; to: LCP1 encodes lymphocyte cytosolic protein and has a role in actin cross-linking in haematopoietic cells.

PMID: 41056520 describes 4 families with 10 affected individuals who presented with neutropenia +/- lymphopenia and hypogammaglobulinemia. 2 individuals developed acute leukemia.

Variant type included missense, splice and inframe del. Appears there is some genotype phenotype correlation in regards to severity of disease.
All variants appropriately rare in gnomAD v4.

Supportive functional studies with IPSC produced with variant seen in affected individuals, these haematopoietic progenitors failed to produce CFU-G colonies with rescue upon introduction of gene corrected cells.
Exact mechanism of disease remains unclear.

PMID: 41056520 describes additional family with 5 affected individuals who also had neutropenia +/- lymphopenia, hypogammaglobulinemia as well as deafness.
Mendeliome v1.3505 LCP1 Sarah Milton reviewed gene: LCP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40510848, PMID: 41056520; Phenotypes: Combined immunodeficiency, MONDO:0015131, LCP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3505 SLC27A3 Zornitza Stark Marked gene: SLC27A3 as ready
Mendeliome v1.3505 SLC27A3 Zornitza Stark Gene: slc27a3 has been classified as Red List (Low Evidence).
Mendeliome v1.3505 YTHDC2 Zornitza Stark Marked gene: YTHDC2 as ready
Mendeliome v1.3505 YTHDC2 Zornitza Stark Gene: ythdc2 has been classified as Green List (High Evidence).
Mendeliome v1.3505 Zornitza Stark Copied gene YTHDC2 from panel Primary Ovarian Insufficiency_Premature Ovarian Failure
Mendeliome v1.3505 YTHDC2 Zornitza Stark gene: YTHDC2 was added
gene: YTHDC2 was added to Mendeliome. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: YTHDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YTHDC2 were set to 29033321, 29360036, 35138268
Phenotypes for gene: YTHDC2 were set to Primary ovarian failure, MONDO:0005387
Mendeliome v1.3504 OTUD7A Zornitza Stark Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074; 33381903
Mendeliome v1.3503 OTUD7A Zornitza Stark Classified gene: OTUD7A as Green List (high evidence)
Mendeliome v1.3503 OTUD7A Zornitza Stark Gene: otud7a has been classified as Green List (High Evidence).
Mendeliome v1.3502 OTUD7A Zornitza Stark Tag SV/CNV tag was added to gene: OTUD7A.
Mendeliome v1.3502 ARMC5 Zornitza Stark Marked gene: ARMC5 as ready
Mendeliome v1.3502 ARMC5 Zornitza Stark Gene: armc5 has been classified as Green List (High Evidence).
Mendeliome v1.3502 PPIB Zornitza Stark Publications for gene: PPIB were set to 19781681; 32392875
Mendeliome v1.3501 PPIB Zornitza Stark Mode of inheritance for gene: PPIB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3500 PPIB Zornitza Stark edited their review of gene: PPIB: Changed publications: 19781681, 32392875, 41045073; Changed phenotypes: Osteogenesis imperfecta, type IX, MIM# 259440, Optic atrophy (MONDO:0003608), PPIB-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3500 SLC27A3 Sarah Milton gene: SLC27A3 was added
gene: SLC27A3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC27A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC27A3 were set to PMID: 41054338
Phenotypes for gene: SLC27A3 were set to Inherited neurodegenerative disorder, MONDO:0024237, SLC27A3-related
Review for gene: SLC27A3 was set to RED
Added comment: SLC27A3 encodes for very long chain acyl CoA synthetase 3 which function to catalyse the formation of fatty acyl coA using long and very long chain fatty acids as substrates.

PMID: 41054338 describes one individual with a presumed homozgous stop gain variant in SLC27A3 who presented with progressive ataxia, optic atrophy, cognitive deterioration, mood disorder and progressive cortical atrophy on MRI-B.
Onset of symptoms at 18 months with significant progression from 12 years of age.
Duo exome testing performed (not segregated in both parents).

No homozygous LOF variants in gnomAD v4.

Some supportive functional data in paper with no protein expressed in patient cells as detected by western blot and patient's cells were found to have more neutral lipids than controls.

More literature is required to increase the robustness of this assertion.
Sources: Literature
Mendeliome v1.3499 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Green List (high evidence)
Mendeliome v1.3499 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Green List (High Evidence).
Mendeliome v1.3498 TMEM17 Chirag Patel Phenotypes for gene: TMEM17 were changed from Meckel syndrome MONDO:0018921; TMEM17-related to Meckel syndrome MONDO:0018921, TMEM17-related
Mendeliome v1.3497 TMEM17 Chirag Patel Publications for gene TMEM17 were changed from 41054827, 40841990 to 41054827, 40841990
Mendeliome v1.3496 FCN3 Zornitza Stark Classified gene: FCN3 as Red List (low evidence)
Mendeliome v1.3496 FCN3 Zornitza Stark Gene: fcn3 has been classified as Red List (Low Evidence).
Mendeliome v1.3496 TMEM17 Chirag Patel Classified gene: TMEM17 as Green List (high evidence)
Mendeliome v1.3496 TMEM17 Chirag Patel Gene: tmem17 has been classified as Green List (High Evidence).
Mendeliome v1.3495 FCN3 Zornitza Stark edited their review of gene: FCN3: Added comment: Same recurrent hmz variant in all reported cases, downgrade.; Changed rating: RED
Mendeliome v1.3495 OTUD7A Rylee Peters reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29395075, 31997314, 33381903, 36180924, 41028987; Phenotypes: Neurodevelopmental disorder with hypotonia and seizures (MIM#620790), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3495 TMEM17 Chirag Patel edited their review of gene: TMEM17: Added comment: 2 additional unrelated fetuses with clinical diagnosis of Meckel-Gruber syndrome (occipital encephalocele, polydactyly, and kidney cysts). WES identified a founder homozygous missense variant (Arg94Trp) in TMEM17 gene.

Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a C. elegans model system, demonstrate a loss-of-function mechanism. The study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling.; Changed rating: GREEN; Changed publications: 41054827, 40841990
Mendeliome v1.3495 PRKACA Chirag Patel Source Literature was removed from PRKACA.
Source Expert Review was added to PRKACA.
Phenotypes for gene: PRKACA were changed from Cardioacrofacial dysplasia 1, MIM# 619142; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 1, MIM# 619142; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability; Pigmented nodular adrenocortical disease, primary, 4, MONDO:0014359
Publications for gene PRKACA were changed from 33058759; 31130284; 24571724, 25924874, 40066253, 37988664, 39006359 to 33058759; 31130284; 24571724, 25924874, 40066253, 37988664, 39006359
Mendeliome v1.3494 PDE11A Chirag Patel Source Victorian Clinical Genetics Services was removed from PDE11A.
Source Expert List was added to PDE11A.
Phenotypes for gene: PDE11A were changed from Pigmented nodular adrenocortical disease, primary, 2 - MIM#610475 to Pigmented nodular adrenocortical disease, primary, 2, MONDO:0012505
Publications for gene PDE11A were changed from 16767104; 18559625; 21047926; 17178847; 39006359, 20351491, 18491255, 18559625 to 16767104; 18559625; 21047926; 17178847; 39006359, 20351491, 18491255, 18559625
Mendeliome v1.3493 PDE8B Chirag Patel Source Victorian Clinical Genetics Services was removed from PDE8B.
Phenotypes for gene: PDE8B were changed from Striatal degeneration, autosomal dominant, MIM#609161 to Striatal degeneration, autosomal dominant, MIM#609161; Pigmented nodular adrenocortical disease, primary, 3, MONDO:0013616
Publications for gene PDE8B were changed from 20085714; 26769607; 26475694; 39006359, 32097969, 18272904, 25971952, 22335482, 18431404 to 20085714; 26769607; 26475694; 39006359, 32097969, 18272904, 25971952, 22335482, 18431404
Mendeliome v1.3492 Chirag Patel Copied gene ARMC5 from panel Primary pigmented nodular adrenocortical disease
Mendeliome v1.3492 ARMC5 Chirag Patel gene: ARMC5 was added
gene: ARMC5 was added to Mendeliome. Sources: Expert Review Green,Literature
Mode of inheritance for gene: ARMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARMC5 were set to 39910635, 41042544, 25853793, 24283224, 24601692, 24708098, 24905064, 39006359, 32097969
Phenotypes for gene: ARMC5 were set to ACTH-independent macronodular adrenal hyperplasia 2, MONDO:0014416
Mendeliome v1.3491 PPIB Rylee Peters reviewed gene: PPIB: Rating: GREEN; Mode of pathogenicity: None; Publications: 41045073; Phenotypes: Osteogenesis imperfecta, type IX, MIM# 259440, Optic atrophy (MONDO:0003608), PPIB-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3491 PRKACA Chirag Patel reviewed gene: PRKACA: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24571724, 25924874, 40066253, 37988664, 39006359; Phenotypes: Pigmented nodular adrenocortical disease, primary, 4, MONDO:0014359; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3491 PDE8B Chirag Patel reviewed gene: PDE8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39006359, 32097969, 18272904, 25971952, 22335482, 18431404; Phenotypes: Pigmented nodular adrenocortical disease, primary, 3, MONDO:0013616; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3491 PDE11A Chirag Patel Classified gene: PDE11A as Green List (high evidence)
Mendeliome v1.3491 PDE11A Chirag Patel Gene: pde11a has been classified as Green List (High Evidence).
Mendeliome v1.3490 PDE11A Chirag Patel reviewed gene: PDE11A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39006359, 16767104, 20351491, 18491255, 18559625; Phenotypes: Pigmented nodular adrenocortical disease, primary, 2, MONDO:0012505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3490 SLC31A1 Rylee Peters reviewed gene: SLC31A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41040850; Phenotypes: Neurodegeneration and seizures due to copper transport defect MIM#620306; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3490 DIP2B_FRA12A_CGG Bryony Thompson Publications for STR: DIP2B_FRA12A_CGG were set to 17236128
Mendeliome v1.3489 DIP2B_FRA12A_CGG Bryony Thompson edited their review of STR: DIP2B_FRA12A_CGG: Added comment: Unsure about the expansions association with disease due to variable phenotypes and possible incomplete penetrance PMID 17236128, 39854091, and 41028987 report 23 unrelated families with heterozygous CGG repeat expansions in the 5′UTR of DIP2B. Sixteen families present with intellectual disability associated with the FRA12A fragile site, while seven families (including two siblings, five ataxia probands, and one dystonia case) exhibit neurodevelopmental disability with progressive movement disorders (chorea, dystonia, ataxia). Functional studies demonstrate reduced DIP2B expression via promoter hypermethylation. Segregation analysis shows segregation from unaffected parents (possibly reduced penetrance) and de novo events. DIP2B expansion OR 2.8 (p=0.04) in ataxia cohort (5/788) vs gnomAD.; Changed publications: 17236128, 33510257, 39854091, 41028987; Changed phenotypes: intellectual disability, FRA12A type MONDO:0007634
Mendeliome v1.3489 CFAP74 Zornitza Stark Phenotypes for gene: CFAP74 were changed from Primary ciliary dyskinesia; infertility to ciliary dyskinesia, primary, 49, without situs inversus MONDO:0859353
Mendeliome v1.3488 CFAP74 Zornitza Stark Classified gene: CFAP74 as Green List (high evidence)
Mendeliome v1.3488 CFAP74 Zornitza Stark Gene: cfap74 has been classified as Green List (High Evidence).
Mendeliome v1.3487 RBM15 Zornitza Stark Marked gene: RBM15 as ready
Mendeliome v1.3487 RBM15 Zornitza Stark Gene: rbm15 has been classified as Red List (Low Evidence).
Mendeliome v1.3487 SSPO Zornitza Stark Marked gene: SSPO as ready
Mendeliome v1.3487 SSPO Zornitza Stark Gene: sspo has been classified as Green List (High Evidence).
Mendeliome v1.3487 SSPO Zornitza Stark Classified gene: SSPO as Green List (high evidence)
Mendeliome v1.3487 SSPO Zornitza Stark Gene: sspo has been classified as Green List (High Evidence).
Mendeliome v1.3486 PPFIA2 May Tun Hla Maw changed review comment from: Encodes Liprin-alpha2.
Predominantly expressed in brain in the pre- and post-synaptic compartments.
Liprin has three domains with N-terminal coiled coil domain (CCD), central (IDRs) and three tandem C-terminal sterile alpha motif (SAM) domains.

Gene-disease association: neurodevelopmental disorder.
Mode of pathogenicity is unclear; haploinsufficiency has not been proven as disease-causing mechanism.

Evidence summary:
Previously reported heterozygous de novo variants in two unrelated individuals with a neurodevelopmental disorder. Large cohort studies identified seven additional individuals with rare de novo variants with intellectual disability or developmental delay. Reported variants are mostly missense, and the rest includes non-sense, in-frame deletion, splice site variants. Eight out of these variants are located in the known functional domains (CCD, IDR, SAM). All of these variants were absent in gnomAD.

Other phenotypes in these individuals include IUGR, macrocephaly, dystonia, choreatic movement, nystagmus, ataxia, hyperactivity, coarsened gyration, immature opercularization and a coarse corpus callosum, and hypotonia.

Functional studies:
Homozygous mice with PPFIA2-knockout developed a neurologic phenotype as well as ophthalmologic features. Heterozygous mice did not have apparent phenotype.
Sources: Literature; to: Encodes Liprin-alpha2.
Predominantly expressed in brain in the pre- and post-synaptic compartments.
Liprin has three domains with N-terminal coiled coil domain (CCD), central (IDRs) and three tandem C-terminal sterile alpha motif (SAM) domains.

Mode of pathogenicity is unclear; haploinsufficiency has not been proven as disease-causing mechanism.

Evidence summary:
Previously reported heterozygous de novo variants in two unrelated individuals with a neurodevelopmental disorder. Large cohort studies identified seven additional individuals with rare de novo variants with intellectual disability or developmental delay. Reported variants are mostly missense, and the rest includes non-sense, in-frame deletion, splice site variants. Eight out of these variants are located in the known functional domains (CCD, IDR, SAM). All of these variants were absent in gnomAD.

Other phenotypes in these individuals include IUGR, macrocephaly, dystonia, choreatic movement, nystagmus, ataxia, hyperactivity, coarsened gyration, immature opercularization and a coarse corpus callosum, and hypotonia.

Functional studies:
Homozygous mice with PPFIA2-knockout developed a neurologic phenotype as well as ophthalmologic features. Heterozygous mice did not have apparent phenotype.
Sources: Literature
Mendeliome v1.3486 SSPO Sarah Milton changed review comment from: The HGNC approved symbol for this gene is SSPOP which refers to SCO-spondin pseudogene. Recently, it has been demonstrated this gene produces a functional protein; subcommissural organ-spondin, which plays a role in neural development and function. Given the previous pseudogene status most annotation will include n. as opposed to c. numbers (including in gnomAD v4).

PMID: 41077560 describes 4 individuals from 3 families with biallelic variants in SSPOP with a neurodevelopmental disorder. Phenotype is encompassed by epilepsy (onset <2 years old), developmental delay, autism and behavioural issues.
Variant types include missense, frameshift and splice site.

No homozygous nonsense/frameshift variants in gnomad v4. (some hom splice site).

Supportive functional studies including zebrafish knockout with epileptiform activity. Mouse knockout demonstrated reduced reissner’s fibre formation/smaller brain ventricles/spinal curvature anomalies.

It was noted by authors another publication PMID: 32028786 discussed 2 related individuals - a grandmother and grandchild with homozygous frameshift variants in SSPOP (exact variant not provided) who both were just documented to have cervical cleft, no mention of ID/epilepsy.
Sources: Literature; to: The HGNC approved symbol for this gene is SSPOP which refers to SCO-spondin pseudogene. Recently, it has been demonstrated this gene produces a functional protein; subcommissural organ-spondin, which is a large secreted glycoprotein that plays a role in neural development and function. Given the previous pseudogene status most annotation will include n. as opposed to c. numbers (including in gnomAD v4).

PMID: 41077560 describes 4 individuals from 3 families with biallelic variants in SSPOP with a neurodevelopmental disorder. Phenotype is encompassed by epilepsy (onset <2 years old), developmental delay, autism and behavioural issues.
Variant types include missense, frameshift and splice site.

No homozygous nonsense/frameshift variants in gnomad v4. (some hom splice site).

Supportive functional studies including zebrafish knockout with epileptiform activity. Mouse knockout demonstrated reduced reissner’s fibre formation/smaller brain ventricles/spinal curvature anomalies.

It was noted by authors another publication PMID: 32028786 discussed 2 related individuals - a grandmother and grandchild with homozygous frameshift variants in SSPOP (exact variant not provided) who both were just documented to have cervical cleft, no mention of ID/epilepsy.
Sources: Literature
Mendeliome v1.3486 SSPO Sarah Milton gene: SSPO was added
gene: SSPO was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: SSPO.
Mode of inheritance for gene: SSPO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SSPO were set to PMID: 41077560
Phenotypes for gene: SSPO were set to Neurodevelopmental disorder, MONDO:0700092, SSPOP-related
Review for gene: SSPO was set to GREEN
Added comment: The HGNC approved symbol for this gene is SSPOP which refers to SCO-spondin pseudogene. Recently, it has been demonstrated this gene produces a functional protein; subcommissural organ-spondin, which plays a role in neural development and function. Given the previous pseudogene status most annotation will include n. as opposed to c. numbers (including in gnomAD v4).

PMID: 41077560 describes 4 individuals from 3 families with biallelic variants in SSPOP with a neurodevelopmental disorder. Phenotype is encompassed by epilepsy (onset <2 years old), developmental delay, autism and behavioural issues.
Variant types include missense, frameshift and splice site.

No homozygous nonsense/frameshift variants in gnomad v4. (some hom splice site).

Supportive functional studies including zebrafish knockout with epileptiform activity. Mouse knockout demonstrated reduced reissner’s fibre formation/smaller brain ventricles/spinal curvature anomalies.

It was noted by authors another publication PMID: 32028786 discussed 2 related individuals - a grandmother and grandchild with homozygous frameshift variants in SSPOP (exact variant not provided) who both were just documented to have cervical cleft, no mention of ID/epilepsy.
Sources: Literature
Mendeliome v1.3485 RBM15 Sangavi Sivagnanasundram gene: RBM15 was added
gene: RBM15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBM15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBM15 were set to 41058181
Phenotypes for gene: RBM15 were set to Congenital mirror movements, RBM15-related, MONDO:0016558
Review for gene: RBM15 was set to RED
Added comment: One 27-year-old proband reported with mild mirror movements affecting only hands.
De novo heterozygous was identified in the affected individual and absent from asymptomatic parents - p.Ser175Lysfs∗8 - absent in gnomADv4.1
RBM15 is constraint for LOF according to gnomAD v4.1 [pLI = 1;o/e = 0.11 (0.06 - 0.21)] however, LoF isn't an established mechanism of disease.
Sources: Literature
Mendeliome v1.3484 CFAP74 Sangavi Sivagnanasundram changed review comment from: Additional reported individuals supporting gene-disease association.; to: Additional reported individuals in four unrelated families supporting gene-disease association.
Mendeliome v1.3484 CFAP74 Sangavi Sivagnanasundram reviewed gene: CFAP74: Rating: GREEN; Mode of pathogenicity: None; Publications: 41078601, 39362668, 36459505, 32555313; Phenotypes: ciliary dyskinesia, primary, 49, without situs inversus MONDO:0859353; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3484 SNAI2 Sangavi Sivagnanasundram reviewed gene: SNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 41073431; Phenotypes: Waardenburg syndrome type 2D MONDO:0012144; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3484 PPFIA2 Zornitza Stark Marked gene: PPFIA2 as ready
Mendeliome v1.3484 PPFIA2 Zornitza Stark Gene: ppfia2 has been classified as Green List (High Evidence).
Mendeliome v1.3484 PPFIA2 Zornitza Stark Mode of pathogenicity for gene: PPFIA2 was changed from Other to None
Mendeliome v1.3483 PPFIA2 Zornitza Stark Classified gene: PPFIA2 as Green List (high evidence)
Mendeliome v1.3483 PPFIA2 Zornitza Stark Gene: ppfia2 has been classified as Green List (High Evidence).
Mendeliome v1.3482 EIPR1 Zornitza Stark Marked gene: EIPR1 as ready
Mendeliome v1.3482 EIPR1 Zornitza Stark Gene: eipr1 has been classified as Green List (High Evidence).
Mendeliome v1.3482 EIPR1 Zornitza Stark Classified gene: EIPR1 as Green List (high evidence)
Mendeliome v1.3482 EIPR1 Zornitza Stark Gene: eipr1 has been classified as Green List (High Evidence).
Mendeliome v1.3481 ARHGAP19 Zornitza Stark Marked gene: ARHGAP19 as ready
Mendeliome v1.3481 ARHGAP19 Zornitza Stark Gene: arhgap19 has been classified as Green List (High Evidence).
Mendeliome v1.3481 ARHGAP19 Zornitza Stark Classified gene: ARHGAP19 as Green List (high evidence)
Mendeliome v1.3481 ARHGAP19 Zornitza Stark Gene: arhgap19 has been classified as Green List (High Evidence).
Mendeliome v1.3480 AGBL3 Bryony Thompson Marked gene: AGBL3 as ready
Mendeliome v1.3480 AGBL3 Bryony Thompson Gene: agbl3 has been classified as Red List (Low Evidence).
Mendeliome v1.3480 AGBL3 Bryony Thompson gene: AGBL3 was added
gene: AGBL3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGBL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGBL3 were set to 41042736
Phenotypes for gene: AGBL3 were set to Hypocomplementemic urticarial vasculitis MONDO:0018227
Review for gene: AGBL3 was set to RED
Added comment: PMID:41042736 reports one patient from a single consanguineous family with biallelic loss‑of‑function AGBL3 variant presenting with hypocomplementemic urticarial vasculitis syndrome, childhood‑onset fever, urticarial rash, arthralgia, and low complement levels.
Sources: Literature
Mendeliome v1.3479 EIPR1 Thomas Cloney gene: EIPR1 was added
gene: EIPR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to Mendelian neurodevelopmental disorder MONDO:0100500, EIPR1-related
Penetrance for gene: EIPR1 were set to unknown
Review for gene: EIPR1 was set to GREEN
Added comment: Report of 8 individuals from 6 unrelated consanguinous families with homozygous EIPR1 variants (5 different variants).
Phenotype: All had global developmental delay (range of severity), with significant motor delay (5/8 never attained walking). Neurological manifestations: 2/8 Hypotonia, 4/8 had spasticity. 5/8 had microcepahly. MRI Brain abnormalities included: delayed myelination, hypoplasia of the corpus callosum, mild cerebellar atrophy, dysmorphic lateral ventricles. (Limited phenotypic information in pre-print - all in supplementary data)
Functional data: In vitro functional work show reduced protrien levels and interaction with EARP and GARP; and in vivo zebrafish models with knowckout of EIPR1 result in neurodevelopmental and locomotor defects
Sources: Literature
Mendeliome v1.3479 PPFIA2 May Tun Hla Maw gene: PPFIA2 was added
gene: PPFIA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPFIA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPFIA2 were set to 41044885
Phenotypes for gene: PPFIA2 were set to Neurodevelopmental disorder, MONDO:0700092, PPFIA2 related
Mode of pathogenicity for gene: PPFIA2 was set to Other
Review for gene: PPFIA2 was set to GREEN
Added comment: Encodes Liprin-alpha2.
Predominantly expressed in brain in the pre- and post-synaptic compartments.
Liprin has three domains with N-terminal coiled coil domain (CCD), central (IDRs) and three tandem C-terminal sterile alpha motif (SAM) domains.

Gene-disease association: neurodevelopmental disorder.
Mode of pathogenicity is unclear; haploinsufficiency has not been proven as disease-causing mechanism.

Evidence summary:
Previously reported heterozygous de novo variants in two unrelated individuals with a neurodevelopmental disorder. Large cohort studies identified seven additional individuals with rare de novo variants with intellectual disability or developmental delay. Reported variants are mostly missense, and the rest includes non-sense, in-frame deletion, splice site variants. Eight out of these variants are located in the known functional domains (CCD, IDR, SAM). All of these variants were absent in gnomAD.

Other phenotypes in these individuals include IUGR, macrocephaly, dystonia, choreatic movement, nystagmus, ataxia, hyperactivity, coarsened gyration, immature opercularization and a coarse corpus callosum, and hypotonia.

Functional studies:
Homozygous mice with PPFIA2-knockout developed a neurologic phenotype as well as ophthalmologic features. Heterozygous mice did not have apparent phenotype.
Sources: Literature
Mendeliome v1.3479 BRSK1 Zornitza Stark Phenotypes for gene: BRSK1 were changed from Epilepsy, MONDO:0005027, BRSK1-related to Neurodevelopmental disorder, MONDO:0700092, BRSK1-related
Mendeliome v1.3478 BRSK1 Zornitza Stark Marked gene: BRSK1 as ready
Mendeliome v1.3478 BRSK1 Zornitza Stark Gene: brsk1 has been classified as Green List (High Evidence).
Mendeliome v1.3478 BRSK1 Zornitza Stark Classified gene: BRSK1 as Green List (high evidence)
Mendeliome v1.3478 BRSK1 Zornitza Stark Gene: brsk1 has been classified as Green List (High Evidence).
Mendeliome v1.3477 PNPT1 Zornitza Stark Publications for gene: PNPT1 were set to 31752325; 30244537; 28594066; 28645153; 33199448; 33199448
Mendeliome v1.3476 PNPT1 Zornitza Stark edited their review of gene: PNPT1: Added comment: Additional reports for association between mono allelic variants and SCA:

PMID:39729134 (2024) reported an 11-year-old male of Indian descent with childhood-onset ataxia and severe sensorineural hearing loss. Genetic analysis identified heterozygous 3' splice site variant in the PNPT1 gene (c.2014-3 C > G).

PMID:39899068 (2025) reported a 1-year-8-month-old female proband of Brazilian descent with Spinocerebellar Ataxia 25 that presented with progressive ataxia, cerebellar atrophy, and sensory neuropathy. She was identified with a novel heterozygous truncating variant in PNPT1 (c.2068del), which she inherited from her father. Although the father was previously reported as asymptomatic, he was affected with axonal and demyelinating polyneuropathy but not ataxia upon detailed examination.

PMID:39924761 (2025) reported two unrelated families, where all individuals presented with sensory ataxic neuropathy (SAN), while some individuals developed cerebellar signs. Analysis of WGS variant data through the 100,000 Genomes Project identified two different heterozygous variants in these families. Family 1 underwent a 'quad' study and the previously reported c.2014‐3C>G variant segregated in all affected family members and was absent in all unaffected family members. Sanger sequencing confirmed segregation in two other individuals. c.2014‐3C>G is the same variant that was found in the 3-generation Australian family reported by PMID:35411967, where unaffected family members harboured the variant. A novel nonsense variant (c.2143C>T/ p.Arg715Ter) was found in both affected members of Family 2.

PMID:40757543 (2024) reported an 18-year-old male presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. The patient was identified with a heterozygous pathogenic variant c.162-1G>A in PNPT1 gene.; Changed rating: GREEN; Changed publications: 35411967, 39729134, 39899068, 39924761, 40757543
Mendeliome v1.3476 ARHGAP19 Fahaz Nazer gene: ARHGAP19 was added
gene: ARHGAP19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGAP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGAP19 were set to 41086021
Phenotypes for gene: ARHGAP19 were set to Motor Peripheral Neuropathy; MONDO:0002316; ARHGAP19 related
Review for gene: ARHGAP19 was set to GREEN
Added comment: Biallelic LOF variants in 25 individuals from 20 unrelated families
Phenotype: motor predominant neuropathy
14/23 had assymetric lower limb involvement

Biochemical GAP assays show GAP domain variants cause loss of protein function.
RNA studies show LOF alters expression of genes linked to 3 cellular pathways, compared to controls.
iPSC-derived motor neurons show reduced ARHGAP19 expression

Models: Zebrafish, drosophila loss of function models show movement deficits.

LOF variants reported in 'GAP' domain and outside this domain with no genotype-phenotype correlation noted
Sources: Literature
Mendeliome v1.3476 BRSK1 Cara Beck gene: BRSK1 was added
gene: BRSK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BRSK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRSK1 were set to 41035394
Phenotypes for gene: BRSK1 were set to Epilepsy, MONDO:0005027, BRSK1-related
Review for gene: BRSK1 was set to GREEN
Added comment: PMID:41035394
Six novel BRSK1 variants were identified in seven probands. Five cases were de novo, two inherited. One variant was recurrent.
All had epilepsy (generalised tonic clonic seizures, absence, focal, spasms), 2/7 GDD, 1/1 'mental developmental delay', 1/7 motor delay, 2/7 normal development.
Functional work, including in a mouse model, was consistent with loss of function mechanism and supports pathogenicity of 2 frameshift, 1 nonsense, 1 missense variant, with 2 missense not yet considered pathogenic.
Sources: Literature
Mendeliome v1.3476 ATP6V1B1 Elena Savva Publications for gene: ATP6V1B1 were set to 9916796; 12414817; 16611712; 18798332
Mendeliome v1.3475 ATP6V1B1 Elena Savva Mode of inheritance for gene: ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3474 ATP6V1B1 Elena Savva reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39837581; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM#267300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3474 KLHL20 Zornitza Stark Phenotypes for gene: KLHL20 were changed from Neurodevelopmental disorder (MONDO:0700092), KLHL20-related to Neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, MIM# 621390
Mendeliome v1.3473 KLHL20 Zornitza Stark reviewed gene: KLHL20: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, MIM# 621390; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3473 KCTD15 Zornitza Stark Marked gene: KCTD15 as ready
Mendeliome v1.3473 KCTD15 Zornitza Stark Gene: kctd15 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3473 KCTD15 Zornitza Stark Classified gene: KCTD15 as Amber List (moderate evidence)
Mendeliome v1.3473 KCTD15 Zornitza Stark Gene: kctd15 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3472 OCRL Zornitza Stark Phenotypes for gene: OCRL were changed from Dent disease 2, MIM# 300555; Lowe syndrome , MIM#309000 to Oculocerebrorenal syndrome MONDO:0010645; Dent disease 2, MIM# 300555; Lowe syndrome , MIM#309000
Mendeliome v1.3471 SNAPIN Zornitza Stark Phenotypes for gene: SNAPIN were changed from Neurodevelopmental disorder (MONDO:0700092), SNAPIN-related to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MIM# 621393
Mendeliome v1.3470 SNAPIN Zornitza Stark reviewed gene: SNAPIN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MIM# 621393; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3470 IFNGR2 Zornitza Stark Publications for gene: IFNGR2 were set to 15924140; 18625743; 31222290
Mendeliome v1.3469 IFNGR2 Zornitza Stark changed review comment from: At least 5 unrelated families reported.; to: At least 5 unrelated families reported with bi-allelic disease.
Mendeliome v1.3469 IFNGR2 Zornitza Stark edited their review of gene: IFNGR2: Added comment: PMID 23161749: single case report of heterozygous LoF variant causing disease (but ?missed second hit).; Changed publications: 15924140, 18625743, 31222290, 23161749
Mendeliome v1.3469 LOXL3 Zornitza Stark Phenotypes for gene: LOXL3 were changed from Stickler syndrome to Stickler syndrome, MONDO:0019354, LOXL3-related
Mendeliome v1.3468 LOXL3 Zornitza Stark Publications for gene: LOXL3 were set to 30362103; 25663169
Mendeliome v1.3467 LOXL3 Zornitza Stark Classified gene: LOXL3 as Green List (high evidence)
Mendeliome v1.3467 LOXL3 Zornitza Stark Gene: loxl3 has been classified as Green List (High Evidence).
Mendeliome v1.3466 LOXL3 Zornitza Stark changed review comment from: PMID 41052910: additional family reported, three affected sibs, compound het variants segregated with disease.; to: PMID 41052910: additional family reported, three affected sibs, compound het variants segregated with disease. Zebrafish model also available.
Mendeliome v1.3466 LOXL3 Zornitza Stark edited their review of gene: LOXL3: Added comment: PMID 41052910: additional family reported, three affected sibs, compound het variants segregated with disease.; Changed rating: GREEN; Changed publications: 30362103, 25663169, 41052910; Changed phenotypes: Stickler syndrome, MONDO:0019354, LOXL3-related
Mendeliome v1.3466 CDKL1 Zornitza Stark Classified gene: CDKL1 as Red List (low evidence)
Mendeliome v1.3466 CDKL1 Zornitza Stark Gene: cdkl1 has been classified as Red List (Low Evidence).
Mendeliome v1.3465 CDKL1 Zornitza Stark Deleted their comment
Mendeliome v1.3465 CDKL1 Zornitza Stark edited their review of gene: CDKL1: Changed rating: RED
Mendeliome v1.3465 CDKL1 Zornitza Stark Classified gene: CDKL1 as Amber List (moderate evidence)
Mendeliome v1.3465 CDKL1 Zornitza Stark Gene: cdkl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3464 CDKL1 Zornitza Stark edited their review of gene: CDKL1: Added comment: PMID 40088891 reports two unrelated individuals with de novo heterozygous CDKL1 missense variants (p.Val115Ala, p.Arg169Cys) presenting with childhood‑onset neurodevelopmental disorder, developmental delay and seizures; Drosophila rescue assays show dominant‑negative activity of the variants. However, note that the variants are present at low frequency in gnomAD v4, p.Val115Ala: 2 individuals, p.Arg169Cys: 13 individuals. Some supportive functional data presented. Upgrade to Amber but not Green due to pop counts.; Changed rating: AMBER; Changed publications: 40088891
Mendeliome v1.3464 TEKT3 Zornitza Stark Marked gene: TEKT3 as ready
Mendeliome v1.3464 TEKT3 Zornitza Stark Gene: tekt3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3464 Zornitza Stark Copied gene TEKT3 from panel Infertility and Recurrent Pregnancy Loss
Mendeliome v1.3464 TEKT3 Zornitza Stark gene: TEKT3 was added
gene: TEKT3 was added to Mendeliome. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: TEKT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEKT3 were set to 36708031
Phenotypes for gene: TEKT3 were set to Spermatogenic failure, MONDO:0004983, TEKT3-related
Mendeliome v1.3463 OCRL Sangavi Sivagnanasundram reviewed gene: OCRL: Rating: GREEN; Mode of pathogenicity: None; Publications: 1321346; Phenotypes: oculocerebrorenal syndrome MONDO:0010645; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.3463 NUS1 Sangavi Sivagnanasundram reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100083; Phenotypes: progressive myoclonus epilepsy MONDO:0020074; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3463 NLRP2 Zornitza Stark Phenotypes for gene: NLRP2 were changed from female infertility; early embryonic arrest to Oocyte/zygote/embryo maturation arrest 18, MONDO:0957230
Mendeliome v1.3462 NLRP2 Zornitza Stark Publications for gene: NLRP2 were set to 30877238; 19300480; 29574422; 33090377
Mendeliome v1.3461 NLRP2 Zornitza Stark Mode of inheritance for gene: NLRP2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3460 NLRP2 Zornitza Stark edited their review of gene: NLRP2: Added comment: PMIDs 29574422, 30877238, 35643636, 39887367 and 41044650 report 15 unrelated families with rare NLRP2 variants. Maternal heterozygous variants cause multilocus imprinting disturbance (MLID) presenting as Beckwith‑Wiedemann syndrome, Silver‑Russell syndrome, transient neonatal diabetes mellitus, unspecified imprinting disorder and pseudohypoparathyroidism type‑1B. Biallelic loss‑of‑function variants cause autosomal recessive primary female infertility with early embryonic arrest (embryos arresting at the 2–4‑cell stage). Functional studies show reduced NLRP2 protein in patient‑derived cells and mouse Nlrp2 knockout recapitulating the embryonic arrest phenotype. No contradictory evidence exists for the well‑supported phenotypes.; Changed publications: 29574422, 30877238, 35643636, 39887367, 41044650
Mendeliome v1.3460 NLRP2 Zornitza Stark reviewed gene: NLRP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3460 MVK Zornitza Stark Phenotypes for gene: MVK were changed from Mevalonic aciduria MIM# 610377 to Mevalonic aciduria MIM#610377; Porokeratosis 3, multiple types, MIM# 175900
Mendeliome v1.3459 MVK Zornitza Stark Mode of inheritance for gene: MVK was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3458 MVK Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease associations.
Mendeliome v1.3458 MVK Zornitza Stark edited their review of gene: MVK: Changed phenotypes: Mevalonic aciduria MIM#610377, Porokeratosis 3, multiple types, MIM# 175900; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3458 LBR Zornitza Stark Phenotypes for gene: LBR were changed from Greenberg skeletal dysplasia, MIM# 215140 to Greenberg skeletal dysplasia, MIM#215140; Pelger-Huet anomaly, MIM# 169400
Mendeliome v1.3457 LBR Zornitza Stark Mode of inheritance for gene: LBR was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3456 LBR Zornitza Stark changed review comment from: Overlap with ATD in particular.
Sources: Expert list; to: Well established mono- and biallelic gene-disease associations.
Sources: Expert list
Mendeliome v1.3456 LBR Zornitza Stark edited their review of gene: LBR: Changed phenotypes: Greenberg skeletal dysplasia, MIM#215140, Pelger-Huet anomaly, MIM# 169400; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3456 CFAP206 Zornitza Stark Phenotypes for gene: CFAP206 were changed from Multiple morphological abnormalities of the flagella to Spermatogenic failure 102, MIM# 621387
Mendeliome v1.3455 CFAP206 Zornitza Stark reviewed gene: CFAP206: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 102, MIM# 621387; Mode of inheritance: None
Mendeliome v1.3455 MOCS3 Zornitza Stark Phenotypes for gene: MOCS3 were changed from Molybdenum cofactor deficiency MONDO:0020480 to Molybdenum cofactor deficiency, type B2, MIM# 621373
Mendeliome v1.3454 MOCS3 Zornitza Stark edited their review of gene: MOCS3: Changed phenotypes: Molybdenum cofactor deficiency, type B2, MIM# 621373
Mendeliome v1.3454 NRL Zornitza Stark Phenotypes for gene: NRL were changed from Retinitis pigmentosa 27 - MIM#613750; Retinal degeneration, autosomal recessive, clumped pigment type to Retinitis pigmentosa 27 - MIM#613750; Enhanced S-cone syndrome 2, MIM# 621371
Mendeliome v1.3453 NRL Zornitza Stark reviewed gene: NRL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Enhanced S-cone syndrome 2, MIM# 621371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3453 KCTD15 Achchuthan Shanmugasundram gene: KCTD15 was added
gene: KCTD15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCTD15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCTD15 were set to 38296633
Phenotypes for gene: KCTD15 were set to frontonasal dysplasia, MONDO:0016643
Mode of pathogenicity for gene: KCTD15 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: KCTD15 was set to AMBER
Added comment: PMID:38296633 (2024) reported a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in the affected father and daughter via exome sequencing and the variant segregated with the phenotype. A de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was identified via targeted DNA sequencing in a similarly affected sporadic patient.

There is some functional evidence available from structural analyses, which demonstrated that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.
Sources: Literature
Mendeliome v1.3453 RIPOR2 Arina Puzriakova edited their review of gene: RIPOR2: Added comment: PMID: 37864412 - a distinct homozygous LOF variant (c.1561C>T (p.Arg521*)) in exon 14 of the RIPOR2 gene was identified by WES in three siblings from a consanguineous Tunisian family with non-syndromic bilateral profound hearing and vestibular dysfunctions. Parents were unaffected heterozygous carriers. No other variants in hearing loss genes were found. Zebrafish model with a stop codon inserted within ripor2 exon 14 showed that F2 larva did not exhibit a different hearing or balance behaviour compared to wild-type.; Changed publications: 24958875, 32631815, 37864412; Changed phenotypes: Deafness, autosomal dominant 21, OMIM:607017, Deafness, autosomal recessive 104, OMIM:616515; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3453 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNH1-related; {Encephalopathy, acute, infection-induced, susceptibiliyt to, 12}, MIM# 620461 to Encephalopathy, acute, infection-induced, susceptibility to, 12 MIM#620461
Mendeliome v1.3452 EXT2 Zornitza Stark Phenotypes for gene: EXT2 were changed from Seizures, scoliosis, and macrocephaly syndrome, MIM#616682 to Exostoses, multiple, type 2 MIM#133701; Seizures, scoliosis, and macrocephaly syndrome, MIM#616682
Mendeliome v1.3451 NKX2-1 Zornitza Stark Phenotypes for gene: NKX2-1 were changed from Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700 to NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, MONDO:0100520; Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700
Mendeliome v1.3450 NLRC4 Zornitza Stark Phenotypes for gene: NLRC4 were changed from Familial cold autoinflammatory syndrome 4 - MIM#616115; Autoinflammation with infantile enterocolitis - MIM#616050 to periodic fever-infantile enterocolitis-autoinflammatory syndrome MONDO:0014472
Mendeliome v1.3449 NMNAT1 Zornitza Stark Phenotypes for gene: NMNAT1 were changed from Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260; Leber congenital amaurosis 9, MIM# 608553 to NMNAT1-related retinopathy MONDO:0800101; Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260; Leber congenital amaurosis 9, MIM# 608553
Mendeliome v1.3448 NOG Zornitza Stark Phenotypes for gene: NOG were changed from 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) to NOG-related symphalangism spectrum disorder MONDO:0100521
Mendeliome v1.3447 NPHP3 Sangavi Sivagnanasundram reviewed gene: NPHP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872122, 19177160; Phenotypes: Nephronophthisis MONDO:0019005; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3447 NPHP1 Sangavi Sivagnanasundram reviewed gene: NPHP1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 1 MONDO:0009728; Mode of inheritance: None
Mendeliome v1.3447 NOTCH2 Sangavi Sivagnanasundram reviewed gene: NOTCH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Acroosteolysis dominant type MONDO:0007057, Alagille syndrome MONDO:0007318; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3447 NOG Sangavi Sivagnanasundram reviewed gene: NOG: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: NOG-related symphalangism spectrum disorder MONDO:0100521; Mode of inheritance: None
Mendeliome v1.3447 NMNAT1 Sangavi Sivagnanasundram reviewed gene: NMNAT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: NMNAT1-related retinopathy MONDO:0800101; Mode of inheritance: None
Mendeliome v1.3447 NLRC4 Sangavi Sivagnanasundram reviewed gene: NLRC4: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: periodic fever-infantile enterocolitis-autoinflammatory syndrome MONDO:0014472; Mode of inheritance: None
Mendeliome v1.3447 NKX2-1 Sangavi Sivagnanasundram edited their review of gene: NKX2-1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3447 NKX2-1 Sangavi Sivagnanasundram reviewed gene: NKX2-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, MONDO:0100520; Mode of inheritance: None
Mendeliome v1.3447 TBCB Zornitza Stark Phenotypes for gene: TBCB were changed from Neurodevelopmental disorder, MONDO:0700092, TBCB-related to Neurodevelopmental disorder with behavioral abnormalities and childhood onset spastic paraplegia, MIM# 621382
Mendeliome v1.3446 TBCB Zornitza Stark reviewed gene: TBCB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with behavioral abnormalities and childhood onset spastic paraplegia, MIM# 621382; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3446 SETD5 Zornitza Stark edited their review of gene: SETD5: Changed rating: GREEN
Mendeliome v1.3446 FSHR Lucy Spencer reviewed gene: FSHR: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Ovarian dysgenesis 1 MIM#233300, Ovarian hyperstimulation syndrome MIM#608115; Mode of inheritance: None
Mendeliome v1.3446 FOXE3 Lucy Spencer commented on gene: FOXE3
Mendeliome v1.3446 EXT2 Lucy Spencer reviewed gene: EXT2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Exostoses, multiple, type 2 MIM#133701; Mode of inheritance: None
Mendeliome v1.3446 RNH1 Lucy Spencer reviewed gene: RNH1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Encephalopathy, acute, infection-induced, susceptibility to, 12 MIM#620461; Mode of inheritance: None
Mendeliome v1.3446 RMI2 Lucy Spencer reviewed gene: RMI2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Bloom syndrome MONDO:0008876, RMI2-related; Mode of inheritance: None
Mendeliome v1.3446 RLBP1 Lucy Spencer reviewed gene: RLBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: RLBP1-related retinopathy MONDO:0100444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3446 RIPK1 Lucy Spencer reviewed gene: RIPK1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammation with episodic fever and lymphadenopathy MIM#618852; Mode of inheritance: None
Mendeliome v1.3446 RING1 Lucy Spencer reviewed gene: RING1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), RING1-related; Mode of inheritance: None
Mendeliome v1.3446 RIMS1 Lucy Spencer reviewed gene: RIMS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone-rod dystrophy MONDO:0015993, RIMS1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3446 RHOH Lucy Spencer reviewed gene: RHOH: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 129 MIM#618307; Mode of inheritance: None
Mendeliome v1.3446 TBX2 Zornitza Stark Marked gene: TBX2 as ready
Mendeliome v1.3446 TBX2 Zornitza Stark Added comment: Comment when marking as ready: Green for the association with skeletal disorder, Amber for association with deafness.
Mendeliome v1.3446 TBX2 Zornitza Stark Gene: tbx2 has been classified as Green List (High Evidence).
Mendeliome v1.3446 TBX2 Zornitza Stark Phenotypes for gene: TBX2 were changed from Vertebral anomalies and variable endocrine and T-cell dysfunction - MIM#618223 to Vertebral anomalies and variable endocrine and T-cell dysfunction - MIM#618223; Hearing loss disorder, MONDO:0005365, TBX2-related
Mendeliome v1.3445 TBX2 Zornitza Stark Classified gene: TBX2 as Green List (high evidence)
Mendeliome v1.3445 TBX2 Zornitza Stark Gene: tbx2 has been classified as Green List (High Evidence).
Mendeliome v1.3444 TBX2 Zornitza Stark Classified gene: TBX2 as Amber List (moderate evidence)
Mendeliome v1.3444 TBX2 Zornitza Stark Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3443 TBX2 Krithika Murali Classified gene: TBX2 as Green List (high evidence)
Mendeliome v1.3443 TBX2 Krithika Murali Gene: tbx2 has been classified as Green List (High Evidence).
Mendeliome v1.3442 TBX2 Krithika Murali edited their review of gene: TBX2: Added comment: PMID: 36733940 Rafeeq et al 2022 report a novel de novo nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in a child with chondrodysplasia and GDD. Skeletal features included spinal deformities, short limbs, metaphyseal and epiphyseal dysplasia, and bilateral developmental dislocation of the hip (DDH).

PMID: 35311234 Makitie et al 2022 report a three-generation Finnish family with autosomal dominant osteochondrodysplasia and empty sella. Affected individuals (age range 24-44 years) exhibited unusual codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Clinical characteristics also include mild dysmorphic features, reduced sitting height ratio, and obesity.; Changed rating: GREEN
Mendeliome v1.3442 SLC7A2 Zornitza Stark Marked gene: SLC7A2 as ready
Mendeliome v1.3442 SLC7A2 Zornitza Stark Gene: slc7a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3442 SLC7A2 Zornitza Stark Classified gene: SLC7A2 as Amber List (moderate evidence)
Mendeliome v1.3442 SLC7A2 Zornitza Stark Gene: slc7a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3441 SLC7A2 Zornitza Stark gene: SLC7A2 was added
gene: SLC7A2 was added to Mendeliome. Sources: Literature
founder tags were added to gene: SLC7A2.
Mode of inheritance for gene: SLC7A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC7A2 were set to 41015522
Phenotypes for gene: SLC7A2 were set to Leukodystrophy, MONDO:0019046, SLC7A2-related
Review for gene: SLC7A2 was set to AMBER
Added comment: RAVINE leukoencephalopathy (RLE) is a hereditary autosomal recessive disease characterized by typical clinical and radiological signs that has so far been observed only in patients of Reunionese origin. The term RAVINE is a French acronym for the main clinical features of the disease: Réunion, Anorexie, Vomissements Incoercibles, signes NEurologiques (Reunion, Anorexia, Intractable Vomiting, NEurological signs). Patients with RLE carry the IVS1-1778A>G mutation of the SLC7A2 gene in the homozygous state.

Onset is in infancy. Death typically occurs before the age of 28months in a very narrow time window (23.0±2.2months).

PMID 41015522 summarises data from 40 affected individuals.
Sources: Literature
Mendeliome v1.3440 AMOT Zornitza Stark Marked gene: AMOT as ready
Mendeliome v1.3440 AMOT Zornitza Stark Gene: amot has been classified as Red List (Low Evidence).
Mendeliome v1.3440 AMOT Zornitza Stark Classified gene: AMOT as Red List (low evidence)
Mendeliome v1.3440 AMOT Zornitza Stark Gene: amot has been classified as Red List (Low Evidence).
Mendeliome v1.3439 AMOT Zornitza Stark reviewed gene: AMOT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.3439 EIF3B Zornitza Stark Marked gene: EIF3B as ready
Mendeliome v1.3439 EIF3B Zornitza Stark Gene: eif3b has been classified as Green List (High Evidence).
Mendeliome v1.3439 EIF3B Zornitza Stark Classified gene: EIF3B as Green List (high evidence)
Mendeliome v1.3439 EIF3B Zornitza Stark Gene: eif3b has been classified as Green List (High Evidence).
Mendeliome v1.3438 EIF3B Zornitza Stark gene: EIF3B was added
gene: EIF3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF3B were set to 41033306
Phenotypes for gene: EIF3B were set to Syndromic disease (MONDO:0002254), EIF3B-related
Review for gene: EIF3B was set to GREEN
Added comment: Fourteen individuals reported with mono-allelic variants. The clinical phenotype varied but predominantly included cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioural abnormalities. Zebrafish model recapitulated phenotype.
Sources: Literature
Mendeliome v1.3437 EIF3A Zornitza Stark Marked gene: EIF3A as ready
Mendeliome v1.3437 EIF3A Zornitza Stark Gene: eif3a has been classified as Green List (High Evidence).
Mendeliome v1.3437 EIF3A Zornitza Stark Classified gene: EIF3A as Green List (high evidence)
Mendeliome v1.3437 EIF3A Zornitza Stark Gene: eif3a has been classified as Green List (High Evidence).
Mendeliome v1.3436 EIF3A Zornitza Stark gene: EIF3A was added
gene: EIF3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF3A were set to 41033306
Phenotypes for gene: EIF3A were set to Syndromic disease (MONDO:0002254), EIF3A-related
Review for gene: EIF3A was set to GREEN
Added comment: Four individuals reported with mono-allelic variants. The clinical phenotype varied but predominantly included cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioural abnormalities. Zebrafish model recapitulated phenotype.
Sources: Literature
Mendeliome v1.3435 SF1 Zornitza Stark Marked gene: SF1 as ready
Mendeliome v1.3435 SF1 Zornitza Stark Gene: sf1 has been classified as Green List (High Evidence).
Mendeliome v1.3435 SF1 Zornitza Stark Classified gene: SF1 as Green List (high evidence)
Mendeliome v1.3435 SF1 Zornitza Stark Gene: sf1 has been classified as Green List (High Evidence).
Mendeliome v1.3434 MDGA2 Zornitza Stark Marked gene: MDGA2 as ready
Mendeliome v1.3434 MDGA2 Zornitza Stark Gene: mdga2 has been classified as Green List (High Evidence).
Mendeliome v1.3434 MDGA2 Zornitza Stark Classified gene: MDGA2 as Green List (high evidence)
Mendeliome v1.3434 MDGA2 Zornitza Stark Gene: mdga2 has been classified as Green List (High Evidence).
Mendeliome v1.3433 WNT4 Zornitza Stark Publications for gene: WNT4 were set to 22503279; 21377155; 16959810; 18179883; 15317892; 18182450
Mendeliome v1.3432 WNT4 Zornitza Stark edited their review of gene: WNT4: Changed publications: 22503279, 21377155, 16959810, 18179883, 15317892, 18182450, 40992710
Mendeliome v1.3432 WNT4 Zornitza Stark commented on gene: WNT4: Biallelic variants in WNT4 have been linked to SERKAL syndrome, an autosomal recessive disorder characterized by 46,XX sex reversal and dysgenesis of the kidneys, adrenals, and lungs. SERKAL syndrome has only been described in a single consanguineous kindred with four affected fetuses.

PMID 40992710 reports second affected family, consanguineous, which had an affected fetus with CDH and an affected child had orofacial clefting.

A subset of Wnt4 null mouse embryos had perimembranous VSDs, anterior and posterior sac CDH, and soft palate clefts.

Bi-allelic association: two consanguineous families and a mouse model, maintain AMBER rating.
Mendeliome v1.3432 PDIA6 Zornitza Stark Phenotypes for gene: PDIA6 were changed from Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes to multiple congenital anomalies, MONDO:0019042, PDIA6-related
Mendeliome v1.3431 PDIA6 Zornitza Stark Publications for gene: PDIA6 were set to
Mendeliome v1.3430 PDIA6 Zornitza Stark Classified gene: PDIA6 as Green List (high evidence)
Mendeliome v1.3430 PDIA6 Zornitza Stark Gene: pdia6 has been classified as Green List (High Evidence).
Mendeliome v1.3429 MIA3 Zornitza Stark Publications for gene: MIA3 were set to 32101163; 33778321
Mendeliome v1.3428 MIA3 Zornitza Stark Classified gene: MIA3 as Green List (high evidence)
Mendeliome v1.3428 MIA3 Zornitza Stark Gene: mia3 has been classified as Green List (High Evidence).
Mendeliome v1.3427 CASP8 Zornitza Stark Publications for gene: CASP8 were set to 12353035; 25814141; 12654726; 17213198; 16148088
Mendeliome v1.3426 CASP8 Zornitza Stark Classified gene: CASP8 as Green List (high evidence)
Mendeliome v1.3426 CASP8 Zornitza Stark Gene: casp8 has been classified as Green List (High Evidence).
Mendeliome v1.3425 CASP8 Zornitza Stark Tag founder tag was added to gene: CASP8.
Mendeliome v1.3425 CASP8 Zornitza Stark edited their review of gene: CASP8: Added comment: Additional individual reported, bring up total to 7 individuals from 5 families. All had the same homozygous missense variant, p.Arg265Trp. Some known to be distantly related. CIDP was a common manifestation.

GREEN but any variants apart from the founder variant should be treated with caution.; Changed rating: GREEN; Changed publications: 41026346; Changed phenotypes: Autoimmune lymphoproliferative syndrome, type IIB MIM#607271; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3425 PTBP1 Zornitza Stark Phenotypes for gene: PTBP1 were changed from to Neurodevelopmental disorder (MONDO:0700092), PTBP1-related
Mendeliome v1.3424 PTBP1 Zornitza Stark Publications for gene: PTBP1 were set to
Mendeliome v1.3423 PTBP1 Zornitza Stark Mode of inheritance for gene: PTBP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3422 PTBP1 Zornitza Stark Classified gene: PTBP1 as Green List (high evidence)
Mendeliome v1.3422 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Green List (High Evidence).
Mendeliome v1.3421 CACNB1 Zornitza Stark Phenotypes for gene: CACNB1 were changed from Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related to Congenital muscular dystrophy MONDO:0020121; Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related
Mendeliome v1.3420 CACNB1 Zornitza Stark Publications for gene: CACNB1 were set to 27832566; 8943043; 29212769
Mendeliome v1.3419 CACNB1 Zornitza Stark Mode of inheritance for gene: CACNB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3418 CACNB1 Zornitza Stark Classified gene: CACNB1 as Amber List (moderate evidence)
Mendeliome v1.3418 CACNB1 Zornitza Stark Gene: cacnb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3417 ZDHHC18 Zornitza Stark Marked gene: ZDHHC18 as ready
Mendeliome v1.3417 ZDHHC18 Zornitza Stark Gene: zdhhc18 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3417 SWSAP1 Zornitza Stark Marked gene: SWSAP1 as ready
Mendeliome v1.3417 SWSAP1 Zornitza Stark Gene: swsap1 has been classified as Red List (Low Evidence).
Mendeliome v1.3417 SWSAP1 Zornitza Stark Classified gene: SWSAP1 as Red List (low evidence)
Mendeliome v1.3417 SWSAP1 Zornitza Stark Gene: swsap1 has been classified as Red List (Low Evidence).
Mendeliome v1.3416 FAP Zornitza Stark Marked gene: FAP as ready
Mendeliome v1.3416 FAP Zornitza Stark Gene: fap has been classified as Red List (Low Evidence).
Mendeliome v1.3416 FAP Zornitza Stark Classified gene: FAP as Red List (low evidence)
Mendeliome v1.3416 FAP Zornitza Stark Gene: fap has been classified as Red List (Low Evidence).
Mendeliome v1.3415 NFXL1 Zornitza Stark Marked gene: NFXL1 as ready
Mendeliome v1.3415 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3415 NFXL1 Zornitza Stark Classified gene: NFXL1 as Amber List (moderate evidence)
Mendeliome v1.3415 NFXL1 Zornitza Stark Gene: nfxl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Marked gene: ZSWIM7 as ready
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Gene: zswim7 has been classified as Green List (High Evidence).
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Classified gene: ZSWIM7 as Green List (high evidence)
Mendeliome v1.3414 ZSWIM7 Zornitza Stark Gene: zswim7 has been classified as Green List (High Evidence).
Mendeliome v1.3413 PTBP2 Zornitza Stark Marked gene: PTBP2 as ready
Mendeliome v1.3413 PTBP2 Zornitza Stark Gene: ptbp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3413 PTBP2 Zornitza Stark Classified gene: PTBP2 as Amber List (moderate evidence)
Mendeliome v1.3413 PTBP2 Zornitza Stark Gene: ptbp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3412 KLK15 Zornitza Stark Marked gene: KLK15 as ready
Mendeliome v1.3412 KLK15 Zornitza Stark Gene: klk15 has been classified as Red List (Low Evidence).
Mendeliome v1.3412 KLK15 Zornitza Stark Classified gene: KLK15 as Red List (low evidence)
Mendeliome v1.3412 KLK15 Zornitza Stark Gene: klk15 has been classified as Red List (Low Evidence).
Mendeliome v1.3411 KLK15 Zornitza Stark reviewed gene: KLK15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3411 INCENP Zornitza Stark Marked gene: INCENP as ready
Mendeliome v1.3411 INCENP Zornitza Stark Gene: incenp has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3411 INCENP Zornitza Stark Classified gene: INCENP as Amber List (moderate evidence)
Mendeliome v1.3411 INCENP Zornitza Stark Gene: incenp has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3410 GSTZ1 Zornitza Stark Marked gene: GSTZ1 as ready
Mendeliome v1.3410 GSTZ1 Zornitza Stark Gene: gstz1 has been classified as Green List (High Evidence).
Mendeliome v1.3410 GSTZ1 Zornitza Stark Classified gene: GSTZ1 as Green List (high evidence)
Mendeliome v1.3410 GSTZ1 Zornitza Stark Gene: gstz1 has been classified as Green List (High Evidence).
Mendeliome v1.3409 FSIP2 Zornitza Stark Marked gene: FSIP2 as ready
Mendeliome v1.3409 FSIP2 Zornitza Stark Gene: fsip2 has been classified as Green List (High Evidence).
Mendeliome v1.3409 FSIP2 Zornitza Stark Classified gene: FSIP2 as Green List (high evidence)
Mendeliome v1.3409 FSIP2 Zornitza Stark Gene: fsip2 has been classified as Green List (High Evidence).
Mendeliome v1.3408 CDK9 Zornitza Stark Marked gene: CDK9 as ready
Mendeliome v1.3408 CDK9 Zornitza Stark Gene: cdk9 has been classified as Green List (High Evidence).
Mendeliome v1.3407 ABCB4 Chirag Patel Publications for gene ABCB4 were changed from 8666348; 17726488; 18482588; 28924228; 32376413; 9419367; 26474921; 32793533; 11313315 to 8666348; 17726488; 18482588; 28924228; 32376413; 9419367; 26474921; 32793533; 11313315
Mendeliome v1.3406 ABCB4 Chirag Patel Source Victorian Clinical Genetics Services was removed from ABCB4.
Phenotypes for gene: ABCB4 were changed from Cholestasis, progressive familial intrahepatic 3 MIM#602347; disorder of bile acid metabolism; Gallbladder disease 1 (MIM#600803) to Progressive familial intrahepatic cholestasis type 3, MONDO:0011214; Cholestasis, intrahepatic, of pregnancy, 3 MIM#614972; disorder of bile acid metabolism; Gallbladder disease 1 (MIM#600803)
Mendeliome v1.3405 ABCC8 Chirag Patel Source Victorian Clinical Genetics Services was removed from ABCC8.
Source Expert list was added to ABCC8.
Phenotypes for gene: ABCC8 were changed from Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800 to Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800; Pulmonary arterial hypertension, MONDO:0015924, ABCC8-related
Publications for gene ABCC8 were changed from 21054355, 32027066, 32376986, 30354297, 35811711, 32934261, 31727138 to 21054355, 32027066, 32376986, 30354297, 35811711, 32934261, 31727138
Mendeliome v1.3404 AGTPBP1 Chirag Patel Phenotypes for gene: AGTPBP1 were changed from Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276 to Neurodegeneration, childhood-onset, with cerebellar atrophy, MONDO:0032650
Publications for gene AGTPBP1 were changed from 30420557, 28600779, 30976113, 38153683, 28325758 to 30420557, 28600779, 30976113, 38153683, 28325758
Mendeliome v1.3403 ATP1A3 Chirag Patel Source Victorian Clinical Genetics Services was removed from ATP1A3.
Phenotypes for gene: ATP1A3 were changed from Alternating hemiplegia of childhood 2, MIM# 614820; CAPOS syndrome, MIM# 601338; Dystonia-12, MIM# 128235; Polymicrogyria to ATP1A3-associated neurological disorder, MONDO:0700002
Publications for gene ATP1A3 were changed from 15260953, 22842232, 24468074, 33762331, 29861155, 31425744 to 15260953, 22842232, 24468074, 33762331, 29861155, 31425744
Mendeliome v1.3402 ALS2 Chirag Patel Source Literature was removed from ALS2.
Source ClinGen was added to ALS2.
Phenotypes for gene: ALS2 were changed from Infantile onset ascending spastic paralysis (MIM#607225); Juvenile amyotrophic lateral sclerosis 2 (MIM#205100); Juvenile primary lateral sclerosis (MIM#606353) to ALS2-related motor neuron disease, MONDO:0100227
Publications for gene ALS2 were changed from 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358 to 30128655, 33409823, 11586298, 16240357, 23282280, 24562058, 33155358
Mendeliome v1.3401 ALG14 Chirag Patel Source Victorian Clinical Genetics Services was removed from ALG14.
Source Expert list was added to ALG14.
Publications for gene ALG14 were changed from 30221345, 23404334, 28733338, 33751823, 34971077 to 30221345, 23404334, 28733338, 33751823, 34971077
Mendeliome v1.3400 AGK Chirag Patel Source Victorian Clinical Genetics Services was removed from AGK.
Source Expert list was added to AGK.
Mendeliome v1.3399 DHX9 Chirag Patel Source Literature was removed from DHX9.
Source Expert list was added to DHX9.
Phenotypes for gene: DHX9 were changed from Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Charcot-Marie-Tooth disease, MONDO:0015626 to Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Charcot-Marie-Tooth disease, MONDO:0015626, DHX9-related
Mendeliome v1.3398 DGUOK Chirag Patel Source Victorian Clinical Genetics Services was removed from DGUOK.
Source ClinGen was added to DGUOK.
Publications for gene DGUOK were changed from 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938 to 11687800, 12874104, 15887277, 23043144, 26874653, 18205204, 29137425, 30956829, 35750291, 28215579, 20301766, 28215579, 17073823, 31127938
Mendeliome v1.3397 DHH Chirag Patel Classified gene: DHH as Green List (high evidence)
Mendeliome v1.3397 DHH Chirag Patel Gene: dhh has been classified as Green List (High Evidence).
Mendeliome v1.3396 DHH Chirag Patel Source Victorian Clinical Genetics Services was removed from DHH.
Source Expert list was added to DHH.
Phenotypes for gene: DHH were changed from 46XY gonadal dysgenesis with minifascicular neuropathy MIM#607080; 46XY sex reversal 7 MIM#233420 to 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, MONDO:0011766
Rating Changed from Green List (high evidence) to Red List (low evidence)
Mendeliome v1.3394 DNAJC6 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJC6.
Source Expert list was added to DNAJC6.
Publications for gene DNAJC6 were changed from 22563501, 23211418, 26528954, 33983693 to 22563501, 23211418, 26528954, 33983693
Mendeliome v1.3393 DNAH8 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAH8.
Source ClinGen was added to DNAH8.
Phenotypes for gene: DNAH8 were changed from Spermatogenic failure 46, MIM#619095; Asthenozoospermia; primary ciliary dyskinesia to Spermatogenic failure 46, MONDO:0033673; Primary ciliary dyskinesia, MONDO:0016575, DNAH8-related
Publications for gene DNAH8 were changed from 31178125, 32619401, 32681648, 33704367, 24307375 to 31178125, 32619401, 32681648, 33704367, 24307375
Mendeliome v1.3392 DNAH1 Chirag Patel Classified gene: DNAH1 as Green List (high evidence)
Mendeliome v1.3392 DNAH1 Chirag Patel Gene: dnah1 has been classified as Green List (High Evidence).
Mendeliome v1.3391 DNAH1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAH1.
Source ClinGen was added to DNAH1.
Phenotypes for gene: DNAH1 were changed from primary ciliary dyskinesia,37 MIM#617577; Spermatogenic failure 18 MIM#617576 to Spermatogenic failure 18, MONDO:0054615; Primary ciliary dyskinesia 7, MONDO:0012748
Publications for gene DNAH1 were changed from 34867808, 31507630, 24360805, 27798045, 11371505, 27798045, 29449551, 25927852, 31765523, 33577779, 34210339 to 34867808, 31507630, 24360805, 27798045, 11371505, 27798045, 29449551, 25927852, 31765523, 33577779, 34210339
Rating Changed from Green List (high evidence) to Red List (low evidence)
Mendeliome v1.3390 DHCR24 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHCR24.
Phenotypes for gene: DHCR24 were changed from Desmosterolosis MIM#602398; Disorders of the metabolism of sterols to Desmosterolosis, MONDO:0011217
Publications for gene DHCR24 were changed from 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936 to 11519011, 33524375, 21671375, 12457401, 29175559, 21559050, 33027564, 38239854, 30891795, 25637936
Mendeliome v1.3389 DEF6 Chirag Patel Phenotypes for gene: DEF6 were changed from Immunodeficiency 87 and autoimmunity, MIM# 619573; Systemic autoimmunity to Immunodeficiency 87 and autoimmunity, MONDO:0030457
Mendeliome v1.3388 DDX11 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDX11.
Source ClinGen was added to DDX11.
Phenotypes for gene: DDX11 were changed from Warsaw breakage syndrome, MIM# 613398; MONDO:0013252 to Warsaw breakage syndrome, MONDO:0013252
Publications for gene DDX11 were changed from 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203 to 20137776, 23033317, 30216658, 30924321, 32855419, 36703504, 26089203
Mendeliome v1.3387 DDHD1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDHD1.
Source ClinGen was added to DDHD1.
Phenotypes for gene: DDHD1 were changed from Spastic paraplegia 28, autosomal recessive, 609340; MONDO:0012256 to Hereditary spastic paraplegia 28, MONDO:0012256
Publications for gene DDHD1 were changed from 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578 to 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, 27999540, 33600578
Mendeliome v1.3386 DCLRE1C Chirag Patel Source Victorian Clinical Genetics Services was removed from DCLRE1C.
Source Expert list was added to DCLRE1C.
Phenotypes for gene: DCLRE1C were changed from Severe combined immunodeficiency, Athabascan type MIM# 602450; Omenn syndrome, MIM# 603554 to Severe combined immunodeficiency due to DCLRE1C deficiency, MONDO:0011225
Publications for gene DCLRE1C were changed from 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179 to 12055248, 34220820, 11336668, 19953608, 15731174, 16540517, 18034425, 12504013, 15699179
Mendeliome v1.3385 DCDC2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DCDC2.
Source Victorian Clinical Genetics Services was removed from DCDC2.
Source Expert list was added to DCDC2.
Phenotypes for gene: DCDC2 were changed from Nephronophthisis 19, MIM# 616217; Sclerosing cholangitis, neonatal, MIM# 617394 to Nephronophthisis 19, MIM# 616217; Sclerosing cholangitis, neonatal, MIM# 617394; Deafness, autosomal recessive 66, MIM# 610212
Mendeliome v1.3384 DBR1 Chirag Patel Publications for gene DBR1 were changed from 39023559, 29474921, 37656279 to 39023559, 29474921, 37656279
Mendeliome v1.3383 DNM2 Chirag Patel Publications for gene DNM2 were changed from 15731758; 17636067; 33459893; 31628461; 23092955; 16227997; 33458580; 30232666; 24465259; 23938035 to 15731758; 17636067; 33459893; 31628461; 23092955; 16227997; 33458580; 30232666; 24465259; 23938035
Mendeliome v1.3382 MAFA Sangavi Sivagnanasundram gene: MAFA was added
gene: MAFA was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MAFA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAFA were set to 29339498
Phenotypes for gene: MAFA were set to Insulinomatosis and diabetes mellitus, OMIM #:147630
Review for gene: MAFA was set to GREEN
Added comment: Addition of this review to Mendeliome, was only on the hyperinsulinism panel

2 families with 36 individuals with AD inheritance of diabetes mellitus or insulinomatosis (adult-onset recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumours of pancreas). WES identified the same missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes in both families. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.
Sources: Other
Mendeliome v1.3382 DHX38 Arina Puzriakova changed review comment from: - PMID: 35719279 (2022) - another consanguineous family from Saudi Arabia with two sisters presented affected by retinitis pigmentosa since childhood. Whole exome sequencing identified a missense homozygous variant (c.2571C>T, p.(Ala857=)) in the DHX38 gene which segregated with the phenotype. No functional studies performed.

PMID: 37867960 (2023) - zebrafish knockout model shows a role in the development of the retina; to: - PMID: 35719279 (2022) - another consanguineous family from Saudi Arabia with two sisters presented affected by retinitis pigmentosa since childhood. Whole exome sequencing identified a missense homozygous variant (c.2571C>T, p.(Ala857=)) in the DHX38 gene which segregated with the phenotype. No functional studies performed.

- PMID: 37867960 (2023) - zebrafish knockout model shows a role in the development of the retina
Mendeliome v1.3382 DHX38 Arina Puzriakova reviewed gene: DHX38: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3382 UGGT1 Zornitza Stark Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation - MONDO:0015286; UGGT1-CDG to Congenital disorder of glycosylation, type IICC, MIM# 621381
Mendeliome v1.3381 UGGT1 Zornitza Stark reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IICC, MIM# 621381; Mode of inheritance: None
Mendeliome v1.3381 INCENP Rylee Peters gene: INCENP was added
gene: INCENP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INCENP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INCENP were set to 41005306
Phenotypes for gene: INCENP were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769, INCENP-related
Review for gene: INCENP was set to AMBER
Added comment: 3 unrelated women presenting with abnormal oocyte morphology and/or low fertilisation rate from a large cohort of 3627 individuals. WES identified biallelic missense variants:
R267Q (gnomAD v4: 1717 hets, 12 homs), R280W (5 hets, 0 homs), P444L (207 hets, 0 homs), R693W (686 hets, 1 hom), K816T (110 hets, 1 hom), K890E (3 hets, 0 homs).

siRNA-mediated knock-down of INCENP in mouse oocytes reduced polar-body extrusion rates, demonstrating that loss of function of the protein affects oocyte maturation.
Sources: Literature
Mendeliome v1.3381 ANKRD24 Rylee Peters reviewed gene: ANKRD24: Rating: RED; Mode of pathogenicity: None; Publications: 40989574; Phenotypes: Sensorineural hearing loss disorder MONDO:0020678, ANKRD24-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3381 SWSAP1 Rylee Peters gene: SWSAP1 was added
gene: SWSAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SWSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SWSAP1 were set to 40991243
Phenotypes for gene: SWSAP1 were set to Primary ovarian insufficiency, MONDO:0005387, SWSAP1-related
Review for gene: SWSAP1 was set to RED
Added comment: Cohort with severe isolated premature ovarian insufficiency. 1x individual homozygous for a frameshift SWSAP1 variant, c.353del, p.(Gly118AlafsTer2), absent from gnomAD v4.

Functional: western-blot indicates reduced stability of the truncated protein; the truncated SWSAP1 variant fails to complement the IH-HR (interhomolog homologous recombination) defect of Swsap1−/− cells (undetected IH-HR activity).
Sources: Literature
Mendeliome v1.3381 FSIP2 Rylee Peters gene: FSIP2 was added
gene: FSIP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSIP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FSIP2 were set to 30137358; 40968718; 36632462; 33631238
Phenotypes for gene: FSIP2 were set to Spermatogenic failure 34, MIM#618153
Review for gene: FSIP2 was set to GREEN
Added comment: Multiple unrelated cases with multiple morphological abnormalities of the sperm flagella (MMAF) carrying biallelic variants.
Sources: Literature
Mendeliome v1.3381 AMOT Rylee Peters gene: AMOT was added
gene: AMOT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMOT was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AMOT were set to 40892511
Phenotypes for gene: AMOT were set to Congenital hydrocephalus MONDO:0016349, AMOT-related
Review for gene: AMOT was set to AMBER
Added comment: 1x family with isolated X-linked congenital hydrocephalus – clinical presentation considered late, identified in the third trimester. Variant segregated with disease in 6x affected hemizygous males (4x live-born and 2x terminated male fetuses). Carrier females are apparently normal (no brain MRI was performed).

Exome sequencing identified start loss variant, c.2T>C p.(Met1Thr). Functional analyses identify that the variant results in a protein lacking 91 amino acids from the N-terminus and leads to abnormally increased AMOT protein levels (increased stability due to loss of degradation signals), which disrupts epithelial and endothelial barrier integrity.
Sources: Literature
Mendeliome v1.3381 HECTD4 Elena Savva reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28191890, 31981491, 31785789; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3381 MDGA2 Sangavi Sivagnanasundram changed review comment from: Affected individuals present with a broad neurodevelopmental impairment phenotype.

Pre-print - https://doi.org/10.1101/2025.08.28.25330873
Individuals with developmental and epileptic encephalopathy (DEE)
8 individuals from 6 consanguineous families exhibiting infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features.
7 different biallelic LoF variants were identified
p.Tyr913Ter, p.Arg404Ter, p.Leu920Ter, c.421-1G>A, p.Lys391SerfsTer7 and c.421-96_595+99del - all variants are rare or absent in gnomAD v4.1
In vitro functional studies of three nonsense variants in mammalian expression systems and hippocampal cultured neurons that resulted in impaired MDGA2 membrane trafficking are supportive of a loss-of-function mechanism.

PMID: 40168357, 27608760
A knockout mouse model showed that MGAD2-deficient mice presented with autism-like behaviours (social deficits, repetitive behaviour, and cognitive impairment).
The mice also showed abnormalities in excitatory synapses.
Sources: Other; to: Affected individuals present with a broad neurodevelopmental impairment-like phenotype.

Pre-print - https://doi.org/10.1101/2025.08.28.25330873
Individuals with developmental and epileptic encephalopathy (DEE)
8 individuals from 6 consanguineous families exhibiting infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features.
7 different biallelic LoF variants were identified
p.Tyr913Ter, p.Arg404Ter, p.Leu920Ter, c.421-1G>A, p.Lys391SerfsTer7 and c.421-96_595+99del - all variants are rare or absent in gnomAD v4.1
In vitro functional studies of three nonsense variants in mammalian expression systems and hippocampal cultured neurons that resulted in impaired MDGA2 membrane trafficking are supportive of a loss-of-function mechanism.

PMID: 40168357, 27608760
A knockout mouse model showed that MGAD2-deficient mice presented with autism-like behaviours (social deficits, repetitive behaviour, and cognitive impairment).
The mice also showed abnormalities in excitatory synapses.
Sources: Other
Mendeliome v1.3381 MDGA2 Sangavi Sivagnanasundram gene: MDGA2 was added
gene: MDGA2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MDGA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDGA2 were set to https://doi.org/10.1101/2025.08.28.25330873; 40168357; 27608760
Phenotypes for gene: MDGA2 were set to MDGA2-related neurodevelopmental disorder MONDO:0700092
Review for gene: MDGA2 was set to GREEN
Added comment: Affected individuals present with a broad neurodevelopmental impairment phenotype.

Pre-print - https://doi.org/10.1101/2025.08.28.25330873
Individuals with developmental and epileptic encephalopathy (DEE)
8 individuals from 6 consanguineous families exhibiting infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features.
7 different biallelic LoF variants were identified
p.Tyr913Ter, p.Arg404Ter, p.Leu920Ter, c.421-1G>A, p.Lys391SerfsTer7 and c.421-96_595+99del - all variants are rare or absent in gnomAD v4.1
In vitro functional studies of three nonsense variants in mammalian expression systems and hippocampal cultured neurons that resulted in impaired MDGA2 membrane trafficking are supportive of a loss-of-function mechanism.

PMID: 40168357, 27608760
A knockout mouse model showed that MGAD2-deficient mice presented with autism-like behaviours (social deficits, repetitive behaviour, and cognitive impairment).
The mice also showed abnormalities in excitatory synapses.
Sources: Other
Mendeliome v1.3381 CACNB1 Sangavi Sivagnanasundram reviewed gene: CACNB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 41023410; Phenotypes: Congenital muscular dystrophy MONDO:0020121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3381 ATP5O Bryony Thompson Tag new gene name tag was added to gene: ATP5O.
Mendeliome v1.3381 DDOST Bryony Thompson Phenotypes for gene: DDOST were changed from Congenital disorder of glycosylation, type Ir, MIM# 614507 to DDOST-congenital disorder of glycosylation MONDO:0013789; inherited oocyte maturation defect MONDO:0014769
Mendeliome v1.3380 DDOST Bryony Thompson Publications for gene: DDOST were set to 22305527
Mendeliome v1.3379 DDOST Bryony Thompson Classified gene: DDOST as Green List (high evidence)
Mendeliome v1.3379 DDOST Bryony Thompson Gene: ddost has been classified as Green List (High Evidence).
Mendeliome v1.3378 DDOST Bryony Thompson reviewed gene: DDOST: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305527, 34462534, 36214423, 37848450, 33413482, 36631682, 41005306; Phenotypes: DDOST-congenital disorder of glycosylation MONDO:0013789, inherited oocyte maturation defect MONDO:0014769; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3378 MIA3 Sangavi Sivagnanasundram reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 40948380, 40119123; Phenotypes: odontochondrodysplasia MONDO:0031169; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3378 RYR3 Bryony Thompson Classified gene: RYR3 as Green List (high evidence)
Mendeliome v1.3378 RYR3 Bryony Thompson Gene: ryr3 has been classified as Green List (High Evidence).
Mendeliome v1.3377 RYR3 Bryony Thompson Phenotypes for gene: RYR3 were changed from Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062) to congenital heart disease MONDO:0005453; Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062)
Mendeliome v1.3376 RYR3 Bryony Thompson Publications for gene: RYR3 were set to 29498452; 32451403; 31230720; 25262651
Mendeliome v1.3375 RYR3 Bryony Thompson reviewed gene: RYR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39762984, 41022857, 39840699, 39220738, 25262651, 29667327; Phenotypes: congenital heart disease MONDO:0005453, developmental and epileptic encephalopathy MONDO:0100062; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3375 ZDHHC18 Bryony Thompson Classified gene: ZDHHC18 as Amber List (moderate evidence)
Mendeliome v1.3375 ZDHHC18 Bryony Thompson Gene: zdhhc18 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3374 ZDHHC18 Bryony Thompson changed review comment from: ZDHHC18 appears among significant CHD genes in the de novo enrichment analysis. Two de novo missense variants (W290L, G297A) were identified in 2 probands via trio analysis in a CHD cohort.
Sources: Literature; to: ZDHHC18 appears among significant CHD genes in the de novo enrichment analysis. Two de novo missense variants (W290L, G297A) were identified in 2 probands via trio analysis in a CHD cohort. No functional assays conducted.
Sources: Literature
Mendeliome v1.3374 ZDHHC18 Bryony Thompson gene: ZDHHC18 was added
gene: ZDHHC18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZDHHC18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZDHHC18 were set to 41022857
Phenotypes for gene: ZDHHC18 were set to congenital heart disease MONDO:0005453
Review for gene: ZDHHC18 was set to AMBER
Added comment: ZDHHC18 appears among significant CHD genes in the de novo enrichment analysis. Two de novo missense variants (W290L, G297A) were identified in 2 probands via trio analysis in a CHD cohort.
Sources: Literature
Mendeliome v1.3373 TM2D3 Zornitza Stark Phenotypes for gene: TM2D3 were changed from Neurodevelopmental disorder, MONDO:0700092, TM2D3-related to Neurocardiorenal malformation syndrome, MIM# 621379
Mendeliome v1.3372 TM2D3 Zornitza Stark edited their review of gene: TM2D3: Changed phenotypes: Neurocardiorenal malformation syndrome, MIM# 621379
Mendeliome v1.3372 ATXN7L3 Zornitza Stark Phenotypes for gene: ATXN7L3 were changed from Neurodevelopmental disorder, MONDO_0100500, ATXN7L3-related to Harel-Tora neurodevelopmental syndrome, MIM# 621377
Mendeliome v1.3371 ATXN7L3 Zornitza Stark reviewed gene: ATXN7L3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Harel-Tora neurodevelopmental syndrome, MIM# 621377; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3371 NAMPT Bryony Thompson Marked gene: NAMPT as ready
Mendeliome v1.3371 NAMPT Bryony Thompson Gene: nampt has been classified as Red List (Low Evidence).
Mendeliome v1.3371 NAMPT Bryony Thompson gene: NAMPT was added
gene: NAMPT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAMPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAMPT were set to 41004591
Phenotypes for gene: NAMPT were set to hereditary motor and sensory neuropathy MONDO:0015358
Review for gene: NAMPT was set to RED
Added comment: A single family reported.
Disease Context: sensory and motor neuropathy with motor coordination impairment, muscle atrophy/weakness, foot/hand deformities, loss of sensation and positive Babinski sign
Families: 1 family
Patients: 2
Phenotype: impaired motor coordination, muscle atrophy/weakness, foot and hand deformities, diminished sensation, positive Babinski sign
Mode of inheritance: Biallelic (autosomal recessive; parents heterozygous carriers, affected siblings homozygous). No mention of consanguinity
Variants: c.472G>C (p.P158A) (missense)
Population Frequency: gnomAD: 0
Segregation: parents heterozygous, both affected siblings homozygous (pedigree confirmed)
Functional Studies: recombinant NAMPT protein activity assay; thermal shift stability assay; patient fibroblast bioenergetic, mitochondrial and oxidative stress assays; CRISPR‑generated isogenic fibroblasts; homozygous p.P158A mouse model showing metabolic, synaptic and motor neuron defects; rescue with NMN/P7C3
Prior Reports: none.
Sources: Literature
Mendeliome v1.3370 DBX1 Bryony Thompson Marked gene: DBX1 as ready
Mendeliome v1.3370 DBX1 Bryony Thompson Gene: dbx1 has been classified as Red List (Low Evidence).
Mendeliome v1.3370 DBX1 Bryony Thompson gene: DBX1 was added
gene: DBX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBX1 were set to 40995053
Phenotypes for gene: DBX1 were set to central hypoventilation syndrome, congenital MONDO:0800031
Review for gene: DBX1 was set to RED
Added comment: Disease Context: Congenital central hypoventilation syndrome (atypical CCHS) with central hypotonia, global developmental delay, seizures, autoaggressive behavior
Families: 1 (1 unrelated)
Patients: 1
Phenotype: congenital central hypoventilation, central hypotonia, global developmental delay, seizures, autoaggressive behavior
Mode of inheritance: Biallelic (consanguineous parents (first cousins))
Variants: c.340_341delGC (frameshift)
Population Frequency: NR
Segregation: NR
Functional Studies: mouse Dbx1 knockout lethality indicating essential role in respiration
Prior Reports: 0
Sources: Literature
Mendeliome v1.3369 TRIM49 Bryony Thompson Marked gene: TRIM49 as ready
Mendeliome v1.3369 TRIM49 Bryony Thompson Gene: trim49 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3369 TRIM49 Bryony Thompson Classified gene: TRIM49 as Amber List (moderate evidence)
Mendeliome v1.3369 TRIM49 Bryony Thompson Gene: trim49 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3368 TRIM49 Bryony Thompson changed review comment from: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not (Box 438, Box 440, Box 439). This constitutes convincing functional evidence for pathogenicity in two families.
Sources: Literature; to: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not. This constitutes convincing functional evidence for pathogenicity in two families.
Sources: Literature
Mendeliome v1.3368 TRIM49 Bryony Thompson gene: TRIM49 was added
gene: TRIM49 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM49 were set to 40956390
Phenotypes for gene: TRIM49 were set to retinitis pigmentosa MONDO:0019200
Review for gene: TRIM49 was set to AMBER
Added comment: Two unrelated families (consanguineous marriage in Family 2; possible maternal uniparental disomy in Family 1) carry rare biallelic TRIM49 variants (c.1184C>A and c.1134_1137delTCTT) that are absent from 7 283 in‑house controls and have extremely low gnomAD frequencies. Functional experiments in human RPE cell lines demonstrate that loss of TRIM49 impairs autophagic flux, ULK1 expression and POS phagocytosis, and that overexpression of wild‑type TRIM49 rescues these defects whereas mutant TRIM49 (M1/M2) does not (Box 438, Box 440, Box 439). This constitutes convincing functional evidence for pathogenicity in two families.
Sources: Literature
Mendeliome v1.3367 PCDHA9 Bryony Thompson Marked gene: PCDHA9 as ready
Mendeliome v1.3367 PCDHA9 Bryony Thompson Gene: pcdha9 has been classified as Red List (Low Evidence).
Mendeliome v1.3367 PCDHA9 Bryony Thompson gene: PCDHA9 was added
gene: PCDHA9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCDHA9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCDHA9 were set to 29477871; 40988636
Phenotypes for gene: PCDHA9 were set to Hirschsprung disease MONDO:0018309; root resorption MONDO:0001997
Review for gene: PCDHA9 was set to RED
Added comment: Single publication reporting an association with Hirschsprung disease, including a missense in a family (p.Gly572Arg) that is too common in gnomAD to be associated with disease and 2 rare missense in 2 sporadic cases. Knockdown in a cell line increased proliferation and
migration, but suppressed apoptosis. A single publication with a single missense reported in association with short root anomaly.
Sources: Literature
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Marked gene: RNU6ATAC as ready
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Gene: rnu6atac has been classified as Red List (Low Evidence).
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Classified gene: RNU6ATAC as Red List (low evidence)
Mendeliome v1.3366 RNU6ATAC Zornitza Stark Gene: rnu6atac has been classified as Red List (Low Evidence).
Mendeliome v1.3365 HYPK Zornitza Stark Publications for gene: HYPK were set to Clinical Genetics Early View
Mendeliome v1.3364 DNAH14 Zornitza Stark reviewed gene: DNAH14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.3364 TLN1 Zornitza Stark Publications for gene: TLN1 were set to 30888838; 35861643
Mendeliome v1.3363 BCAT1 Zornitza Stark Marked gene: BCAT1 as ready
Mendeliome v1.3363 BCAT1 Zornitza Stark Gene: bcat1 has been classified as Red List (Low Evidence).
Mendeliome v1.3363 BCAT1 Zornitza Stark Classified gene: BCAT1 as Red List (low evidence)
Mendeliome v1.3363 BCAT1 Zornitza Stark Gene: bcat1 has been classified as Red List (Low Evidence).
Mendeliome v1.3362 BCAT1 Lucy Spencer gene: BCAT1 was added
gene: BCAT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BCAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAT1 were set to 41029903
Phenotypes for gene: BCAT1 were set to Neurodevelopmental disorder (MONDO:0700092), BCAT1-related
Review for gene: BCAT1 was set to RED
Added comment: PMID: 41029903 One patient with a suspected neurometabolic disorder; congenital blindness and suspected Leber Congenital Amaurosis, microcephaly, failure to thrive, profound global developmental delay and extensive delayed myelination on MRI. AT 10 he was non-verbal and non-ambulatory with regression of motor skills and -3SD for height and weight. Compound heterozygous for Phe264Leu (539 hets but no homs in gnomad v4) and Glu348Lys (over 8000 hets and 24 homs in gnomad v4).

in compound heterozygous iPSCs a severe 75% reduction in BCAT1 protein levels was seen, but mRNA levels were normal suggesting the variants affect protein stability or increased degradation.
Sources: Literature
Mendeliome v1.3362 TLN1 Lucy Spencer edited their review of gene: TLN1: Added comment: PMID: 40960860 de novo L353F identified in a patient with increased nuchal translucency, leukopenia, thrombocytopenia, congenital cataracts, multiple episodes of acute bronchitis, skin lesions and swelling after exercise in cold weather. Overlapping authors with PMID: 35861643, and they are postulating this is a 2nd case of the condition reported there. Some functional studies showing decreased thermal stability, has slower cellular migration and that it was slightly more aggregation-prone than WT.

Shared symptoms between both patients; leukopenia, thrombocytopenia, congenital cataract, and recurring episodes of acute bronchitis. Both mutations situated in the talin-1 head F2F3 domains and both have been shown to have defects in cellular migration and integrin activation.; Changed rating: AMBER; Changed publications: 40960860; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3362 TLN1 Lucy Spencer reviewed gene: TLN1: Rating: RED; Mode of pathogenicity: None; Publications: 39704176; Phenotypes: Capillary leak syndrome MONDO:0001956, TLN1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.3362 DNAH14 Lucy Spencer reviewed gene: DNAH14: Rating: AMBER; Mode of pathogenicity: None; Publications: 36344539, 41002930; Phenotypes: Neurodevelopmental disorder MONDO:0700092, DNAH14-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3362 HYPK Sangavi Sivagnanasundram reviewed gene: HYPK: Rating: ; Mode of pathogenicity: None; Publications: 40986405; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, HYPK-related; Mode of inheritance: None
Mendeliome v1.3362 RNU6ATAC Lucy Spencer gene: RNU6ATAC was added
gene: RNU6ATAC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062
Phenotypes for gene: RNU6ATAC were set to Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related
Review for gene: RNU6ATAC was set to RED
Added comment: PMID: 40975062 1 patient compound heterozygous for n.36T>G and n.28C>T. Has short stature, microcephaly, hypotonia, neurodevelopmental delay, ID, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus and oculomotor apraxia. Identified in a cohort of individuals with an excess of significant intron retention outliers in minor intron containing genes which are usually removed by the minor spliceosome of which RNU6ATAC is a part (as is RNU4ATAC). Proband had no candidate variants in RNU4ATAC or RNU12. Both RNU6ATAC variants are in a highly conserved 39bp region, and affect nucleotides predicted to be important for binding to U4ATAC.
Sources: Literature
Mendeliome v1.3362 NFXL1 Lucy Spencer gene: NFXL1 was added
gene: NFXL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NFXL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFXL1 were set to 40430072; 41024252
Phenotypes for gene: NFXL1 were set to Syndromic disease (MONDO:0002254), NFXL1-related
Review for gene: NFXL1 was set to AMBER
Added comment: PMID: 40430072 2 siblings with psychosis and schizophrenia, homozygous for Cys441Tyr. Some modelling suggested a deleterious affect but no functional studies performed.

PMID: 41024252 8 patients from 7 families with joint hyperlaxity, with or without short stature and renal disease. 6 families were homozygous for p.(Cys539Trpfs*64) while the other two were homozygous for p.(Lys681*). Paper described both as founder variants but they are rare/absent in gnomad.

Joint hyperlaxity (7), chronic kidney disease/FSGS (2) small echogenic kidneys (3), acute kidney injury (1), dysmorphic features (6), short stature (6), speech delay (3).

One patient also had epilepsy, developmental delay and spasticity however c.728+1G>A in WDR45 explained this part of her phenotype. Other patients also had more severe outlying symptoms with no other explanation mentioned: 1 with developmental delay, hearing loss, brain malformations, skeletal abnormalities, and another a 3 year old who passed away following a complex medical course including blue sclera, proximal tibial fracture, severe respiratory distress due to a chest infection, and acute kidney injury.

Amber given the variable phenotype findings of the reported patients and only 2 homozygous variants identified so far
Sources: Literature
Mendeliome v1.3362 PTBP1 Lucy Spencer changed review comment from: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss
variants also leading to increased protein stability.; to: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Variants a mix of missense and startloss, and were confirmed de novo in 23/17 cases.

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss
variants also leading to increased protein stability.
Mendeliome v1.3362 PTBP1 Lucy Spencer reviewed gene: PTBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40965981; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), PTBP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3362 PTBP2 Lucy Spencer gene: PTBP2 was added
gene: PTBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP2 were set to 40965981
Phenotypes for gene: PTBP2 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP2-related
Review for gene: PTBP2 was set to AMBER
Added comment: PMID: 40965981 2 males with developmental delay, ID, autistic features. 1 had some dysmorphic features and tonic-clonic seizures. both probands had a de novo variant in PTBP2 NM_021190.4:c.2T>C (p.Met1?) and NM_021190.4:c.41G>C (p.Arg14Thr), absent from gnomad. Transfection of the variants in transfection in NIH-3T3 cells showed the missense had cytoplasmic retention and colocalization with processing bodies, and that there were 2 alternative downstream start sites Met32 and Met35 that may be used instead.
Sources: Literature
Mendeliome v1.3362 GSTZ1 Lucy Spencer changed review comment from: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years.

PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development.

PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron.
Sources: Literature; to: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years.

PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development.

PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron. Val99Met has 1170 hets and 4 homs in gnomad, as this condition appears to be clinically benign this is not a concern.

Currently rated as moderate by ClinGen, the review does not include the most recent paper
Sources: Literature
Mendeliome v1.3362 GSTZ1 Lucy Spencer gene: GSTZ1 was added
gene: GSTZ1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GSTZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSTZ1 were set to 27876694; 38535121; 41009955
Phenotypes for gene: GSTZ1 were set to Maleylacetoacetate isomerase deficiency MIM#617596
Review for gene: GSTZ1 was set to GREEN
Added comment: PMID: 27876694 Six newborns with hypersuccinylacetonaemia but normal coagulation testing on initial evaluation. 4 probands homozygous for the recurrent variant c.449C>T (p.Ala150Val), 1 compound heterozygous for c.259C>T (p.Arg87Ter) and c.68-12G>A, and the last only had a single hit c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met showed reduced enzyme activity. Suggested to be a benign biochemical finding as in all patients clinical course has been normal for up to 13 years.

PMID: 38535121 proband with elevated succinylacetone in DBS on newborn screening. at 2 weeks old this had normalized but traces of succinylacetone were found in urine. Found to have a homozygous variant c.136−2A>G, the mother was heterozygous while the father was homozygous (variant has 2 hets no homs in gnomad). The father was 32yrs old with no medical complaints and a biochemical work up was normal. the proband had microcephaly and short stature but otherwise normal development.

PMID: 41009955 2 probands with elevated succinylacetone and normal tyrosine levels on NBS. Patient 1 compound heterozygous for c.68-12G>A and c.464_471delinsCTGGG (in frame), patient 2 compound heterozygous for c.68-12G>A and c.295G>A, p.(Val99Met). Patient 1 at 4 yrs of age had normal tyrosine, liver and kidney function tests, and regular development. patient 2 at 2yrs old had good clinical conditions, regular growth and development. RNA seq of the c.68-12G>A variant showed it lead to the out of frame 10bp retention of the intron.
Sources: Literature
Mendeliome v1.3362 ITGAV Zornitza Stark Phenotypes for gene: ITGAV were changed from Syndromic disease, MONDO:0002254, ITGAV-related to Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Mendeliome v1.3361 ITGAV Zornitza Stark Classified gene: ITGAV as Green List (high evidence)
Mendeliome v1.3361 ITGAV Zornitza Stark Gene: itgav has been classified as Green List (High Evidence).
Mendeliome v1.3360 ITGAV Zornitza Stark edited their review of gene: ITGAV: Changed phenotypes: Neurodevelopmental disorder with speech delay and behavioural abnormalities, MIM# 621372
Mendeliome v1.3360 ITGAV Zornitza Stark edited their review of gene: ITGAV: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Mendeliome v1.3360 UBR5 Zornitza Stark Phenotypes for gene: UBR5 were changed from Neurodevelopmental disorder MONDO:0700092, UBR5-related to Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372
Mendeliome v1.3359 UBR5 Zornitza Stark reviewed gene: UBR5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech delay and behavioral abnormalities, MIM# 621372; Mode of inheritance: None
Mendeliome v1.3359 CDK9 Bryony Thompson Classified gene: CDK9 as Green List (high evidence)
Mendeliome v1.3359 CDK9 Bryony Thompson Gene: cdk9 has been classified as Green List (High Evidence).
Mendeliome v1.3358 CDK9 Bryony Thompson gene: CDK9 was added
gene: CDK9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 40954203; 33640901; 30237576; 26633546
Phenotypes for gene: CDK9 were set to multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome MONDO:0015160; CHARGE-like syndrome with retinal dystrophy
Review for gene: CDK9 was set to GREEN
Added comment: Biallelic variants in at least six unrelated families:
1) proband that displays retinal dystrophy without a CHARGE-like malformation syndrome (c.862G>A/p.A288T + c.961C>T/p.P321S).
2) A boy with a phenotype resembling CHARGE syndrome (multiple anomalies involving the eyes, ears, cleft lip, and palate, and intellectual disability) with retinal dystrophy (p.A288T/p.R303C),
3-7) 4 consanguineous families homozygous for p.R225C, including a set of cousins.
CDK9 variants demonstrated decreased kinase activity. One of the studies suggested the extent the kinase activity is reduced may account for the absence/presence of the CHARGE-like phenotype with retinal dystrophy
Sources: Literature
Mendeliome v1.3357 DNMT1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNMT1.
Source ClinGen was added to DNMT1.
Source Literature was added to DNMT1.
Phenotypes for gene: DNMT1 were changed from Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, 604121; Neuropathy, hereditary sensory, type IE, 614116 to Hereditary sensory neuropathy-deafness-dementia syndrome, MONDO:0013584
Publications for gene DNMT1 were changed from 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424 to 22328086, 23904686, 24727570, 25678562, 23521649, 23365052, 21532572, 27602171, 25033457, 31984424
Mendeliome v1.3356 DNM1L Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1L.
Source Literature was added to DNM1L.
Source ClinGen was added to DNM1L.
Phenotypes for gene: DNM1L were changed from Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 - MIM#614388 (AD, AR); Optic atrophy 5 - MIM#610708 (AD) to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MONDO:0013726; Optic atrophy 5 - MIM#610708 (AD)
Publications for gene DNM1L were changed from 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748, 28969390, 30850373, 17460227 to 31587467, 27145208, 26604000, 27301544, 26931468, 33718295, 30109270, 26825290, 27328748, 28969390, 30850373, 17460227
Mendeliome v1.3355 DES Chirag Patel Source Victorian Clinical Genetics Services was removed from DES.
Source ClinGen was added to DES.
Source Literature was added to DES.
Phenotypes for gene: DES were changed from Cardiomyopathy, dilated, 1I, MIM# 604765; Myopathy, myofibrillar, 1 , MIM#601419; Arrhythmogenic right ventricular cardiomyopathy to Cardiomyopathy, dilated, 1I, MIM# 604765; Myofibrillar myopathy 1, MONDO:0011076; Arrhythmogenic right ventricular cardiomyopathy, MONDO:0016587
Publications for gene DES were changed from 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 19879535, 33947203, 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 22395865, 20718792 to 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 19879535, 33947203, 19879535, 20423733, 23168288, 20829228, 22403400, 29212896, 22395865, 20718792
Mendeliome v1.3354 DAAM2 Chirag Patel Publications for gene DAAM2 were changed from 33232676; 38860410; 36972684 to 33232676; 38860410; 36972684
Mendeliome v1.3353 FAP Sangavi Sivagnanasundram gene: FAP was added
gene: FAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FAP were set to 40949908
Phenotypes for gene: FAP were set to congenital pulmonary airway malformation MONDO:0016580
Review for gene: FAP was set to RED
Added comment: Only 1 reported fetus with a diagnosis of congenital pulmonary airway malformation
Heterozygous variant identified - c.T269G:p.L90W.
The variant is present in gnomAD v4.1 - EAS AF - 0.007% (4 hets)
Sources: Literature
Mendeliome v1.3353 PDIA6 Sarah Milton edited their review of gene: PDIA6: Changed phenotypes: multiple congenital anomalies, MONDO:0019042, PDIA6-related
Mendeliome v1.3353 SF1 Sarah Milton changed review comment from: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
Variant types included missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature; to: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
12 confirmed to have de novo variants including missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature
Mendeliome v1.3353 SF1 Sarah Milton gene: SF1 was added
gene: SF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF1 were set to PMID: 40987292
Phenotypes for gene: SF1 were set to Neurodevelopmental disorder, MONDO:0700092, SF1-related
Review for gene: SF1 was set to GREEN
Added comment: SF1 is involved in the first step of spliceosome complex assembly by recognizing the intron branchpoint consensus sequence at the 3′ splice site of the pre-mRNA. It is also involved in regulating alternative splicing

PMID: 40987292 describes 15 affected individuals with a neurodevelopmental disorder with monoallelic variants in SF1. Affected individuals had developmental delay, mild to moderate ID, behavioural disorders, seizures (3/15), brachydactyly (5/15), nail hypoplasia (5/15).
Variant types included missense and high impact LOF (nonsense and frameshift).

Most variants were appropriately rare in gnomAD v4 however one reported variant had 9 hets.
pLI for SF1 is 1 with overall few LOF variants in gene.

Supportive functional studies reported in publication. SF1 deficient neural progenitor cells showed altered gene expression in genes involved in neuronal differentiation/synaptic transmission and axonal guidance.
Sources: Literature
Mendeliome v1.3353 DDR2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDR2.
Source Literature was added to DDR2.
Phenotypes for gene: DDR2 were changed from Spondylometaepiphyseal dysplasia, short limb-hand type, MIM#271665; Warburg-Cinotti syndrome, MIM# 618175 to Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, MONDO:0010077; Warburg-cinotti syndrome, MONDO:0032579
Publications for gene DDR2 were changed from 30449416, 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872 to 30449416, 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872
Mendeliome v1.3352 DEPDC5 Chirag Patel Source Victorian Clinical Genetics Services was removed from DEPDC5.
Source Literature was added to DEPDC5.
Publications for gene DEPDC5 were changed from 31444548; 23542697; 23542701; 36067010; 32848577 to 31444548; 23542697; 23542701; 36067010; 32848577
Mendeliome v1.3351 DHDDS Chirag Patel Source Victorian Clinical Genetics Services was removed from DHDDS.
Source Literature was added to DHDDS.
Publications for gene DHDDS were changed from 27343064, 21295283, 28130426, 29276052, 32483926, 36046393, 24078709, 28005406, 36046393, 29100083, 36628425, 34382076 to 27343064, 21295283, 28130426, 29276052, 32483926, 36046393, 24078709, 28005406, 36046393, 29100083, 36628425, 34382076
Mendeliome v1.3350 DHTKD1 Chirag Patel Classified gene: DHTKD1 as Green List (high evidence)
Mendeliome v1.3350 DHTKD1 Chirag Patel Gene: dhtkd1 has been classified as Green List (High Evidence).
Mendeliome v1.3349 DHTKD1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DHTKD1.
Source Victorian Clinical Genetics Services was removed from DHTKD1.
Source ClinGen was added to DHTKD1.
Phenotypes for gene: DHTKD1 were changed from Alpha-aminoadipic and alpha-ketoadipic aciduria MIM#204750, AR; Charcot-Marie-Tooth disease, axonal, type 2Q, MIM#615025 to 2-aminoadipic 2-oxoadipic aciduria MONDO:0008774; Charcot-Marie-Tooth disease axonal type 2Q MONDO:0014012
Publications for gene DHTKD1 were changed from 26141459, 25860818, 23141293, 23141294, 29661920, 28902413 to 26141459, 25860818, 23141293, 23141294, 29661920, 28902413
Rating Changed from Green List (high evidence) to Red List (low evidence)
Mendeliome v1.3348 DHX37 Chirag Patel Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS); Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731 to 46,XY sex reversal 11, MONDO:8000015; Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Publications for gene DHX37 were changed from 31337883; 31745530; 31287541; 26539891; 31256877 to 31337883; 31745530; 31287541; 26539891; 31256877
Mendeliome v1.3347 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26912466; 24781755; 26463574; 33662367; 36212620; 39076976; 39120629 to 27808407; 28003573; 28815995; 26912466; 24781755; 26463574; 33662367; 36212620; 39076976; 39120629
Mendeliome v1.3346 ZSWIM7 Sangavi Sivagnanasundram changed review comment from: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature; to: Established gene-disease association. Biallelic variants reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature
Mendeliome v1.3346 ZSWIM7 Sangavi Sivagnanasundram gene: ZSWIM7 was added
gene: ZSWIM7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZSWIM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZSWIM7 were set to 32719396, 33713115, 40991243, 40991243
Phenotypes for gene: ZSWIM7 were set to Spermatogenic failure 71 MONDO:0030787; Ovarian dysgenesis 10 MONDO:0030736
Review for gene: ZSWIM7 was set to GREEN
Added comment: Established gene-disease association. Reported in unrelated individuals with either azoospermia or primary ovarian insufficiency

Spermatogenic failure:

PMID: 32719396
Homozygous males presenting with non-obstructive azoospermia
c.201+1G>T - absent from gnomAD v4.1
c.231_232del;p.(Cys78Phefs*21) - FAF 0.04%

PMID: 33713115 - 2 unrelated Chinese males with non-obstructive azoospermia from consanguineous families presented with homozygous c.231_232del;p.(Cys78Phefs*21)
CRISPR/Cas9 mouse model showed that in the mutant mice had smaller testes compared to their control littermates and no sperm in histological analysis recapitulating spermatogenic arrest.

Primary ovarian insufficiency (POI):

PMID: 40991243
Four french individuals with a diagnosis of premature ovarian insufficiency (POI) identified with variants in ZSWIM7

Patient 1: Homozygous deletion c.231_232del
Patient 2: Compound het c.231_232del;c.22del (p.Val8LeufsTer6)
Patient 3: Compound het c.231_232del; c.151C>T (NFE AF 0.002%)
Paitent 4: Homozygous c.176C>T p.(Arg51Ter)

PMID: 40991243
Two sisters from a consanguineous pedigree presented in adolescence with absent puberty and primary amenorrhea
Both sisters homozygous for c.173G>C and unaffected mother heterozygous for the variant
Sources: Literature
Mendeliome v1.3346 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26912466; 24781755; 26463574 to 27808407; 28003573; 28815995; 26912466; 24781755; 26463574
Mendeliome v1.3345 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26463574; 26912466; 24781755 to 27808407; 28003573; 28815995; 26463574; 26912466; 24781755
Mendeliome v1.3344 DIAPH1 Chirag Patel Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26463574; 24781755 to 27808407; 28003573; 28815995; 26463574; 24781755
Mendeliome v1.3343 DIAPH1 Chirag Patel Phenotypes for gene: DIAPH1 were changed from DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714
Publications for gene DIAPH1 were changed from 24781755; 24781755; 27808407; 28003573; 28815995; 26463574 to 24781755; 24781755; 27808407; 28003573; 28815995; 26463574
Mendeliome v1.3342 DIAPH1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DIAPH1.
Source Literature was added to DIAPH1.
Phenotypes for gene: DIAPH1 were changed from Deafness; thrombocytopenia 124900; Seizures; cortical blindness; microcephaly 616632 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635
Mendeliome v1.3341 PDIA6 Sarah Milton reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40974269, 35856135, 33495992; Phenotypes: Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes and polycystic kidney disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3341 DLX3 Chirag Patel reviewed gene: DLX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15666299, 9467018, 18203197, 9783705, 10466415, 9467018; Phenotypes: Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093, Tricho-dento-osseous syndrome, MONDO:0008592; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3341 DLX3 Chirag Patel Phenotypes for gene: DLX3 were changed from Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093 to Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093; Tricho-dento-osseous syndrome, MONDO:0008592
Publications for gene DLX3 were changed from 15666299, 9467018, 18203197, 9783705, 10466415, 9467018 to 15666299, 9467018, 18203197, 9783705, 10466415, 9467018
Mendeliome v1.3340 DLX3 Chirag Patel Classified gene: DLX3 as Green List (high evidence)
Mendeliome v1.3340 DLX3 Chirag Patel Gene: dlx3 has been classified as Green List (High Evidence).
Mendeliome v1.3339 DLX3 Chirag Patel Source Victorian Clinical Genetics Services was removed from DLX3.
Source Literature was added to DLX3.
Phenotypes for gene: DLX3 were changed from Amelogenesis imperfecta, type IV, MIM# 104510; Trichodontoosseous syndrome, MIM# 190320 to Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism, MONDO:0007093
Publications for gene DLX3 were changed from 9467018; 15666299 to 9467018; 15666299
Rating Changed from Green List (high evidence) to Red List (low evidence)
Mendeliome v1.3338 RNF31 Zornitza Stark Marked gene: RNF31 as ready
Mendeliome v1.3338 RNF31 Zornitza Stark Added comment: Comment when marking as ready: Alias: HOIP
Mendeliome v1.3338 RNF31 Zornitza Stark Gene: rnf31 has been classified as Green List (High Evidence).
Mendeliome v1.3338 LEO1 Chirag Patel Classified gene: LEO1 as Green List (high evidence)
Mendeliome v1.3338 LEO1 Chirag Patel Gene: leo1 has been classified as Green List (High Evidence).
Mendeliome v1.3337 LEO1 Chirag Patel reviewed gene: LEO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40993282, 33004838, 31785789, 40671880, 29674594; Phenotypes: Neurodevelopmental disorder MONDO:0700092, LEO-1 related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3337 MDC1 Zornitza Stark Marked gene: MDC1 as ready
Mendeliome v1.3337 MDC1 Zornitza Stark Gene: mdc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3337 MDC1 Zornitza Stark Publications for gene: MDC1 were set to PMID: 40954969, 34089056
Mendeliome v1.3336 MDC1 Zornitza Stark Classified gene: MDC1 as Amber List (moderate evidence)
Mendeliome v1.3336 MDC1 Zornitza Stark Gene: mdc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3335 SYNE2 Zornitza Stark Phenotypes for gene: SYNE2 were changed from Emery-Dreifuss muscular dystrophy 5, autosomal dominant MIM#612999 to Emery-Dreifuss muscular dystrophy 5, autosomal dominant MIM#612999; Neurodevelopmental disorder, MONDO:0700092, SYNE2 related
Mendeliome v1.3334 SYNE2 Zornitza Stark Publications for gene: SYNE2 were set to 32184094; 17761684; 40757551
Mendeliome v1.3333 SYNE2 Zornitza Stark Mode of inheritance for gene: SYNE2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3332 KLK15 Sangavi Sivagnanasundram gene: KLK15 was added
gene: KLK15 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KLK15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLK15 were set to 40949095
Phenotypes for gene: KLK15 were set to hypermobile Ehlers-Danlos syndrome MONDO:0007523
Review for gene: KLK15 was set to AMBER
Added comment: Two unrelated families with individuals affected with hEDS
Heterozygous p.Gly226Asp was identified in both families and segregated with disease across other affected individuals and not presented in unaffected family members.
Note: p.Gly226Asp - FAF 0.4970% in gnomAD v4.1

CRISPR-Cas9-generated Klk15G224D/+ knock in mouse model showed a decrease in tendon elasicity, mitral valve prolapse, collagen fibril thinning which is supportive to show the mouse model recapitulated human phenotype.

More evidence is required to support gene-disease association given only one variant in two families and supportive mouse model have been reported.
Sources: Other
Mendeliome v1.3332 CNTD2 Zornitza Stark Marked gene: CNTD2 as ready
Mendeliome v1.3332 CNTD2 Zornitza Stark Gene: cntd2 has been classified as Green List (High Evidence).
Mendeliome v1.3332 CNTD2 Zornitza Stark Classified gene: CNTD2 as Green List (high evidence)
Mendeliome v1.3332 CNTD2 Zornitza Stark Gene: cntd2 has been classified as Green List (High Evidence).
Mendeliome v1.3331 CNTD2 Zornitza Stark Tag new gene name tag was added to gene: CNTD2.
Mendeliome v1.3331 CLIC5 Chirag Patel Classified gene: CLIC5 as Green List (high evidence)
Mendeliome v1.3331 CLIC5 Chirag Patel Gene: clic5 has been classified as Green List (High Evidence).
Mendeliome v1.3330 CLIC5 Chirag Patel reviewed gene: CLIC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40957967, 40928595, 33114113; Phenotypes: Autosomal recessive nonsyndromic hearing loss 103, MONDO:0014469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3330 CLIC5 Chirag Patel Source Victorian Clinical Genetics Services was removed from CLIC5.
Source Literature was added to CLIC5.
Phenotypes for gene: CLIC5 were changed from Deafness, autosomal recessive 103, MIM# 616042 to Autosomal recessive nonsyndromic hearing loss 103, MONDO:0014469
Mendeliome v1.3329 CNTD2 Sangavi Sivagnanasundram gene: CNTD2 was added
gene: CNTD2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CNTD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTD2 were set to 41005306
Phenotypes for gene: CNTD2 were set to Oocyte/zygote/embryo maturation arrest MONDO:0014769
Review for gene: CNTD2 was set to GREEN
Added comment: HGNC approved new gene name: CCNP

3 unrelated women presenting with primary infertility and oocyte/embryo defects in IVF.
Different biallelic variants were identified - all variants were either absent or rare enough in gnomAD v4.1 for AR gene (p.L59Wfs*11, p.Y231N, and c.358-1G>A).

In vivo mouse model showed that the overexpression of mutant CNTD2 mRNA in mouse zygotes led to early embryonic arrest.
Sources: Other
Mendeliome v1.3329 SYNE2 Chirag Patel reviewed gene: SYNE2: Rating: RED; Mode of pathogenicity: None; Publications: 34573277; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SYNE2 related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3329 INTS6 Zornitza Stark Phenotypes for gene: INTS6 were changed from to Neurodevelopmental disorder, MONDO:0700092, INTS6-related
Mendeliome v1.3328 INTS6 Zornitza Stark Mode of inheritance for gene: INTS6 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3327 INTS6 Zornitza Stark Classified gene: INTS6 as Green List (high evidence)
Mendeliome v1.3327 INTS6 Zornitza Stark Gene: ints6 has been classified as Green List (High Evidence).
Mendeliome v1.3326 CCDC188 Zornitza Stark Marked gene: CCDC188 as ready
Mendeliome v1.3326 CCDC188 Zornitza Stark Gene: ccdc188 has been classified as Green List (High Evidence).
Mendeliome v1.3326 CCDC188 Zornitza Stark Classified gene: CCDC188 as Green List (high evidence)
Mendeliome v1.3326 CCDC188 Zornitza Stark Gene: ccdc188 has been classified as Green List (High Evidence).
Mendeliome v1.3325 SPDYC Zornitza Stark Marked gene: SPDYC as ready
Mendeliome v1.3325 SPDYC Zornitza Stark Gene: spdyc has been classified as Green List (High Evidence).
Mendeliome v1.3325 PCDHA13 Zornitza Stark Marked gene: PCDHA13 as ready
Mendeliome v1.3325 PCDHA13 Zornitza Stark Gene: pcdha13 has been classified as Red List (Low Evidence).
Mendeliome v1.3325 PCDHA13 Chirag Patel gene: PCDHA13 was added
gene: PCDHA13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCDHA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCDHA13 were set to 40988636
Phenotypes for gene: PCDHA13 were set to Hypoplastic left heart syndrome, MONDO:0004933
Review for gene: PCDHA13 was set to RED
Added comment: WES in 68 subjects with HLHS identified 1 individual with co-occurrence (i.e. digenic) of a SAP130 gene variant (p. S639G) and PCDHA13 gene variant (p. A22V). GnomAD frequencies for variants are: 0.00003% (PCDHA13 variant) and 0.01% with numerous homozygotes (SAP130 variant). The PCDHA13 variant is situated in a region highly conserved across the PCDHA gene family (which is highly homologous), especially PCDHA10 which is the ortholog of mouse Pcdha9.

Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, and Pcdha9 increases penetrance of aortic valve abnormalities. Mutations in Sap130 and Pcdha9 were validated by CRISPR–Cas9 genome editing in mice as being digenic causes of HLHS.
Sources: Literature
Mendeliome v1.3324 SPDYC Chirag Patel Classified gene: SPDYC as Green List (high evidence)
Mendeliome v1.3324 SPDYC Chirag Patel Gene: spdyc has been classified as Green List (High Evidence).
Mendeliome v1.3323 SPDYC Chirag Patel gene: SPDYC was added
gene: SPDYC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPDYC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPDYC were set to 41005306
Phenotypes for gene: SPDYC were set to Primary ovarian failure, MONDO:0005387
Review for gene: SPDYC was set to GREEN
Added comment: 4 unrelated female patients with primary infertility caused by oocyte/embryo defects, from a large cohort of 3,627 patients. WES identified rare biallelic variants in SPDYC gene (p.R52Vfs∗50, p.R188C, p.P287H). Overexpression of mutant SPDYC mRNA in mouse oocytes caused disruption of the ability of the protein to overcome milrinone-mediated inhibition of meiotic resumption with two of the variants (p.R52Vfs∗50 and p.R188C). SPDYC is involved in crucial processes involving cyclin-dependent kinases during the phase transition of the mitotic cell cycle.
Sources: Literature
Mendeliome v1.3322 CCDC188 Chirag Patel gene: CCDC188 was added
gene: CCDC188 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC188 were set to 41004021
Phenotypes for gene: CCDC188 were set to Male infertility due to acephalic spermatozoa, MONDO:0035153
Review for gene: CCDC188 was set to GREEN
Added comment: 2 patients from 2 unrelated families with acephalic spermatozoa syndrome. WES identified biallelic variants in CCDC188 gene (1 x homozygous, 1 x compound heterozygous). The variants (c.481C > T [p.Gln161*] and c.1022 + 1G > A [p. K325Afs*110]) were rare in gnomAD and segregated in the family with heterozygous carrier parents. Western blotting, RT-PCR, qPCR, and immunofluorescence showed depletion of CCDC188 protein (and SUN5 and PMFBP1 protein) in patient sperm. Mutations in SUN5 and PMFBP1 genes account for 75% patients with acephalic spermatozoa syndrome.
Sources: Literature
Mendeliome v1.3322 CCDC188 Chirag Patel gene: CCDC188 was added
gene: CCDC188 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC188 were set to 41004021
Phenotypes for gene: CCDC188 were set to Male infertility due to acephalic spermatozoa, MONDO:0035153
Review for gene: CCDC188 was set to GREEN
Added comment: 2 patients from 2 unrelated families with acephalic spermatozoa syndrome. WES identified biallelic variants in CCDC188 gene (1 x homozygous, 1 x compound heterozygous). The variants (c.481C > T [p.Gln161*] and c.1022 + 1G > A [p. K325Afs*110]) were rare in gnomAD and segregated in the family with heterozygous carrier parents. Western blotting, RT-PCR, qPCR, and immunofluorescence showed depletion of CCDC188 protein (and SUN5 and PMFBP1 protein) in patient sperm. Mutations in SUN5 and PMFBP1 genes account for 75% patients with acephalic spermatozoa syndrome.
Sources: Literature
Mendeliome v1.3321 INTS6 Sarah Milton changed review comment from: INTS6 encodes a member of the integrator complex which plays a role in RNA polymerase II transcription termination and small nuclear RNA processing.

PMID: 40966122 describes 24 affected individuals from 23 families with a variable neurodevelopmental disorder. Variant types included monoallelic missense, nonsense, frameshift and splice site.
Phenotypes included autism, variable language and motor delay, variable ID/developmental delay, sleep disturbances and epilepsy in a small subset.

21 variants were confirmed to be de novo.
All variants either absent in gnomad v4 or had 1 heterozygote only.
pLI for INTS6 is 1 and few overall LOF variants in gnomAD v4 in gene.

Supportive functional studies including biallelic knockout mice demonstrating abnormal brain morphology. Heterozygous knockout mice assessed to have abnormal behaviour and reduced learning efficiency and memory retention. Some variant specific studies performed consistent with loss of function mechanism.; to: INTS6 encodes a member of the integrator complex which plays a role in RNA polymerase II transcription termination and small nuclear RNA processing.

PMID: 40966122 describes 24 affected individuals from 23 families with a neurodevelopmental disorder. Variant types included monoallelic missense, nonsense, frameshift and splice site.
Phenotypes included autism, variable language and motor delay, variable ID/developmental delay, sleep disturbances and epilepsy in a small subset.

21 variants were confirmed to be de novo.
All variants either absent in gnomad v4 or had 1 heterozygote only.
pLI for INTS6 is 1 and few overall LOF variants in gnomAD v4 in gene.

Supportive functional studies including biallelic knockout mice demonstrating abnormal brain morphology. Heterozygous knockout mice assessed to have abnormal behaviour and reduced learning efficiency and memory retention. Some variant specific studies performed consistent with loss of function mechanism.
Mendeliome v1.3321 INTS6 Sarah Milton reviewed gene: INTS6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40966122; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, INTS6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3321 TH Zornitza Stark Marked gene: TH as ready
Mendeliome v1.3321 TH Zornitza Stark Gene: th has been classified as Green List (High Evidence).
Mendeliome v1.3321 TH Zornitza Stark Classified gene: TH as Green List (high evidence)
Mendeliome v1.3321 TH Zornitza Stark Gene: th has been classified as Green List (High Evidence).
Mendeliome v1.3320 TH Zornitza Stark changed review comment from: Well established association with infantile onset DOPA-reponsive dystonia.
Sources: Literature; to: Well established association with infantile onset DOPA-responsive dystonia.
Sources: Literature
Mendeliome v1.3320 TH Zornitza Stark gene: TH was added
gene: TH was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TH were set to Segawa syndrome, recessive MIM#605407
Review for gene: TH was set to GREEN
Added comment: Well established association with infantile onset DOPA-reponsive dystonia.
Sources: Literature
Mendeliome v1.3319 TCIRG1 Zornitza Stark Phenotypes for gene: TCIRG1 were changed from Osteopetrosis, autosomal recessive 1, MIM# 259700 to Osteopetrosis, autosomal recessive 1, MIM# 259700; severe congenital neutropenia, MONDO:0018542, TCIRG1-related
Mendeliome v1.3318 TCIRG1 Zornitza Stark Publications for gene: TCIRG1 were set to 34624559; 34210262; 30084437; 28816234
Mendeliome v1.3317 TCIRG1 Zornitza Stark Mode of inheritance for gene: TCIRG1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3316 TCIRG1 Zornitza Stark edited their review of gene: TCIRG1: Added comment: PMID: 40964614, now total of 6 families with neutropenia and supportive functional data, upgrade mono-allelic association to Green.; Changed publications: 34624559, 34210262, 30084437, 28816234, 40964614
Mendeliome v1.3316 MDC1 Sarah Milton gene: MDC1 was added
gene: MDC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDC1 were set to PMID: 40954969, 34089056
Phenotypes for gene: MDC1 were set to Oligoasthenoteratozoospermia, MONDO:0850098, MDC1-related
Review for gene: MDC1 was set to AMBER
Added comment: MDC1 encodes mediator of DNA damage checkpoint I protein.

PMID: 40954969 describes 2 affected individuals with biallelic loss of function (nonsense and start loss) variants in MDC1 with reduced sperm count, abnormal morphology and poor motility. 1 family consanguineous.
PMID: 34089056 describes 1 similarly affected individual with 2 loss of function variants not confirmed in trans.
All adequately rare in gnomad v4.
No homozygous NMD predicted variants in gnomad v4.

Knockout mice models show meiotic arrest in spermatocytes which subsequently undergo apoptosis.

Functional studies performed in PMID:40954969 showed lack of protein in affected patient cells and lack of colocalization usual partner protein. Didn't demonstrate conclusively loss of downstream function.
Sources: Literature
Mendeliome v1.3316 SPAST Zornitza Stark Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant (MIM#182601), AD to Spastic paraplegia 4, autosomal dominant (MIM#182601), AD; Cerebral Palsy MONDO:0006497, SPAST-related, AR
Mendeliome v1.3315 SPAST Zornitza Stark Publications for gene: SPAST were set to 30476002; 30006150
Mendeliome v1.3314 SPAST Zornitza Stark Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3313 SPAST Zornitza Stark reviewed gene: SPAST: Rating: GREEN; Mode of pathogenicity: None; Publications: 41000004; Phenotypes: Cerebral Palsy MONDO:0006497, SPAST-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3313 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679; 40442284
Mendeliome v1.3312 RNU2-2P Zornitza Stark Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3311 RNU2-2P Zornitza Stark changed review comment from: PMID 40950445: reports bi-alleic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.; to: PMID 40950445: reports bi-allelic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.
Mendeliome v1.3311 RNU2-2P Zornitza Stark changed review comment from: PMID 40950445: reports bi-alleic cases. One variant frequently de novo in trans with inherited variant.; to: PMID 40950445: reports bi-alleic cases in a cohort of over 100 individuals. One variant frequently de novo in trans with inherited variant.
Mendeliome v1.3311 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Added comment: PMID 40950445: reports bi-alleic cases. One variant frequently de novo in trans with inherited variant.; Changed publications: 40210679, 40442284, 40950445; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3311 PKD1 Zornitza Stark Mode of inheritance for gene: PKD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3310 PKD1 Zornitza Stark edited their review of gene: PKD1: Added comment: Rare reports of bi-allelic disease presenting antenatally.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.3310 OSMR Zornitza Stark Phenotypes for gene: OSMR were changed from Amyloidosis, primary localized cutaneous, 1 - MIM#105250 to Amyloidosis, primary localized cutaneous, 1 - MIM#105250; Inborn error of immunity, MONDO:0003778, OSMR-related
Mendeliome v1.3309 OSMR Zornitza Stark Publications for gene: OSMR were set to 19375894; 19528426; 25054142; 20507362; 19690585
Mendeliome v1.3308 OSMR Zornitza Stark Mode of inheritance for gene: OSMR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3307 OSMR Zornitza Stark reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 40970115; Phenotypes: Inborn error of immunity, MONDO:0003778, OSMR-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3307 MAP3K1 Zornitza Stark Publications for gene: MAP3K1 were set to 21129722; 32986312
Mendeliome v1.3306 MAP3K1 Zornitza Stark commented on gene: MAP3K1: PMID 39062623: single family reported with deafness and homozygous missense, but two supportive mouse models. RED for this association and MOI.
Mendeliome v1.3306 ASXL3 Zornitza Stark Publications for gene: ASXL3 were set to 28100473; 27901041; 23383720
Mendeliome v1.3305 ASXL3 Zornitza Stark changed review comment from: PMID 32696347: two families with compound het variants and congenital heart disease, some functional data.; to: PMID 32696347: two families with compound het variants and congenital heart disease, some functional data. RED for this MOI and association.
Mendeliome v1.3305 ASXL3 Zornitza Stark edited their review of gene: ASXL3: Added comment: PMID 32696347: two families with compound het variants and congenital heart disease, some functional data.; Changed publications: 28100473, 27901041, 23383720, 32696347
Mendeliome v1.3305 MSTO1 Lucy Spencer reviewed gene: MSTO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3305 EMB Zornitza Stark Marked gene: EMB as ready
Mendeliome v1.3305 EMB Zornitza Stark Gene: emb has been classified as Red List (Low Evidence).
Mendeliome v1.3305 MRPS36 Zornitza Stark Marked gene: MRPS36 as ready
Mendeliome v1.3305 MRPS36 Zornitza Stark Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3305 MRPS36 Zornitza Stark Tag new gene name tag was added to gene: MRPS36.
Mendeliome v1.3305 MRC2 Krithika Murali Marked gene: MRC2 as ready
Mendeliome v1.3305 MRC2 Krithika Murali Gene: mrc2 has been classified as Red List (Low Evidence).
Mendeliome v1.3305 MRC2 Krithika Murali gene: MRC2 was added
gene: MRC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRC2 were set to PMID: 38953222
Phenotypes for gene: MRC2 were set to Wolff-Parkinson-White syndrome - MONDO:0008685, MRC2-related
Review for gene: MRC2 was set to RED
Added comment: PMID: 38953222 - Multiple indiviuals from 1 family with het MRC2 variant c.2969A>G; p.Glu990Gly and SVT or WPW reported. In vivo electrophysiological studies/optical mapping in knock-in mice with the E990G variant demonstrated higher incidence of inducible SVT and retrograde conduction through an accessory pathway. Studies in human cardiac fibroblasts revealed enhanced migration in Mrc2-knockdown cells.
Sources: Literature
Mendeliome v1.3304 EMB Krithika Murali gene: EMB was added
gene: EMB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EMB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMB were set to PMID: 40999499
Phenotypes for gene: EMB were set to Hirschsprung disease - MONDO:0018309, EMB-related
Added comment: Li et al 2025 report enrichment of rare EMB variants in a cohort of patients with Hirschsprung disease. No additional phenotypic or variant information provided. Various in vitro studies and zebrafish/knockout mouse model associate loss of EMB with HSCR phenotype.
Sources: Literature
Mendeliome v1.3303 MRPS36 Krithika Murali Classified gene: MRPS36 as Amber List (moderate evidence)
Mendeliome v1.3303 MRPS36 Krithika Murali Gene: mrps36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3302 MRPS36 Krithika Murali gene: MRPS36 was added
gene: MRPS36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS36 were set to PMID: 41018056; 38685873
Phenotypes for gene: MRPS36 were set to Leigh syndrome - MONDO:0009723, MRPS36/KGD4-related
Review for gene: MRPS36 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported with biallelic MRPS36 variants (current HGNC is KGD4). Gene encodes E4 subunit of OGDHC complex. Individuals present with a phenotype consistent with Leigh syndrome including seizures, hypotonia, dystonia, brain imaging anomalies, persistent lactic acidosis. Cardiomyopathy also reported.

Patient-derived fibroblast studies demonstrates reduced OGDHC enzymatic activity, however, this functional evidence is not gene or variant-specific.
Sources: Literature
Mendeliome v1.3301 CPD Sarah Milton changed review comment from: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature; to: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to assist in function of the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Mendeliome v1.3301 JPH2 Zornitza Stark Classified gene: JPH2 as Green List (high evidence)
Mendeliome v1.3301 JPH2 Zornitza Stark Gene: jph2 has been classified as Green List (High Evidence).
Mendeliome v1.3300 CPD Zornitza Stark Marked gene: CPD as ready
Mendeliome v1.3300 CPD Zornitza Stark Gene: cpd has been classified as Green List (High Evidence).
Mendeliome v1.3300 CPD Zornitza Stark Classified gene: CPD as Green List (high evidence)
Mendeliome v1.3300 CPD Zornitza Stark Gene: cpd has been classified as Green List (High Evidence).
Mendeliome v1.3299 THAP4 Zornitza Stark Marked gene: THAP4 as ready
Mendeliome v1.3299 THAP4 Zornitza Stark Gene: thap4 has been classified as Red List (Low Evidence).
Mendeliome v1.3299 THAP4 Zornitza Stark gene: THAP4 was added
gene: THAP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THAP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THAP4 were set to 40949908
Phenotypes for gene: THAP4 were set to Congenital pulmonary airway malformation, MONDO:0016580, THAP4-related
Review for gene: THAP4 was set to RED
Added comment: Single individual with a missense variant reported in a CPAM cohort.
Sources: Literature
Mendeliome v1.3298 ALDH1B1 Zornitza Stark Marked gene: ALDH1B1 as ready
Mendeliome v1.3298 ALDH1B1 Zornitza Stark Gene: aldh1b1 has been classified as Red List (Low Evidence).
Mendeliome v1.3298 ALDH1B1 Zornitza Stark gene: ALDH1B1 was added
gene: ALDH1B1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALDH1B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALDH1B1 were set to 40988636
Phenotypes for gene: ALDH1B1 were set to Congenital pulmonary airway malformation, MONDO:0016580, ALDH1B1-related
Review for gene: ALDH1B1 was set to RED
Added comment: Single individual with missense variant reported in a CPAM cohort.
Sources: Literature
Mendeliome v1.3297 MUC3A Zornitza Stark Marked gene: MUC3A as ready
Mendeliome v1.3297 MUC3A Zornitza Stark Gene: muc3a has been classified as Red List (Low Evidence).
Mendeliome v1.3297 MUC3A Zornitza Stark gene: MUC3A was added
gene: MUC3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MUC3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MUC3A were set to 40949908
Phenotypes for gene: MUC3A were set to Congenital pulmonary airway malformation, MONDO:0016580, MUC3A-related
Review for gene: MUC3A was set to RED
Added comment: Three individuals with LoF variants identified in a CPAM cohort. However, all three variants are present in gnomAD, one of them in over 1500 individuals.
Sources: Literature
Mendeliome v1.3296 GTF2I Zornitza Stark Marked gene: GTF2I as ready
Mendeliome v1.3296 GTF2I Zornitza Stark Gene: gtf2i has been classified as Green List (High Evidence).
Mendeliome v1.3296 DMRT2 Krithika Murali edited their review of gene: DMRT2: Added comment: PMID: 29681102 Bouman et al 2018 paper SH3PXD2B reviewed - not coding in canonical transcript, 4 homs in gnomAD v4. In summary, 2 unrelated individuals with severe skeletal dysplasia and other extra-skeletal features and one mouse model with severe skeletal dysplasia supporting Green classification.; Changed rating: GREEN
Mendeliome v1.3296 DMRT2 Krithika Murali changed review comment from: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature; to: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature
Mendeliome v1.3296 DMRT2 Krithika Murali Classified gene: DMRT2 as Green List (high evidence)
Mendeliome v1.3296 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Green List (High Evidence).
Mendeliome v1.3295 DMRT2 Krithika Murali changed review comment from: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Fran Ter Haar syndrome which is also known to have skeletal features. The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature; to: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature
Mendeliome v1.3295 DMRT2 Krithika Murali Phenotypes for gene: DMRT2 were changed from skeletal dysplasia MONDO:0018230; DMRT2-related to skeletal dysplasia MONDO:0018230,DMRT2-related
Mendeliome v1.3294 DMRT2 Krithika Murali Marked gene: DMRT2 as ready
Mendeliome v1.3294 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3294 DMRT2 Krithika Murali Classified gene: DMRT2 as Amber List (moderate evidence)
Mendeliome v1.3294 DMRT2 Krithika Murali Gene: dmrt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3293 DMRT2 Krithika Murali gene: DMRT2 was added
gene: DMRT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292
Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related
Review for gene: DMRT2 was set to AMBER
Added comment: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios.

PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Fran Ter Haar syndrome which is also known to have skeletal features. The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type.

PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency.

Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT.
Sources: Literature
Mendeliome v1.3292 GTF2I Zornitza Stark Classified gene: GTF2I as Green List (high evidence)
Mendeliome v1.3292 GTF2I Zornitza Stark Gene: gtf2i has been classified as Green List (High Evidence).
Mendeliome v1.3291 GTF2I Zornitza Stark gene: GTF2I was added
gene: GTF2I was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GTF2I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GTF2I were set to 40962490
Phenotypes for gene: GTF2I were set to Neurodevelopmental disorder MONDO:0700092, GTF2I-related
Review for gene: GTF2I was set to GREEN
Added comment: 7 individuals reported with de novo variants in this gene and a neurodevelopmental disorder. All but one of the variants are absent from gnomAD v4 (one het present for the indel variant).
Sources: Literature
Mendeliome v1.3290 BBOX1 Zornitza Stark Marked gene: BBOX1 as ready
Mendeliome v1.3290 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3290 BBOX1 Zornitza Stark Classified gene: BBOX1 as Amber List (moderate evidence)
Mendeliome v1.3290 BBOX1 Zornitza Stark Gene: bbox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3289 BBOX1 Zornitza Stark gene: BBOX1 was added
gene: BBOX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BBOX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BBOX1 were set to 41022783
Phenotypes for gene: BBOX1 were set to Carnitine deficiency, MONDO:0017716, BBOX1-related
Review for gene: BBOX1 was set to AMBER
Added comment: Three individuals from two unrelated families reported, presenting with myopathy, neurodevelopmental delay, and later-onset psychiatric manifestations. C. elegans knockout and patient-variant models show embryonic lethality rescued by L‑carnitine supplementation
Sources: Literature
Mendeliome v1.3288 CPD Sarah Milton changed review comment from: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature; to: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Mendeliome v1.3288 CPD Sarah Milton gene: CPD was added
gene: CPD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CPD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPD were set to PMID: 41026541
Phenotypes for gene: CPD were set to Nonsyndromic genetic hearing loss, MONDO:0019497, CPD-related
Review for gene: CPD was set to GREEN
Added comment: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Mendeliome v1.3288 JPH2 Melanie Marty reviewed gene: JPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30384889, 31227780, 32870709, 35838873, 32879264, 34036930, 23715556, 29540472, 35288587, 37461109, 30847666, 27471098, 23715556; Phenotypes: Cardiomyopathy, hypertrophic, MIM#613873, Cardiomyopathy, dilated, 2E, MIM# 619492; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3288 LEMD2 Bryony Thompson Classified gene: LEMD2 as Green List (high evidence)
Mendeliome v1.3288 LEMD2 Bryony Thompson Added comment: Comment on list classification: Biallelic cataract/cardiomyopathy association Amber & Monoallelic recurrent de novo progeroid syndrome association Green.
Mendeliome v1.3288 LEMD2 Bryony Thompson Gene: lemd2 has been classified as Green List (High Evidence).
Mendeliome v1.3287 LEMD2 Bryony Thompson reviewed gene: LEMD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38757373, 37867468, 30905398; Phenotypes: Marbach-Rustad progeroid syndrome MONDO:0859147; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3287 INPP4A Zornitza Stark Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Mendeliome v1.3286 INPP4A Zornitza Stark Phenotypes for gene: INPP4A were changed from Intellectual disability to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Mendeliome v1.3285 INPP4A Zornitza Stark edited their review of gene: INPP4A: Changed phenotypes: Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MIM# 621354
Mendeliome v1.3285 PLD4 Zornitza Stark Phenotypes for gene: PLD4 were changed from Systemic lupus erythematosus - MONDO:0007915, PLD4-related to Systemic lupus erythematosus 18, MIM# 621369
Mendeliome v1.3284 PLD4 Zornitza Stark reviewed gene: PLD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Systemic lupus erythematosus 18, MIM# 621369; Mode of inheritance: None
Mendeliome v1.3284 IL17RD Bryony Thompson Classified gene: IL17RD as Red List (low evidence)
Mendeliome v1.3284 IL17RD Bryony Thompson Gene: il17rd has been classified as Red List (Low Evidence).
Mendeliome v1.3283 RHOBTB2 Lucy Spencer reviewed gene: RHOBTB2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Complex neurodevelopmental disorder MONDO:0100038, RHOBTB2-related; Mode of inheritance: None
Mendeliome v1.3283 RHOB Lucy Spencer edited their review of gene: RHOB: Changed phenotypes: Cerebral palsy MONDO:0006497, RHOB-related
Mendeliome v1.3283 RHOB Lucy Spencer changed review comment from: Adding a MONDO term cerebral palsy MONDO:000649, RHOB-related; to: Adding a MONDO term cerebral palsy MONDO:0006497, RHOB-related
Mendeliome v1.3283 RHOB Lucy Spencer reviewed gene: RHOB: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral palsy MONDO:000649, RHOB-related; Mode of inheritance: None
Mendeliome v1.3283 RHBDF2 Lucy Spencer reviewed gene: RHBDF2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency disease MONDO:0021094, RHBDF2-related; Mode of inheritance: None
Mendeliome v1.3283 RHBDF1 Lucy Spencer reviewed gene: RHBDF1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Dilated cardiomyopathy MONDO:0005021, RHBDF1-related; Mode of inheritance: None
Mendeliome v1.3283 RGS9BP Lucy Spencer reviewed gene: RGS9BP: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Prolonged electroretinal response suppression 2 MIM#620344; Mode of inheritance: None
Mendeliome v1.3283 RGS9 Lucy Spencer reviewed gene: RGS9: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Prolonged electroretinal response suppression 1 MIM#608415; Mode of inheritance: None
Mendeliome v1.3283 RGS10 Lucy Spencer reviewed gene: RGS10: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency disease MONDO:0021094, RGS10-related; Mode of inheritance: None
Mendeliome v1.3283 RFXAP Lucy Spencer reviewed gene: RFXAP: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MHC class II deficiency 4 MIM#620817; Mode of inheritance: None
Mendeliome v1.3283 RFX5 Lucy Spencer reviewed gene: RFX5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MHC class II deficiency 5 MIM#620818, MHC class II deficiency 3 MIM#620816; Mode of inheritance: None
Mendeliome v1.3283 REV3L Lucy Spencer reviewed gene: REV3L: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Mobius syndrome MONDO:0008006, REV3L-related; Mode of inheritance: None
Mendeliome v1.3283 REN Lucy Spencer reviewed gene: REN: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Tubulointerstitial kidney disease, autosomal dominant, 4 MIM#613092; Mode of inheritance: None
Mendeliome v1.3283 RELA Lucy Spencer reviewed gene: RELA: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory disease, familial, Behcet-like-3 MIM#618287; Mode of inheritance: None
Mendeliome v1.3283 REEP2 Lucy Spencer reviewed gene: REEP2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 72B, autosomal recessive MIM#620606, Spastic paraplegia 72A, autosomal dominant MIM#615625; Mode of inheritance: None
Mendeliome v1.3283 RECQL4 Lucy Spencer reviewed gene: RECQL4: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RECON progeroid syndrome MONDO:0957266, RECQL4-related; Mode of inheritance: None
Mendeliome v1.3283 RECQL Lucy Spencer reviewed gene: RECQL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RECON progeroid syndrome MIM#620370; Mode of inheritance: None
Mendeliome v1.3283 RDH12 Lucy Spencer reviewed gene: RDH12: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RDH12-related recessive retinopathy MONDO:0800099, RDH12-related dominant retinopathy MONDO:0800100; Mode of inheritance: None
Mendeliome v1.3283 RCAN1 Lucy Spencer reviewed gene: RCAN1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Focal segmental glomerulosclerosis MONDO:0100313, RCAN1-related; Mode of inheritance: None
Mendeliome v1.3283 RC3H1 Lucy Spencer reviewed gene: RC3H1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation and systemic hyperinflammation syndrome MIM#618998, Inborn error of immunity, MONDO:0003778, RC3H1-related; Mode of inheritance: None
Mendeliome v1.3283 RBM7 Lucy Spencer reviewed gene: RBM7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy MONDO:0001516, RBM7-related; Mode of inheritance: None
Mendeliome v1.3283 REC8 Lucy Spencer reviewed gene: REC8: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian failure MONDO:0005387, REC8-related; Mode of inheritance: None
Mendeliome v1.3283 BCL11B Zornitza Stark Publications for gene: BCL11B were set to 29985992
Mendeliome v1.3282 ADGRV1 Zornitza Stark Phenotypes for gene: ADGRV1 were changed from Febrile seizures, familial, 4 MIM#604352; Usher syndrome, type 2C MIM#60547; Usher syndrome, type 2C, GPR98/PDZD7 digenic MIM#605472 to Epilepsy, MONDO:0005027, ADGRV1-related; Usher syndrome, type 2C MIM#60547; Usher syndrome, type 2C, GPR98/PDZD7 digenic MIM#605472
Mendeliome v1.3281 ADGRV1 Zornitza Stark Publications for gene: ADGRV1 were set to 22147658, 25572244, 14740321
Mendeliome v1.3280 ADGRV1 Zornitza Stark Mode of inheritance for gene: ADGRV1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3279 ADGRV1 Zornitza Stark reviewed gene: ADGRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29266188, 29261713, 32962041, 34160719, 40673693, 40217298, 36399868, 34744978; Phenotypes: Epilepsy, MONDO:0005027, ADGRV1-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3279 DNM1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM1.
Source Literature was added to DNM1.
Publications for gene DNM1 were changed from 25262651; 27066543; 33372033; 34172529; 36553519; 37900685 to 25262651; 27066543; 33372033; 34172529; 36553519; 37900685
Mendeliome v1.3278 B9D1 Zornitza Stark Phenotypes for gene: B9D1 were changed from Joubert syndrome 27, MIM#617120; Meckel syndrome 9, MIM#614209 to Ciliopathy, MONDO:0005308, B9D1-related
Mendeliome v1.3277 B9D1 Zornitza Stark Publications for gene: B9D1 were set to 24886560; 21493627; 25920555; 21763481; 34338422
Mendeliome v1.3276 RNF31 Zornitza Stark Publications for gene: RNF31 were set to 26008899; 30936877
Mendeliome v1.3275 RNF31 Zornitza Stark Classified gene: RNF31 as Green List (high evidence)
Mendeliome v1.3275 RNF31 Zornitza Stark Gene: rnf31 has been classified as Green List (High Evidence).
Mendeliome v1.3274 RNF31 Zornitza Stark edited their review of gene: RNF31: Added comment: Two more families reported.; Changed rating: GREEN; Changed publications: 26008899, 30936877, 39009172, 41026334
Mendeliome v1.3274 DNAJC5 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJC5.
Source Expert list was added to DNAJC5.
Phenotypes for gene: DNAJC5 were changed from Ceroid lipofuscinosis, neuronal, 4 (Kufs type), autosomal dominant - MIM#162350; ceroid lipofuscinosis, neuronal, 4 (Kufs type) - MONDO:0008083 to Ceroid lipofuscinosis, neuronal, 4 (Kufs type), MONDO:0008083
Mendeliome v1.3273 RASA2 Zornitza Stark Phenotypes for gene: RASA2 were changed from to Noonan syndrome MONDO:0018997, RASA2-related
Mendeliome v1.3272 RAP1A Zornitza Stark Phenotypes for gene: RAP1A were changed from Kabuki syndrome to Kabuki syndrome MONDO:0016512, RAP1A-related
Mendeliome v1.3271 RAMP2 Zornitza Stark Phenotypes for gene: RAMP2 were changed from Primary open angle glaucoma to Open angle glaucoma MONDO:0005338, RAMP2-related
Mendeliome v1.3270 DDB1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DDB1.
Source Literature was added to DDB1.
Phenotypes for gene: DDB1 were changed from White-Kernohan syndrome, MIM# 619426; Syndromic intellectual disability to White-Kernohan syndrome, MIM# 619426
Mendeliome v1.3270 RALGAPA1 Zornitza Stark Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797
Mendeliome v1.3269 RAG2 Zornitza Stark Phenotypes for gene: RAG2 were changed from Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457; Combined cellular and humoral immune defects with granulomas MIM# 233650 to Recombinase activating gene 2 deficiency MONDO:0000573
Mendeliome v1.3268 RAG1 Zornitza Stark Phenotypes for gene: RAG1 were changed from Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity MIM# 609889; Combined cellular and humoral immune defects with granulomas MIM# 233650; Omenn syndrome MIM# 603554; Severe combined immunodeficiency, B cell-negative MIM# 601457 to Recombinase activating gene 1 deficiency MONDO:0000572
Mendeliome v1.3267 DNM2 Chirag Patel Phenotypes for gene: DNM2 were changed from Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Centronuclear myopathy 1, MIM# 160150; Lethal congenital contracture syndrome 5, MIM# 615368 to Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Autosomal dominant centronuclear myopathy MONDO:0008048; Lethal congenital contracture syndrome 5, MIM# 615368
Mendeliome v1.3266 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Intellectual developmental disorder, autosomal dominant 48 MIM#617751
Mendeliome v1.3265 RABL2A Zornitza Stark Phenotypes for gene: RABL2A were changed from male infertility; ciliopathy to Infertility disorder, MONDO:0005047, RABL2A-related
Mendeliome v1.3264 RAB14 Zornitza Stark Phenotypes for gene: RAB14 were changed from Developmental disorders to Neurodevelopmental disorder MONDO:0700092, RAB14-related
Mendeliome v1.3263 DNM2 Chirag Patel Phenotypes for gene: DNM2 were changed from Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Lethal congenital contracture syndrome 5, MIM# 615368 to Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Centronuclear myopathy 1, MIM# 160150; Lethal congenital contracture syndrome 5, MIM# 615368
Mendeliome v1.3262 DNM2 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNM2.
Source Expert list was added to DNM2.
Phenotypes for gene: DNM2 were changed from Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674 to Charcot-Marie-Tooth disease, axonal type 2M, MIM# 606482; Charcot-Marie-Tooth disease, dominant intermediate B, MIM# 606482; MONDO:0011674; Lethal congenital contracture syndrome 5, MIM# 615368
Mendeliome v1.3261 PJA1 Zornitza Stark Phenotypes for gene: PJA1 were changed from Intellectual disability; trigonocephaly to X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148
Mendeliome v1.3260 NDE1 Zornitza Stark Phenotypes for gene: NDE1 were changed from Microhydranencephaly 605013; Lissencephaly 4 (with microcephaly) 614019 to Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116
Mendeliome v1.3259 DALRD3 Chirag Patel Phenotypes for gene: DALRD3 were changed from Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 86 618910 to Developmental and epileptic encephalopathy, 86 MONDO:0030054
Mendeliome v1.3258 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia to NEK9-related lethal skeletal dysplasia MONDO:0014870; Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia
Mendeliome v1.3257 DMGDH Chirag Patel Source Victorian Clinical Genetics Services was removed from DMGDH.
Source Expert list was added to DMGDH.
Phenotypes for gene: DMGDH were changed from Dimethylglycine dehydrogenase deficiency MIM#605850; Disorders and variants of other enzymes that oxidise xenobiotics to Dimethylglycine dehydrogenase deficiency MIM#605850
Mendeliome v1.3256 DMGDH Chirag Patel Classified gene: DMGDH as Red List (low evidence)
Mendeliome v1.3256 DMGDH Chirag Patel Gene: dmgdh has been classified as Red List (Low Evidence).
Mendeliome v1.3255 DMGDH Chirag Patel reviewed gene: DMGDH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dimethylglycine dehydrogenase deficiency MONDO:0011610; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3255 DAB1 Chirag Patel Source Victorian Clinical Genetics Services was removed from DAB1.
Phenotypes for gene: DAB1 were changed from Spinocerebellar ataxia 37 MIM#615945; Ataxia and intellectual disability to Spinocerebellar ataxia 37 MIM#615945; Neurodevelopmental disorder, MONDO:0700092, DAB1-related
Mendeliome v1.3254 DMC1 Chirag Patel Phenotypes for gene: DMC1 were changed from Primary ovarian failure, MONDO:0005387,; Azoospermia, MONDO:010045 to Primary ovarian failure, MONDO:0005387, Azoospermia, MONDO:0100459, DMC1-related
Publications for gene DMC1 were changed from 34794894, 18166824, 29331980, 9660954, 9660953 to 34794894, 18166824, 29331980, 9660954, 9660953
Mendeliome v1.3253 DNAJA1 Chirag Patel Phenotypes for gene: DNAJA1 were changed from Intellectual disability; seizures to Neurodevelopmental disorder, MONDO:0700092, DNAJA1-related
Mendeliome v1.3252 DMC1 Chirag Patel Phenotypes for gene: DMC1 were changed from Primary ovarian insufficiency; non-obstructive azoospermia to Primary ovarian failure, MONDO:0005387,; Azoospermia, MONDO:010045
Mendeliome v1.3251 DLK1 Chirag Patel Phenotypes for gene: DLK1 were changed from central precocious puberty to central precocious puberty, MONDO:0019165
Mendeliome v1.3250 DGCR8 Chirag Patel Phenotypes for gene: DGCR8 were changed from Schwannoma, MONDO:0002546 to Schwannoma, MONDO:0002546; Early-onset multinodular goiter and schwannomatosis, no MIM#
Mendeliome v1.3249 DGCR8 Chirag Patel reviewed gene: DGCR8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwannoma, MONDO:0002546, Early-onset multinodular goiter and schwannomatosis, no MIM#; Mode of inheritance: None
Mendeliome v1.3248 DGCR8 Chirag Patel Source Literature was removed from DGCR8.
Source Expert list was added to DGCR8.
Phenotypes for gene: DGCR8 were changed from Early-onset multinodular goiter and schwannomatosis to Schwannoma, MONDO:0002546
Mendeliome v1.3247 DHX34 Chirag Patel Phenotypes for gene: DHX34 were changed from Intellectual disability; congenital anomalies to Neurodevelopmental disorder, MONDO:0700092, DHX34-related
Mendeliome v1.3245 DLG1 Chirag Patel Phenotypes for gene: DLG1 were changed from Non-syndromic cleft lip and palate to cleft lip/palate MONDO:0016044
Mendeliome v1.3244 DNMBP Chirag Patel Phenotypes for gene: DNMBP were changed from congenital cataract to Cataract 48, MIM#618415
Mendeliome v1.3243 DNAJB11 Chirag Patel Source Victorian Clinical Genetics Services was removed from DNAJB11.
Source Expert list was added to DNAJB11.
Publications for gene DNAJB11 were changed from 29706351, 29777155, 32631624, 35664268, 32775842, 33129895, 34177435 to 29706351, 29777155, 32631624, 35664268, 32775842, 33129895, 34177435
Mendeliome v1.3242 ACTG1 Chirag Patel Source Victorian Clinical Genetics Services was removed from ACTG1.
Source Expert list was added to ACTG1.
Publications for gene ACTG1 were changed from PMID: 29620237, 22366783, 25052316, 28493397, 26188271, 27240540, 13680526, 14684684, 16773128, 19477959, 19497859 to PMID: 29620237, 22366783, 25052316, 28493397, 26188271, 27240540, 13680526, 14684684, 16773128, 19477959, 19497859
Mendeliome v1.3241 BCL11B Sarah Milton reviewed gene: BCL11B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40033098, 37860968, 37337996; Phenotypes: Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities, MONDO:0060763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3241 ADGRV1 Chirag Patel Source Victorian Clinical Genetics Services was removed from ADGRV1.
Source Expert list was added to ADGRV1.
Publications for gene ADGRV1 were changed from 22147658, 25572244, 14740321 to 22147658, 25572244, 14740321
Mendeliome v1.3240 AFP Chirag Patel Publications for gene AFP were changed from 15280901; 18854864, 14699509, 7684942 to 15280901; 18854864, 14699509, 7684942
Mendeliome v1.3239 AFP Chirag Patel Source Victorian Clinical Genetics Services was removed from AFP.
Source Literature was added to AFP.
Mode of inheritance for gene AFP was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3238 AFP Chirag Patel reviewed gene: AFP: Rating: AMBER; Mode of pathogenicity: None; Publications: PubMed: 14699509, 7684942; Phenotypes: [Hereditary persistence of alpha-fetoprotein] MIM#615970; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3238 B9D1 Sarah Milton reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40565534, 40933483; Phenotypes: Ciliopathy, MONDO:0005308, B9D1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3238 B9D1 Sarah Milton Deleted their review
Mendeliome v1.3238 B9D1 Sarah Milton reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40565534, 40933483; Phenotypes: Ciliopathy, MONDO:0005308, B9D1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3238 AKT2 Chirag Patel Source Victorian Clinical Genetics Services was removed from AKT2.
Source Literature was added to AKT2.
Phenotypes for gene: AKT2 were changed from Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; Hypoinsulinemic hypoglycemia with hemihypertrophy, OMIM:240900; Diabetes mellitus, type II , MIM#125853 to Hypoinsulinemic hypoglycemia and body hemihypertrophy, MONDO:0009416; AKT2-related familial partial lipodystrophy MONDO:0019192
Mendeliome v1.3237 ALG2 Chirag Patel Classified gene: ALG2 as Green List (high evidence)
Mendeliome v1.3237 ALG2 Chirag Patel Gene: alg2 has been classified as Green List (High Evidence).
Mendeliome v1.3236 ALG2 Chirag Patel reviewed gene: ALG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12684507, 34980536, 23404334, 30397276, 33644825; Phenotypes: Congenital disorder of glycosylation, type Ii, MIM# 607906; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3236 RASA2 Lucy Spencer reviewed gene: RASA2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome MONDO:0018997, RASA2-related; Mode of inheritance: None
Mendeliome v1.3236 RAP1A Lucy Spencer reviewed gene: RAP1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Kabuki syndrome MONDO:0016512, RAP1A-related; Mode of inheritance: None
Mendeliome v1.3236 RAMP2 Lucy Spencer reviewed gene: RAMP2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Open angle glaucoma MONDO:0005338, RAMP2-related; Mode of inheritance: None
Mendeliome v1.3236 RALGAPA1 Lucy Spencer reviewed gene: RALGAPA1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation MIM#618797; Mode of inheritance: None
Mendeliome v1.3236 RAG2 Lucy Spencer reviewed gene: RAG2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Recombinase activating gene 2 deficiency MONDO:0000573; Mode of inheritance: None
Mendeliome v1.3236 RAG1 Lucy Spencer reviewed gene: RAG1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Recombinase activating gene 1 deficiency MONDO:0000572; Mode of inheritance: None
Mendeliome v1.3236 RAC1 Lucy Spencer reviewed gene: RAC1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 48 MIM#617751; Mode of inheritance: None
Mendeliome v1.3236 RABL2A Lucy Spencer reviewed gene: RABL2A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Infertility disorder, MONDO:0005047, RABL2A-related; Mode of inheritance: None
Mendeliome v1.3236 RAB14 Lucy Spencer reviewed gene: RAB14: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, RAB14-related; Mode of inheritance: None
Mendeliome v1.3236 NDP Zornitza Stark Phenotypes for gene: NDP were changed from Exudative vitreoretinopathy 2, X-linked, MIM 305390; Norrie disease, MIM 310600 to Norrie disease MONDO:0010691; Exudative vitreoretinopathy 2, X-linked, MIM 305390; Norrie disease, MIM 310600
Mendeliome v1.3235 AP2S1 Zornitza Stark Phenotypes for gene: AP2S1 were changed from Hypocalciuric hypercalcaemia, type III, MIM# 600740; MONDO:0010926; Developmental disorder to Hypocalciuric hypercalcaemia, type III, MIM# 600740; MONDO:0010926; Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Mendeliome v1.3234 AP2S1 Zornitza Stark Publications for gene: AP2S1 were set to 33057194; 23222959; 33729479; 33168530; 3204769; 31723423; 29479578
Mendeliome v1.3233 AP2S1 Zornitza Stark edited their review of gene: AP2S1: Added comment: Association with NDD: Several isolated cases with de novo missense variants in large NDD cohorts PMID: 31981491;33057194;35982160;35982159.

26 unrelated NDD in a preprint with 5 recurring de novo missenses p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His https://doi.org/10.1101/2024.07.22.24310683. 70% had epilepsy, 50% brain anomalies.; Changed publications: 23222959, 33729479, 33168530, 3204769, 31723423, 29479578, 31981491, 33057194, 35982160, 35982159; Changed phenotypes: Hypocalciuric hypercalcaemia, type III, MIM# 600740, MONDO:0010926, Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Mendeliome v1.3232 GPHN Bryony Thompson Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, MIM# 615501; Epilepsy; Autism; Intellectual disability to sulfite oxidase deficiency due to molybdenum cofactor deficiency type C MONDO:0014212; complex neurodevelopmental disorder MONDO:0100038
Mendeliome v1.3231 GPHN Bryony Thompson Publications for gene: GPHN were set to 22040219; 11095995; 26613940; 24561070; 23393157; 27604308; 9812897
Mendeliome v1.3230 GPHN Bryony Thompson edited their review of gene: GPHN: Added comment: High evidence - AR Molybdenum cofactor deficiency C - PMID: 22040219, 11095995, 9812897, 34617111 - now 3 unrelated families and a mouse model. LoF is the mechanism of disease.

Amber - AD complex neurodevelopmental disorder - PMID: 26613940, 24561070, 23393157 - de novo missense and de novo/inherited deletions with supporting functional assays. However, incomplete penetrance has been reported for some of the CNVs.; Changed publications: 11095995, 22040219, 9812897, 34617111, 26613940, 24561070, 23393157; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3229 MT-ATP6 Zornitza Stark Publications for gene: MT-ATP6 were set to 40112238
Mendeliome v1.3228 MT-ATP6 Zornitza Stark edited their review of gene: MT-ATP6: Added comment: DEFINITIVE by ClinGen.; Changed publications: 40112238, 1550128, 8554662, 23206802, 1456751, 9270604, 9501263, 10604142, 17352390, 11245730, 16217706, 11731285, 27812026, 25037980, 19747204, 2137962
Mendeliome v1.3228 MT-TY Zornitza Stark Marked gene: MT-TY as ready
Mendeliome v1.3228 MT-TY Zornitza Stark Gene: mt-ty has been classified as Green List (High Evidence).
Mendeliome v1.3228 MT-TY Zornitza Stark Classified gene: MT-TY as Green List (high evidence)
Mendeliome v1.3228 MT-TY Zornitza Stark Gene: mt-ty has been classified as Green List (High Evidence).
Mendeliome v1.3227 MT-TY Zornitza Stark gene: MT-TY was added
gene: MT-TY was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TY.
Mode of inheritance for gene gene: MT-TY was set to MITOCHONDRIAL
Publications for gene: MT-TY were set to 11071502; 11756614; 11594340; 33279411; 30643656; 32684384; 32485333; 33279411
Phenotypes for gene: MT-TY were set to Mitochondrial disease (MONDO:0044970), MT-TY-related
Review for gene: MT-TY was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported. Age of onset in affected individuals is variable and clinical features seen include myopathy with or without ophthalmoplegia. There is at least one case report with a more severe phenotype with neuropathy, ataxia, seizures, myoclonus, sensorineural hearing loss, and pigmentary retinopathy. Muscle biopsy in affected individuals has shown COX-negative and ragged red fibers, with variable mitochondrial respiratory chain enzyme deficiencies. The variants in affected individuals are often present at highest heteroplasmy levels in muscle and may be undetectable in other tissues such as blood and buccal tissue. Multiple single fiber studies were performed in these patients and supportive of variant pathogenicity
Sources: Expert list
Mendeliome v1.3226 MT-TW Zornitza Stark Marked gene: MT-TW as ready
Mendeliome v1.3226 MT-TW Zornitza Stark Gene: mt-tw has been classified as Green List (High Evidence).
Mendeliome v1.3226 MT-TW Zornitza Stark Classified gene: MT-TW as Green List (high evidence)
Mendeliome v1.3226 MT-TW Zornitza Stark Gene: mt-tw has been classified as Green List (High Evidence).
Mendeliome v1.3225 MT-TW Zornitza Stark gene: MT-TW was added
gene: MT-TW was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TW.
Mode of inheritance for gene gene: MT-TW was set to MITOCHONDRIAL
Publications for gene: MT-TW were set to 7695240; 9266739; 9673981; 12776230; 15054399; 18337306; 19809478; 26524491; 23841600; 30937556
Phenotypes for gene: MT-TW were set to Mitochondrial disease (MONDO:0044970), MT-TW-related
Review for gene: MT-TW was set to GREEN
Added comment: DEFINITIVE by ClinGen.

At least 10 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, microcephaly, developmental delay and regression, cognitive decline, fatigue, seizures, ataxia, chorea, muscle wasting, axonal neuropathy, diabetes, liver steatosis and fibrosis, constipation, recurrent vomiting, failure to thrive, pigmentary retinopathy, ptosis, optic atrophy, ophthalmoplegia, sensorineural hearing loss, and hypertrophic and dilated cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS to generalized atrophy and white matter involvement.

Muscle biopsies showed ragged red fibers, COX-deficient fibers, and decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated blood and cerebrospinal fluid lactate. Heteroplasmy levels in affected individuals were highest in muscle and/or liver when multiple tissues were assessed (25 - >95 % in muscle, 1 to >95% in blood, >95% in liver, 1-92% in skin fibroblasts, and 5% in urine when assessed). Functional studies to support variant pathogenicity.
Sources: Expert list
Mendeliome v1.3224 MT-TV Zornitza Stark Marked gene: MT-TV as ready
Mendeliome v1.3224 MT-TV Zornitza Stark Gene: mt-tv has been classified as Green List (High Evidence).
Mendeliome v1.3224 MT-TV Zornitza Stark Classified gene: MT-TV as Green List (high evidence)
Mendeliome v1.3224 MT-TV Zornitza Stark Gene: mt-tv has been classified as Green List (High Evidence).
Mendeliome v1.3223 MT-TV Zornitza Stark gene: MT-TV was added
gene: MT-TV was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TV.
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Publications for gene: MT-TV were set to 9450773; 12056939; 19252805; 15320572; 18314141; 24691472
Phenotypes for gene: MT-TV were set to Mitochondrial disease (MONDO:0044970), MT-TV-related
Review for gene: MT-TV was set to GREEN
Added comment: DEFINITIVE by ClinGen.

At least 8 individuals reported. Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS, cognitive decline, fatigue, migraines, seizures, myoclonic jerks, ataxia, dystonia, dysarthria, imbalance, muscle weakness, axonal sensorimotor polyneuropathy, diabetes, gastrointestinal dysmotility, cataracts, retinitis pigmentosa, sensorineural hearing loss, and hypertrophic cardiomyopathy. Brain imaging was variable and ranged from normal to findings consistent with LSS, cerebellar and cerebral atrophy, brainstem atrophy, and basal ganglia calcifications. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and normal to decreased respiratory chain enzyme activities. Metabolic laboratory investigations revealed elevated lactate.

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (67% to homoplasmic in muscle, 70% to homoplasmic in blood, and homoplasmic in skin fibroblasts).
Sources: Expert list
Mendeliome v1.3222 MT-TT Zornitza Stark Marked gene: MT-TT as ready
Mendeliome v1.3222 MT-TT Zornitza Stark Gene: mt-tt has been classified as Green List (High Evidence).
Mendeliome v1.3222 MT-TT Zornitza Stark Classified gene: MT-TT as Green List (high evidence)
Mendeliome v1.3222 MT-TT Zornitza Stark Gene: mt-tt has been classified as Green List (High Evidence).
Mendeliome v1.3221 MT-TT Zornitza Stark gene: MT-TT was added
gene: MT-TT was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TT.
Mode of inheritance for gene gene: MT-TT was set to MITOCHONDRIAL
Publications for gene: MT-TT were set to 32083134; 8769114; 9367299; 1645537; 8511015; 22638997; 29760464; 30236074; 28187756; 35808913
Phenotypes for gene: MT-TT were set to Mitochondrial disease (MONDO:0044970), MT-TT-related
Review for gene: MT-TT was set to GREEN
Added comment: MODERATE by ClinGen.

At least 10 probands reported with 5 unique variants. Age of onset in affected individuals varied from the neonatal period to more than 50 years. Clinical features in affected individuals included neonatal lactic acidosis; myoclonic epilepsy and ragged red fibers (MERRF); Leber Hereditary Optic Neuropathy (LHON); myopathy, seizures, migraines, pigmentary retinopathy, hearing loss, and diabetes. Brain imaging findings were variable. Muscle biopsies showed ragged red fibers and COX-deficient fibers. Lab investigations showed elevated lactate. Heteroplasmy levels were highest in muscle when multiple tissues were assessed, and ranged from 33% to homoplasmy in muscle.
Sources: Expert list
Mendeliome v1.3220 MT-TS2 Zornitza Stark Marked gene: MT-TS2 as ready
Mendeliome v1.3220 MT-TS2 Zornitza Stark Gene: mt-ts2 has been classified as Green List (High Evidence).
Mendeliome v1.3220 MT-TS2 Zornitza Stark Classified gene: MT-TS2 as Green List (high evidence)
Mendeliome v1.3220 MT-TS2 Zornitza Stark Gene: mt-ts2 has been classified as Green List (High Evidence).
Mendeliome v1.3219 MT-TS2 Zornitza Stark gene: MT-TS2 was added
gene: MT-TS2 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TS2.
Mode of inheritance for gene gene: MT-TS2 was set to MITOCHONDRIAL
Publications for gene: MT-TS2 were set to 9792552; 10090882; 16950817; 21257182; 22369973; 22378285
Phenotypes for gene: MT-TS2 were set to Mitochondrial disease (MONDO:0044970), MT-TS2-related
Review for gene: MT-TS2 was set to GREEN
Added comment: MODERATE by ClinGen.

At least 7 individuals reported. Affected individuals had varying clinical features including cataracts, retinal dystrophy, hearing loss, myopathy, ataxia, seizures, global developmental delay, diabetes, Wolff-Parkinson-White arrhythmia, hypertrophic cardiomyopathy, and hypogonadotropic hypogonadism. Lab investigations revealed elevated blood lactate and elevated creatine kinase. Muscle biopsy, when performed, generally showed reduced activities of complexes I, I+III, III, and/or IV. Brain imaging was normal in some cases. In one individual brain imaging revealed changes in the basal ganglia and diffuse atrophy with an enlarged cisterna magna and in another showed changes in the cerebral white matter.

Heteroplasmy levels were variable – some individuals had the highest levels in muscle with the variant being undetectable in other tissues while others had the variant present at homoplasmy in multiple tissues. Northern blotting and single fiber testing further supported variant pathogenicity.
Sources: Expert list
Mendeliome v1.3218 MT-TS1 Zornitza Stark Marked gene: MT-TS1 as ready
Mendeliome v1.3218 MT-TS1 Zornitza Stark Gene: mt-ts1 has been classified as Green List (High Evidence).
Mendeliome v1.3218 MT-TS1 Zornitza Stark Classified gene: MT-TS1 as Green List (high evidence)
Mendeliome v1.3218 MT-TS1 Zornitza Stark Gene: mt-ts1 has been classified as Green List (High Evidence).
Mendeliome v1.3217 MT-TS1 Zornitza Stark gene: MT-TS1 was added
gene: MT-TS1 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TS1.
Mode of inheritance for gene gene: MT-TS1 was set to MITOCHONDRIAL
Publications for gene: MT-TS1 were set to 7669057; 9778262; 14605505; 23696415; 33279600; 7581383
Phenotypes for gene: MT-TS1 were set to Mitochondrial disease (MONDO:0044970), MT-TS1-related
Review for gene: MT-TS1 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

At least 8 individuals reported. Clinical features seen in affected individuals range from isolated hearing loss to mitochondrial myopathy to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and myoclonus epilepsy, ragged red fibers (MERRF). One case of fatal neonatal lactic acidosis has been reported. Intrafamilial variability has been observed.

Muscle biopsy often shows COX-negative fibers and/or ragged red fibers. A combined mitochondrial chain respiratory deficiency (commonly involving complexes I and IV) may also be observed in muscle biopsies. Heteroplasmy levels in affected individuals are often near homoplasmy in muscle and lower in tissues such as blood and urine, although homoplasmy across multiple tissues has also been seen. One individual had mitochondrial myopathy with heteroplasmy levels as low as 37% heteroplasmy in muscle.

Multiple single fiber studies and cybrid analyses were performed in these patients and are supportive of variant pathogenicity.
Sources: Expert list
Mendeliome v1.3216 MT-TR Zornitza Stark Marked gene: MT-TR as ready
Mendeliome v1.3216 MT-TR Zornitza Stark Gene: mt-tr has been classified as Green List (High Evidence).
Mendeliome v1.3216 MT-TR Zornitza Stark Classified gene: MT-TR as Green List (high evidence)
Mendeliome v1.3216 MT-TR Zornitza Stark Gene: mt-tr has been classified as Green List (High Evidence).
Mendeliome v1.3215 MT-TR Zornitza Stark gene: MT-TR was added
gene: MT-TR was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TR.
Mode of inheritance for gene gene: MT-TR was set to MITOCHONDRIAL
Publications for gene: MT-TR were set to 15286228; 17588757; 19809478; 22781096
Phenotypes for gene: MT-TR were set to mitochondrial disease (MONDO:0044970), MT-TR-related
Review for gene: MT-TR was set to GREEN
Added comment: MODERATE by ClinGen.

At least 4 individuals reported. Cybrid studies and single fiber testing further supported the pathogenicity of several of the reported variants. Age of onset was in childhood and features seen in affected individuals included muscle weakness, ataxia, hypotonia, epilepsy, global developmental delay and regression, pigmentary retinopathy, optic atrophy, renal insufficiency, and hypertrophic cardiomyopathy. Muscle biopsies showed ragged red fibers and COX-negative fibers and variable respiratory chain enzyme deficiencies.
Sources: Expert list
Mendeliome v1.3214 MT-TQ Zornitza Stark Phenotypes for gene: MT-TQ were changed from to Mitochondrial disease (MONDO:0044970), MT-TQ-related
Mendeliome v1.3213 MT-TQ Zornitza Stark edited their review of gene: MT-TQ: Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TQ-related
Mendeliome v1.3213 MT-TQ Zornitza Stark Classified gene: MT-TQ as Amber List (moderate evidence)
Mendeliome v1.3213 MT-TQ Zornitza Stark Gene: mt-tq has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3212 MT-TQ Zornitza Stark gene: MT-TQ was added
gene: MT-TQ was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TQ.
Mode of inheritance for gene gene: MT-TQ was set to MITOCHONDRIAL
Publications for gene: MT-TQ were set to 11171912; 10996779; 17003408; 11335700
Review for gene: MT-TQ was set to AMBER
Added comment: LIMITED by ClinGen.

Three unique variants (m.4332G>A, m.4369_4370insA, m.4381A>G) reported in three probands across 3 publications. Single fiber testing further supported the pathogenicity of several of these variants. Age of onset in affected individuals was five years old, teens, and 20 years old. Clinical features in affected individuals included stroke-like episodes, hearing loss, myopathy, and Leber Hereditary Optic Neuropathy (LHON). Brain imaging was variable. Muscle biopsies showed ragged red fibers and COX-negative fibers. Metabolic screening investigations were only reported in one individual and showed high cerebrospinal fluid (CSF) lactate with normal blood lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (61-87% in muscle).
Sources: Expert list
Mendeliome v1.3211 MT-TP Zornitza Stark Phenotypes for gene: MT-TP were changed from to Mitochondrial disease (MONDO:0044970), MT-TP-related
Mendeliome v1.3210 MT-TP Zornitza Stark Publications for gene: MT-TP were set to
Mendeliome v1.3209 MT-TP Zornitza Stark Tag mtDNA tag was added to gene: MT-TP.
Mendeliome v1.3209 MT-TP Zornitza Stark Classified gene: MT-TP as Green List (high evidence)
Mendeliome v1.3209 MT-TP Zornitza Stark Gene: mt-tp has been classified as Green List (High Evidence).
Mendeliome v1.3208 MT-TP Zornitza Stark reviewed gene: MT-TP: Rating: GREEN; Mode of pathogenicity: None; Publications: 7689388, 11196116, 19223931, 23696415, 19273760, 27536729, 27816331, 32305257, 32419253; Phenotypes: Mitochondrial disease (MONDO:0044970), MT-TP-related; Mode of inheritance: MITOCHONDRIAL
Mendeliome v1.3208 MT-TM Zornitza Stark Marked gene: MT-TM as ready
Mendeliome v1.3208 MT-TM Zornitza Stark Gene: mt-tm has been classified as Green List (High Evidence).
Mendeliome v1.3208 MT-TM Zornitza Stark Classified gene: MT-TM as Green List (high evidence)
Mendeliome v1.3208 MT-TM Zornitza Stark Gene: mt-tm has been classified as Green List (High Evidence).
Mendeliome v1.3207 MT-TM Zornitza Stark gene: MT-TM was added
gene: MT-TM was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TM.
Mode of inheritance for gene gene: MT-TM was set to MITOCHONDRIAL
Publications for gene: MT-TM were set to 9633749; 24711008; 25468263; 30739820; 11335700; 31488384; 31022467; 29174468
Phenotypes for gene: MT-TM were set to mitochondrial disease (MONDO:0044970), MT-TM-related
Review for gene: MT-TM was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported. The condition was first described in a 10-year-old girl with exercise intolerance, myopathy, and short stature with mildly elevated serum lactate. Subsequent publications have shown a consistent phenotype involving a mitochondrial myopathy (typically childhood onset) with elevated lactate. Chronic external progressive ophthalmoplegia (CPEO) is not common but has been reported. Basal ganglia lesions and Leigh syndrome spectrum/mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) overlap have also been reported in one patient. Retinitis pigmentosa has also been reported. Muscle biopsy often shows classic findings of mitochondrial myopathy with COX-negative and ragged red (or blue) fibers. Combined OXPHOS deficiencies in muscle are also observed.
Sources: Expert list
Mendeliome v1.3206 MT-TL2 Zornitza Stark Marked gene: MT-TL2 as ready
Mendeliome v1.3206 MT-TL2 Zornitza Stark Gene: mt-tl2 has been classified as Green List (High Evidence).
Mendeliome v1.3206 MT-TL2 Zornitza Stark Classified gene: MT-TL2 as Green List (high evidence)
Mendeliome v1.3206 MT-TL2 Zornitza Stark Gene: mt-tl2 has been classified as Green List (High Evidence).
Mendeliome v1.3205 MT-TL2 Zornitza Stark gene: MT-TL2 was added
gene: MT-TL2 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TL2.
Mode of inheritance for gene gene: MT-TL2 was set to MITOCHONDRIAL
Publications for gene: MT-TL2 were set to 8923013; 12398839; 19718780; 18977334; 21819490; 15649400; 15591266; 23847141; 20022607; 29052516
Phenotypes for gene: MT-TL2 were set to Mitochondrial disease (MONDO:0044970), MT-TL2-related
Review for gene: MT-TL2 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with a range of clinical phenotypes, including CPEO, retinopathy, hearing loss, myopathy, exercise intolerance, and peripheral neuropathy. There is a substantial amount of functional evidence for the reported variants, including numerous single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects
Sources: Expert list
Mendeliome v1.3204 MT-TL1 Zornitza Stark Marked gene: MT-TL1 as ready
Mendeliome v1.3204 MT-TL1 Zornitza Stark Gene: mt-tl1 has been classified as Green List (High Evidence).
Mendeliome v1.3204 MT-TL1 Zornitza Stark Classified gene: MT-TL1 as Green List (high evidence)
Mendeliome v1.3204 MT-TL1 Zornitza Stark Gene: mt-tl1 has been classified as Green List (High Evidence).
Mendeliome v1.3203 MT-TL1 Zornitza Stark gene: MT-TL1 was added
gene: MT-TL1 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TL1.
Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL
Publications for gene: MT-TL1 were set to 9323566; 12221518; 20471262; 23220830; 23273904; 24338029; 23582502; 11271374; 23258140
Phenotypes for gene: MT-TL1 were set to Mitochondrial disease (MONDO:0044970), MT-TL1-related
Review for gene: MT-TL1 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with a range of clinical presentations, including MELAS, myoclonus epilepsy, ragged red fibers (MERRF), Leigh syndrome spectrum, progressive external ophthalmoplegia (PEO), and maternally inherited deafness and diabetes (MIDD), as well as myopathy, hypertrophic cardiomyopathy, and renal disease. At least 7 unique variants reported with a substantial amount of functional evidence, including numerous cybrid analyses, single fiber studies, and respiratory chain analyses showing clear evidence of OXPHOS defects.
Sources: Expert list
Mendeliome v1.3202 MT-TK Zornitza Stark edited their review of gene: MT-TK: Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TK-related
Mendeliome v1.3202 MT-TK Zornitza Stark Phenotypes for gene: MT-TK were changed from Mitochondrial disease (MONDO:0044970), MT-TK-relatednd to Mitochondrial disease (MONDO:0044970), MT-TK-related
Mendeliome v1.3201 MT-TK Zornitza Stark Marked gene: MT-TK as ready
Mendeliome v1.3201 MT-TK Zornitza Stark Gene: mt-tk has been classified as Green List (High Evidence).
Mendeliome v1.3201 MT-TK Zornitza Stark Classified gene: MT-TK as Green List (high evidence)
Mendeliome v1.3201 MT-TK Zornitza Stark Gene: mt-tk has been classified as Green List (High Evidence).
Mendeliome v1.3200 MT-TK Zornitza Stark gene: MT-TK was added
gene: MT-TK was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TK.
Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL
Publications for gene: MT-TK were set to 9380435; 19618438; 17410322; 25559684; 1361099; 10868777; 35821181; 36675808
Phenotypes for gene: MT-TK were set to Mitochondrial disease (MONDO:0044970), MT-TK-relatednd
Review for gene: MT-TK was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported with wide spectrum of clinical presentations including MERRF, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome spectrum, and mitochondrial neurogastrointestinal encephalopathy (MNGIE), as well as lipomas, myopathy, hypertrophic cardiomyopathy, hearing loss, diabetes, and episodic ataxia. Variant pathogenicity is supported by cybrid analyses, single fiber studies, and respiratory chain studies showing clear evidence of OXPHOS defects.
Sources: Expert list
Mendeliome v1.3199 MT-TI Zornitza Stark Marked gene: MT-TI as ready
Mendeliome v1.3199 MT-TI Zornitza Stark Gene: mt-ti has been classified as Green List (High Evidence).
Mendeliome v1.3199 MT-TI Zornitza Stark Classified gene: MT-TI as Green List (high evidence)
Mendeliome v1.3199 MT-TI Zornitza Stark Gene: mt-ti has been classified as Green List (High Evidence).
Mendeliome v1.3198 MT-TI Zornitza Stark gene: MT-TI was added
gene: MT-TI was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TI.
Mode of inheritance for gene gene: MT-TI was set to MITOCHONDRIAL
Publications for gene: MT-TI were set to 15121771; 21982779; 23395828; 16120360; 9473477; 12767666; 10065021; 7646516; 20884012; 21292040; 1632786; 23696415; 34607911
Phenotypes for gene: MT-TI were set to Mitochondrial disease (MONDO:0044970), MT-TI-related
Review for gene: MT-TI was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 10 individuals reported. Clinical presentations included LSS, myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), in addition to rhabdomyolysis, cardiomyopathy, encephalopathy, exercise intolerance, muscle weakness, hypertension2, hypercholesterolaemia, and hypomagnesaemia. Heteroplasmy levels of MT-TI can be variable in tissues from the same individual. In general, variants tend to be lower in tissues such as blood, saliva, and buccal swab and urine and muscle heteroplasmy levels tend to be higher.
Sources: Expert list
Mendeliome v1.3197 NEK9 Sangavi Sivagnanasundram reviewed gene: NEK9: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: NEK9-related lethal skeletal dysplasia MONDO:0014870; Mode of inheritance: None
Mendeliome v1.3197 MT-TH Zornitza Stark Marked gene: MT-TH as ready
Mendeliome v1.3197 MT-TH Zornitza Stark Gene: mt-th has been classified as Green List (High Evidence).
Mendeliome v1.3197 MT-TH Zornitza Stark Classified gene: MT-TH as Green List (high evidence)
Mendeliome v1.3197 MT-TH Zornitza Stark Gene: mt-th has been classified as Green List (High Evidence).
Mendeliome v1.3196 MT-TH Zornitza Stark gene: MT-TH was added
gene: MT-TH was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-TH.
Mode of inheritance for gene gene: MT-TH was set to MITOCHONDRIAL
Publications for gene: MT-TH were set to 12682337; 14967777; 15111688; 21704194; 21931169; 23696415; 35092007; 24920829; 21704194
Phenotypes for gene: MT-TH were set to Mitochondrial disease (MONDO:0044970), MT-TH-related
Review for gene: MT-TH was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 5 individuals reported. Age of onset in affected individuals varied from adolescence to the 40s. Clinical features included stroke-like episodes, seizures, myoclonus, ataxia, optic atrophy, retinal dystrophy, cataracts, hearing loss, hypogonadism, and mood disorder. Cerebellar vermis hypoplasia and signal changes in the basal ganglia, dentate nuclei, temporal lobes, and occipital lobes were seen on brain imaging.

Tissue biopsies identified ragged red fibers and COX-negative fibers. Laboratory investigations showed increased blood and cerebrospinal fluid lactate. Decreased activities of complexes I and IV were variably seen in muscle. Heteroplasmy levels of the variants in affected individuals ranged from 81% to homoplasmic in muscle, 33-87% in urine, 1-60% in blood, and undetectable to homoplasmic in fibroblasts. Single fiber testing, cybrid analysis, and Northern blot analysis further supported variant pathogenicity.

This gene-disease relationship is also supported by known biochemical function and functional alteration in patient and non-patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TH; PMID: 24920829, 21704194).
Sources: Expert list
Mendeliome v1.3195 MT-TG Zornitza Stark Marked gene: MT-TG as ready
Mendeliome v1.3195 MT-TG Zornitza Stark Gene: mt-tg has been classified as Green List (High Evidence).
Mendeliome v1.3195 MT-TG Zornitza Stark Classified gene: MT-TG as Green List (high evidence)
Mendeliome v1.3195 MT-TG Zornitza Stark Gene: mt-tg has been classified as Green List (High Evidence).
Mendeliome v1.3194 MT-TG Zornitza Stark Tag mtDNA tag was added to gene: MT-TG.
Mendeliome v1.3194 MT-TG Zornitza Stark gene: MT-TG was added
gene: MT-TG was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TG was set to MITOCHONDRIAL
Publications for gene: MT-TG were set to 8079988; 9199564; 11971101; 16120360; 32337339; 35432167; 10090480
Phenotypes for gene: MT-TG were set to Mitochondrial disease (MONDO:0044970), MT-TG-related
Review for gene: MT-TG was set to GREEN
Added comment: MODERATE by ClinGen.

Four variants reported in at least 6 individuals. Age of onset in affected individuals varied from early in life to the 20s. Clinical features included hypertrophic cardiomyopathy, myopathy, peripheral neuropathy, exercise intolerance, headache, seizures, ataxia, dystonic posturing, optic atrophy, retinal dystrophy, cataracts, and hearing loss. Progressive atrophy and bilateral basal ganglia calcifications were seen on brain imaging.

Tissue biopsies identified ragged red fibers and decreased COX histochemical activity in muscle. Lab values showed increased blood lactate and increased creatine kinase. Decreased activities of complexes I, III, and IV were observed in biopsied muscle.

Heteroplasmy levels of the variants in affected individuals ranged from 88-92% in muscle, 40-56% in urine, undetectable to 32% in blood, 27% in buccal samples, and was undetectable when assessed in fibroblasts. Single fiber testing and cybrid analysis further supported variant pathogenicity. This gene-disease relationship is also supported by known biochemical function and functional alterations in patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in MT-TG; PMID: 10090480).
Sources: Expert list
Mendeliome v1.3193 MT-TF Zornitza Stark edited their review of gene: MT-TF: Changed phenotypes: Mitochondrial disease (MONDO:0044970), MT-TF-related
Mendeliome v1.3193 MT-TF Zornitza Stark Marked gene: MT-TF as ready
Mendeliome v1.3193 MT-TF Zornitza Stark Gene: mt-tf has been classified as Green List (High Evidence).
Mendeliome v1.3193 MT-TF Zornitza Stark Phenotypes for gene: MT-TF were changed from Mitochondrial disease (MONDO:0044970), MT-TF-relatedn to Mitochondrial disease (MONDO:0044970), MT-TF-related
Mendeliome v1.3192 MT-TF Zornitza Stark Classified gene: MT-TF as Green List (high evidence)
Mendeliome v1.3192 MT-TF Zornitza Stark Gene: mt-tf has been classified as Green List (High Evidence).
Mendeliome v1.3191 MT-TF Zornitza Stark Tag mtDNA tag was added to gene: MT-TF.
Mendeliome v1.3191 MT-TF Zornitza Stark gene: MT-TF was added
gene: MT-TF was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TF was set to MITOCHONDRIAL
Publications for gene: MT-TF were set to 14659412; 9771776; 16806928; 21060018; 31463198; 32419253; 34607911; 21424749; 15184630; 20142618; 28267784; 31722346; 35472031; 9636664; 21882289; 16769874; 21914246; 31009750; 18977334
Phenotypes for gene: MT-TF were set to Mitochondrial disease (MONDO:0044970), MT-TF-relatedn
Review for gene: MT-TF was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Over 30 individuals reported. Age of onset in affected individuals varied from childhood to >60 years. Clinical features in affected individuals included mitochondrial myopathy, MELAS, myoclonic epilepsy and ragged red fibers (MERRF), chronic external progressive ophthalmoplegia (CPEO), Gitelman syndrome, epilepsy, epilepsia partialis continua (EPC), chronic kidney disease, retinal dystrophy, sensorineural hearing loss, neuropathy, and neurologic/cognitive/psychiatric decline. Some affected individuals had normal brain imaging while others had cerebral, cerebellar, and/or brainstem atrophy.

Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals. Laboratory investigations showed variable lactate levels (normal to elevated in blood, cerebrospinal fluid, and/or urine) and elevated creatine kinase (CK).

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and ranged from 58%-homoplasmic in muscle; 0-70% in hair, 0-homoplasmic in blood, fibroblast, and urine; and in one individual was 63% in a buccal sample.
Sources: Expert list
Mendeliome v1.3190 MT-TE Zornitza Stark Tag mtDNA tag was added to gene: MT-TE.
Mendeliome v1.3190 MT-TE Zornitza Stark Marked gene: MT-TE as ready
Mendeliome v1.3190 MT-TE Zornitza Stark Gene: mt-te has been classified as Green List (High Evidence).
Mendeliome v1.3190 MT-TE Zornitza Stark Classified gene: MT-TE as Green List (high evidence)
Mendeliome v1.3190 MT-TE Zornitza Stark Gene: mt-te has been classified as Green List (High Evidence).
Mendeliome v1.3189 MT-TE Zornitza Stark gene: MT-TE was added
gene: MT-TE was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TE was set to MITOCHONDRIAL
Publications for gene: MT-TE were set to 8155739; 21194154; 17715279; 23334599; 7726155; 7726154; 9353617; 15048886; 15670724; 23847141; 23334599; 17266923; 17056256
Phenotypes for gene: MT-TE were set to Mitochondrial disease (MONDO:0044970), MT-TE-related
Review for gene: MT-TE was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 15 individuals reported. Age of onset in affected individuals varied from birth to 30s. Clinical features in affected individuals included (benign) infantile reversible COX deficiency myopathy (also referred to RIRCD); chronic external progressive ophthalmoplegia (CPEO), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap, myoclonic epilepsy and ragged red fibers (MERRF); pigmentary retinopathy, migraines, myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, and hearing loss. Brain imaging was variable. Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals.

Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed, and were variable in other tissues when tested.
Sources: Expert list
Mendeliome v1.3188 MT-TD Zornitza Stark Tag mtDNA tag was added to gene: MT-TD.
Mendeliome v1.3188 MT-TD Zornitza Stark Marked gene: MT-TD as ready
Mendeliome v1.3188 MT-TD Zornitza Stark Gene: mt-td has been classified as Green List (High Evidence).
Mendeliome v1.3188 MT-TD Zornitza Stark Classified gene: MT-TD as Green List (high evidence)
Mendeliome v1.3188 MT-TD Zornitza Stark Gene: mt-td has been classified as Green List (High Evidence).
Mendeliome v1.3187 MT-TD Zornitza Stark gene: MT-TD was added
gene: MT-TD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TD was set to MITOCHONDRIAL
Publications for gene: MT-TD were set to 9811342; 10488907; 16059939; 18676632; 23696415; 25447692; 27536005; 30030363; 3054486; 19535463
Phenotypes for gene: MT-TD were set to Mitochondrial disease (MONDO:0044970), MT-TD-related
Review for gene: MT-TD was set to GREEN
Added comment: MODERATE by ClinGen.

At least 3 variants reported in unrelated individuals. These variants were generally present at high levels of heteroplasmy in muscle tissue and at lower to undetectable levels in other tissues such as blood, saliva, buccal tissue, urine, and fibroblasts, highlighting the diagnostic importance of muscle biopsy in MT-TD-related primary mitochondrial disease. Single fiber studies were performed in several individuals with results supporting variant pathogenicity.

This gene-disease association is also supported by functional implication given protein interaction with the multitude of other mitochondrial translation proteins linked to primary mitochondrial disease (PMID: 30030363 ). Respiratory deficient yeast strains due to a single variant in MT-TD have been created and compelling rescue studies have been performed (PMIDs: 7024270, 3054486). E. coli carrying the m.7526A>G variant were also shown to have significantly decreased aminoacylation rates (PMID: 19535463).
Sources: Expert list
Mendeliome v1.3186 MT-TC Zornitza Stark Marked gene: MT-TC as ready
Mendeliome v1.3186 MT-TC Zornitza Stark Gene: mt-tc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3186 MT-TC Zornitza Stark Classified gene: MT-TC as Amber List (moderate evidence)
Mendeliome v1.3186 MT-TC Zornitza Stark Gene: mt-tc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3185 MT-TC Zornitza Stark gene: MT-TC was added
gene: MT-TC was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TC was set to MITOCHONDRIAL
Publications for gene: MT-TC were set to 8829635; 9185178; 17241783; 11453453; 16955414; 32169613; 36039763; 17724295; 35252560; 34433719; 30030363
Phenotypes for gene: MT-TC were set to Mitochondrial disease (MONDO:0044970), MT-TC-related
Review for gene: MT-TC was set to AMBER
Added comment: LIMITED by ClinGen.

There were 3 scoreable probands across >10 publications from 1996-2022. Notably, while cybrid analyses were performed (PMID:36039763), one of the variants, m.5783G>A, was excluded from scoring for three reasons: 1.) the reported phenotype of isolated hearing loss was non-specific and incompletely penetrant, but also 2.) the biochemical impact in cybrids was mild - moderate, and 3.) there was reduction in expression of mitochondrial replication genes (TWNK ~30% of control in cybrids) suggesting an alternative aetiology might be responsible for the biochemical impact reported.

The gene-disease association for MT-TC is also supported by the known interaction with a multitude of other mitochondrial translation proteins (PMID:30030363) and respiratory chain studies and Northern blot analysis supporting MT-TC dysfunction leading to Complex I deficiency (PMID:35252560).
Sources: Expert list
Mendeliome v1.3184 NDP Sangavi Sivagnanasundram reviewed gene: NDP: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Norrie disease MONDO:0010691; Mode of inheritance: None
Mendeliome v1.3184 MT-TA Zornitza Stark Marked gene: MT-TA as ready
Mendeliome v1.3184 MT-TA Zornitza Stark Gene: mt-ta has been classified as Green List (High Evidence).
Mendeliome v1.3184 MT-TA Zornitza Stark Classified gene: MT-TA as Green List (high evidence)
Mendeliome v1.3184 MT-TA Zornitza Stark Gene: mt-ta has been classified as Green List (High Evidence).
Mendeliome v1.3183 MT-TA Zornitza Stark gene: MT-TA was added
gene: MT-TA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-TA was set to MITOCHONDRIAL
Publications for gene: MT-TA were set to 11715067; 17825557; 14569122; 27014581; 20813205; 25873012; 16476954
Phenotypes for gene: MT-TA were set to Mitochondrial disease (MONDO:0044970), MT-TA-related
Review for gene: MT-TA was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 5 individuals reported. Variable age of onset. Features in affected individuals included myopathy (weakness, exercise intolerance), ptosis, ophthalmoplegia, lipomas, and hearing loss. Muscle biopsies showed ragged red fibers and COX-negative fibers, as well as respiratory chain enzyme deficiencies. Heteroplasmy levels in affected individuals tended to be highest in muscle when multiple tissues were assessed and were variable in other tissues when tested.
Sources: Expert list
Mendeliome v1.3182 NDE1 Sangavi Sivagnanasundram reviewed gene: NDE1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly with lissencephaly and/or hydranencephaly, MONDO:0700116; Mode of inheritance: None
Mendeliome v1.3182 NARS Sangavi Sivagnanasundram reviewed gene: NARS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3182 NALCN Sangavi Sivagnanasundram reviewed gene: NALCN: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3182 NAGLU Sangavi Sivagnanasundram reviewed gene: NAGLU: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3182 NAA10 Sangavi Sivagnanasundram reviewed gene: NAA10: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: NAA10-related syndrome, MONDO:0100124; Mode of inheritance: None
Mendeliome v1.3182 MYRF Sangavi Sivagnanasundram reviewed gene: MYRF: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MYRF-related cardiac-urogenital syndrome MONDO:0032653; Mode of inheritance: None
Mendeliome v1.3182 MYOT Sangavi Sivagnanasundram reviewed gene: MYOT: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: myofibrillar myopathy 3, MONDO:0012215; Mode of inheritance: None
Mendeliome v1.3182 PIP5K1C Sangavi Sivagnanasundram commented on gene: PIP5K1C
Mendeliome v1.3182 PITRM1 Sangavi Sivagnanasundram reviewed gene: PITRM1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: spinocerebellar ataxia, autosomal recessive 30, MONDO:0030318; Mode of inheritance: None
Mendeliome v1.3182 PJA1 Sangavi Sivagnanasundram reviewed gene: PJA1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: X-linked complex neurodevelopmental disorder, PJA1-related, MONDO:0100148; Mode of inheritance: None
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Marked gene: MT-RNR1 as ready
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Gene: mt-rnr1 has been classified as Green List (High Evidence).
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Classified gene: MT-RNR1 as Green List (high evidence)
Mendeliome v1.3182 MT-RNR1 Zornitza Stark Gene: mt-rnr1 has been classified as Green List (High Evidence).
Mendeliome v1.3181 MT-RNR1 Zornitza Stark Tag mtDNA tag was added to gene: MT-RNR1.
Mendeliome v1.3181 MT-RNR1 Zornitza Stark gene: MT-RNR1 was added
gene: MT-RNR1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-RNR1 was set to MITOCHONDRIAL
Publications for gene: MT-RNR1 were set to 7698299; 16380089; 12920080; 24252789; 9490575; 8285309; 9040738; 7689389
Phenotypes for gene: MT-RNR1 were set to Mitochondrial disease (MONDO:0044970), MT-RNR1-related
Review for gene: MT-RNR1 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Over 70 affected individuals reported. Two variants, m.1555A>G and m.1494C>T, are recurrent.

These variants are predominantly associated with hearing loss. Some individuals with this variants have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. Age of onset of hearing loss ranged from infancy (after aminoglycoside exposure) to adulthood. Hearing loss has been reported to be variable, stable in some individuals and progressive in others.

Additional variants in this gene have been reported to be associated with primary mitochondrial disease, however insufficient clinical detail was provided and/or there was a lack of comprehensive analyses excluding other causes, therefore these additional variants were not included in the ClinGen curation (m.827A>G – PMIDs: 16650816, 16782057, 18261986; m.961delTinsC - PMIDs: 7550368, 10326749; m.1027A>G – PMIDs: 23328039, 21205314, 20100600; m.1095T>C – PMIDs: 11313749, 11079536, 15637703).
Sources: Expert list
Mendeliome v1.3180 MT-ND6 Zornitza Stark Marked gene: MT-ND6 as ready
Mendeliome v1.3180 MT-ND6 Zornitza Stark Gene: mt-nd6 has been classified as Green List (High Evidence).
Mendeliome v1.3180 MT-ND6 Zornitza Stark Classified gene: MT-ND6 as Green List (high evidence)
Mendeliome v1.3180 MT-ND6 Zornitza Stark Gene: mt-nd6 has been classified as Green List (High Evidence).
Mendeliome v1.3179 MT-ND6 Zornitza Stark gene: MT-ND6 was added
gene: MT-ND6 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND6.
Mode of inheritance for gene gene: MT-ND6 was set to MITOCHONDRIAL
Publications for gene: MT-ND6 were set to 5576045; 20019223; 21196529; 10894222; 14684687; 17535832; 19103152; 21749722; 23813926; 25356405; 14595656; 19062322; 11133798; 30741831; 21364701; 2018041
Phenotypes for gene: MT-ND6 were set to Mitochondrial disease (MONDO:0044970), MT-ND6-related
Review for gene: MT-ND6 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 20 affected individuals reported, the m.14484T>C and m.14487T>C variants are recurrent.

Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and LSS phenotypes, as well as migraines, tremor, multiple sclerosis, and cardiac involvement. The age of onset is also highly variable, ranging from infantile to adult.

Muscle biopsies revealed isolated complex I deficiency, and complex I and III deficiencies; and complex I deficiency was also seen in fibroblasts and liver. Metabolic screening investigations showed elevated lactate and pyruvate in cerebrospinal fluid (CSF) and blood.

Heteroplasmy levels in affected individuals ranged from 50% to >95% in skeletal muscle; 25% to >95% in blood, 76% to >95% in fibroblasts, and 65% to >95% in liver; and ranged in healthy family members from undetectable to 92% in blood, undetectable to 95% in urine, 14% to 95% in hair follicles, 16% to 68% in buccal, and was undetectable in muscle in healthy family members.
Sources: Expert list
Mendeliome v1.3178 MT-ND5 Zornitza Stark Marked gene: MT-ND5 as ready
Mendeliome v1.3178 MT-ND5 Zornitza Stark Gene: mt-nd5 has been classified as Green List (High Evidence).
Mendeliome v1.3178 MT-ND5 Zornitza Stark Classified gene: MT-ND5 as Green List (high evidence)
Mendeliome v1.3178 MT-ND5 Zornitza Stark Gene: mt-nd5 has been classified as Green List (High Evidence).
Mendeliome v1.3177 MT-ND5 Zornitza Stark gene: MT-ND5 was added
gene: MT-ND5 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND5.
Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL
Publications for gene: MT-ND5 were set to 17400793; 11938446; 12624137; 18495510; 23918514; 17535832; 29506874; 23034978; 16816025; 9299505; 18977334
Phenotypes for gene: MT-ND5 were set to Mitochondrial disease (MONDO:0044970), MT-ND5-related
Review for gene: MT-ND5 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 20 individuals reported. Two variants are recurrent (m.13513G>A and m.13094T>C).

Affected individuals present with a broad phenotypic spectrum of disease including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; myoclonus epilepsy, ragged red fibers (MERRF); and cardiomyopathy. The age of onset is also highly variable, ranging from infantile to adult.

Muscle biopsies variably revealed ragged red fibers, isolated complex I deficiency, and variable combined deficiencies of complexes I, III, and/or IV. Metabolic screening investigations showed elevated lactate in cerebrospinal fluid (CSF) and blood and urinary excretion of Krebs cycle intermediates.

Heteroplasmy levels in affected individuals ranged from 28% - 90% in skeletal muscle, 23% to 77% in blood, undetectable to 90% in fibroblasts, 51% - 81% in urine; and ranged in healthy family members from undetectable to 20% in blood, undetectable to 25% to 95% in hair follicles, undetectable to 4-6% muscle, and ranged from 27%-45% in other tissues such as urine and buccal samples in healthy family members.
Sources: Expert list
Mendeliome v1.3176 MT-ND4L Zornitza Stark Marked gene: MT-ND4L as ready
Mendeliome v1.3176 MT-ND4L Zornitza Stark Gene: mt-nd4l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3176 MT-ND4L Zornitza Stark Classified gene: MT-ND4L as Amber List (moderate evidence)
Mendeliome v1.3176 MT-ND4L Zornitza Stark Gene: mt-nd4l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3175 MT-ND4L Zornitza Stark gene: MT-ND4L was added
gene: MT-ND4L was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND4L.
Mode of inheritance for gene gene: MT-ND4L was set to MITOCHONDRIAL
Publications for gene: MT-ND4L were set to 8680405; 11935318; 17003408; 22879922; 24568867
Phenotypes for gene: MT-ND4L were set to Mitochondrial disease (MONDO:0044970), MT-ND4L-related
Review for gene: MT-ND4L was set to AMBER
Added comment: LIMITED by ClinGen.

Seven probands with m.10063T>C have been reported across five publications, all of whom had LHON. These cases were scored with reduced points by ClinGen given the mild impact this variant has been shown to have on complex I function. While three other missense variants (m.10543A>G, m.10591T>G, m.10680G>A) have been reported, the ClinGen Expert Panel agreed there was only sufficient evidence of pathogenicity for the m.10663T>C variant. Cases with m.10680G>A and m.10543A>G and m.10591T>G were reviewed but excluded from scoring due to a lack of compelling functional evidence to support pathogenicity. The m.10543A>G variant has been modeled in E. coli and showed a very mild reduction in NADH dehydrogenase activity (74% of control), which was not sufficient to be included in scoring.
Sources: Expert list
Mendeliome v1.3174 MT-ND4 Zornitza Stark Marked gene: MT-ND4 as ready
Mendeliome v1.3174 MT-ND4 Zornitza Stark Gene: mt-nd4 has been classified as Green List (High Evidence).
Mendeliome v1.3174 MT-ND4 Zornitza Stark Classified gene: MT-ND4 as Green List (high evidence)
Mendeliome v1.3174 MT-ND4 Zornitza Stark Gene: mt-nd4 has been classified as Green List (High Evidence).
Mendeliome v1.3173 MT-ND4 Zornitza Stark gene: MT-ND4 was added
gene: MT-ND4 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND4.
Mode of inheritance for gene gene: MT-ND4 was set to MITOCHONDRIAL
Publications for gene: MT-ND4 were set to 12707444; 16120329; 15576045; 20502985; 27761019; 32445240; 32659360; 3201231
Phenotypes for gene: MT-ND4 were set to Mitochondrial disease (MONDO:0044970), MT-ND4-related
Review for gene: MT-ND4 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

Multiple individuals reported presenting with a broad phenotypic spectrum of clinical features including Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); LSS; cerebellar ataxia, migraines, regression, developmental delay, leukoencephalopathy, myoclonus, seizures, stroke-like episodes, cognitive decline, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, ophthalmoplegia, short stature, and hypertrophic cardiomyopathy. Age of onset varied from infancy to adulthood. Muscle biopsy showed COX-negative fibers and complex I deficiency.

Heteroplasmy levels in affected individuals ranged from 60% - 83% in muscle, 40% - 80% in blood, and 76% - 78% in myoblasts, as well as from 57% - 73% in various other tissues (fibroblasts, liver, urine, buccal). Of note, the m.11778G>A common LHON variant was reported in affected individuals in the homoplasmic and heteroplasmic states.
Sources: Expert list
Mendeliome v1.3172 MT-ND3 Zornitza Stark Marked gene: MT-ND3 as ready
Mendeliome v1.3172 MT-ND3 Zornitza Stark Gene: mt-nd3 has been classified as Green List (High Evidence).
Mendeliome v1.3172 MT-ND3 Zornitza Stark Classified gene: MT-ND3 as Green List (high evidence)
Mendeliome v1.3172 MT-ND3 Zornitza Stark Gene: mt-nd3 has been classified as Green List (High Evidence).
Mendeliome v1.3171 MT-ND3 Zornitza Stark gene: MT-ND3 was added
gene: MT-ND3 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND3.
Mode of inheritance for gene gene: MT-ND3 was set to MITOCHONDRIAL
Publications for gene: MT-ND3 were set to 1928099; 14705112; 14764913; 17152068; 20202874; 25118196; 25384404; 11456298; 19458970; 30199507; 29237403
Phenotypes for gene: MT-ND3 were set to Mitochondrial disease (MONDO:0044970), MT-ND3-related
Review for gene: MT-ND3 was set to GREEN
Added comment: DEFINITIVE by ClinGen.

More than 15 affected individuals reported. Three variants are recurrent (m.10158T>C, m.10191T>C, m.10197G>A). Affected individuals present with a broad phenotypic spectrum of clinical features including LSS; Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); lactic acidosis, epilepsia partialis continua (EPC), epileptic encephalopathy, dystonia, and optic atrophy. The age of onset is also highly variable, ranging from infantile to adult. Muscle biopsy showed and complex I deficiency.
Sources: Expert list
Mendeliome v1.3170 MT-ND2 Zornitza Stark Marked gene: MT-ND2 as ready
Mendeliome v1.3170 MT-ND2 Zornitza Stark Gene: mt-nd2 has been classified as Green List (High Evidence).
Mendeliome v1.3170 MT-ND2 Zornitza Stark Classified gene: MT-ND2 as Green List (high evidence)
Mendeliome v1.3170 MT-ND2 Zornitza Stark Gene: mt-nd2 has been classified as Green List (High Evidence).
Mendeliome v1.3169 MT-ND2 Zornitza Stark gene: MT-ND2 was added
gene: MT-ND2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-ND2 was set to MITOCHONDRIAL
Publications for gene: MT-ND2 were set to 26258512; 16738010; 15781840; 12192017
Phenotypes for gene: MT-ND2 were set to Mitochondrial disease (MONDO:0044970), MT-ND2-related
Review for gene: MT-ND2 was set to GREEN
Added comment: MODERATE by ClinGen.

Multiple individuals reported. Age of onset in affected individuals ranged from 9 months old to childhood. Clinical features in affected individuals included Leigh syndrome spectrum, myopathy, ophthalmoplegia, and ptosis. Muscle biopsies revealed ragged red fibers and complex I deficiency. Metabolic screening labs showed elevated lactate and creatine kinase (CK). Heteroplasmy levels were >95% in blood, fibroblasts, and muscle in the individual with Leigh syndrome spectrum. However in the other two individuals with predominantly myopathic features, the variant was present at >94% in muscle and undetectable in other tissues tested.
Sources: Expert list
Mendeliome v1.3168 MT-ND1 Zornitza Stark Marked gene: MT-ND1 as ready
Mendeliome v1.3168 MT-ND1 Zornitza Stark Gene: mt-nd1 has been classified as Green List (High Evidence).
Mendeliome v1.3168 MT-ND1 Zornitza Stark Classified gene: MT-ND1 as Green List (high evidence)
Mendeliome v1.3168 MT-ND1 Zornitza Stark Gene: mt-nd1 has been classified as Green List (High Evidence).
Mendeliome v1.3167 MT-ND1 Zornitza Stark gene: MT-ND1 was added
gene: MT-ND1 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ND1.
Mode of inheritance for gene gene: MT-ND1 was set to MITOCHONDRIAL
Publications for gene: MT-ND1 were set to 39147111; 36717040; 34656796
Phenotypes for gene: MT-ND1 were set to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-ND1-related
Review for gene: MT-ND1 was set to GREEN
Added comment: Multiple individuals reported with variants in this gene and a range of phenotypes consistent with mitochondrial disease, including LHON and Leigh syndrome.
Sources: Expert list
Mendeliome v1.3166 MT-CYB Zornitza Stark changed review comment from: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease.
Sources: Expert list; to: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease, including Leber's optic atrophy, encephalomyopathy, and cardiomyopathy.
Sources: Expert list
Mendeliome v1.3166 MT-CYB Zornitza Stark Marked gene: MT-CYB as ready
Mendeliome v1.3166 MT-CYB Zornitza Stark Gene: mt-cyb has been classified as Green List (High Evidence).
Mendeliome v1.3166 MT-CYB Zornitza Stark Classified gene: MT-CYB as Green List (high evidence)
Mendeliome v1.3166 MT-CYB Zornitza Stark Gene: mt-cyb has been classified as Green List (High Evidence).
Mendeliome v1.3165 MT-CYB Zornitza Stark gene: MT-CYB was added
gene: MT-CYB was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-CYB.
Mode of inheritance for gene gene: MT-CYB was set to MITOCHONDRIAL
Publications for gene: MT-CYB were set to 39858655; 34804306; 26937408
Phenotypes for gene: MT-CYB were set to mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CYB-related
Review for gene: MT-CYB was set to GREEN
Added comment: Multiple individuals reported with variants in this gene and a range of clinical phenotypes consistent with mitochondrial disease.
Sources: Expert list
Mendeliome v1.3163 MT-CO2 Zornitza Stark Marked gene: MT-CO2 as ready
Mendeliome v1.3163 MT-CO2 Zornitza Stark Gene: mt-co2 has been classified as Green List (High Evidence).
Mendeliome v1.3163 MT-CO2 Zornitza Stark Classified gene: MT-CO2 as Green List (high evidence)
Mendeliome v1.3163 MT-CO2 Zornitza Stark Gene: mt-co2 has been classified as Green List (High Evidence).
Mendeliome v1.3162 MT-CO2 Zornitza Stark gene: MT-CO2 was added
gene: MT-CO2 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-CO2.
Mode of inheritance for gene gene: MT-CO2 was set to MITOCHONDRIAL
Publications for gene: MT-CO2 were set to 37640115; 34325999; 30315213; 28521807
Phenotypes for gene: MT-CO2 were set to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CO2-related
Review for gene: MT-CO2 was set to GREEN
Added comment: Multiple individuals reported with variants in this gene and a range of neurological and neuromuscular presentations consistent with mitochondrial disease.
Sources: Expert list
Mendeliome v1.3161 MT-CO1 Zornitza Stark Marked gene: MT-CO1 as ready
Mendeliome v1.3161 MT-CO1 Zornitza Stark Gene: mt-co1 has been classified as Green List (High Evidence).
Mendeliome v1.3161 MT-CO1 Zornitza Stark Classified gene: MT-CO1 as Green List (high evidence)
Mendeliome v1.3161 MT-CO1 Zornitza Stark Gene: mt-co1 has been classified as Green List (High Evidence).
Mendeliome v1.3160 MT-CO1 Zornitza Stark Tag mtDNA tag was added to gene: MT-CO1.
Mendeliome v1.3160 MT-CO1 Zornitza Stark gene: MT-CO1 was added
gene: MT-CO1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene gene: MT-CO1 was set to MITOCHONDRIAL
Publications for gene: MT-CO1 were set to 30743023; 39460813; 24956508
Phenotypes for gene: MT-CO1 were set to Mitochondrial respiratory chain complex deficiency, MONDO:0000066, MT-CO1-related
Review for gene: MT-CO1 was set to GREEN
Added comment: Multiple individuals reported with a range of clinical presentations consistent with mitochondrial disease.
Sources: Expert list
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Marked gene: MT-ATP8 as ready
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Gene: mt-atp8 has been classified as Green List (High Evidence).
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Classified gene: MT-ATP8 as Green List (high evidence)
Mendeliome v1.3159 MT-ATP8 Zornitza Stark Gene: mt-atp8 has been classified as Green List (High Evidence).
Mendeliome v1.3158 MT-ATP8 Zornitza Stark gene: MT-ATP8 was added
gene: MT-ATP8 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ATP8.
Mode of inheritance for gene gene: MT-ATP8 was set to MITOCHONDRIAL
Publications for gene: MT-ATP8 were set to 40112238
Phenotypes for gene: MT-ATP8 were set to Mitochondrial complex V (ATP synthase) deficiency, MONDO:0014471, MT-ATP8-related
Review for gene: MT-ATP8 was set to GREEN
Added comment: Multiple individuals reported with wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI.
Sources: Expert list
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Marked gene: MT-ATP6 as ready
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Gene: mt-atp6 has been classified as Green List (High Evidence).
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Classified gene: MT-ATP6 as Green List (high evidence)
Mendeliome v1.3157 MT-ATP6 Zornitza Stark Gene: mt-atp6 has been classified as Green List (High Evidence).
Mendeliome v1.3156 MT-ATP6 Zornitza Stark gene: MT-ATP6 was added
gene: MT-ATP6 was added to Mendeliome. Sources: Expert list
mtDNA tags were added to gene: MT-ATP6.
Mode of inheritance for gene gene: MT-ATP6 was set to MITOCHONDRIAL
Publications for gene: MT-ATP6 were set to 40112238
Phenotypes for gene: MT-ATP6 were set to Mitochondrial complex V (ATP synthase) deficiency, MONDO:0014471, MT-ATP6-related
Review for gene: MT-ATP6 was set to GREEN
Added comment: Multiple individuals reported with wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI.
Sources: Expert list
Mendeliome v1.3155 BRSK2 Zornitza Stark Phenotypes for gene: BRSK2 were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BRSK2-related
Mendeliome v1.3154 BRSK2 Zornitza Stark edited their review of gene: BRSK2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BRSK2-related
Mendeliome v1.3154 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract; Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) to Congenital anomaly of kidney and urinary tract, MONDO:0019719, BMP7-related; Isolated craniosynostosis, MONDO:0015337, BMP7-related; Mayer-Rokitansky-Kuster-Hauser syndrome, MONDO:0017771, BMP7-related
Mendeliome v1.3153 BMP7 Sarah Milton reviewed gene: BMP7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital anomaly of kidney and urinary tract, MONDO:0019719, BMP7-related, Isolated craniosynostosis, MONDO:0015337, BMP7-related, Mayer-Rokitansky-Kuster-Hauser syndrome, MONDO:0017771, BMP7-related; Mode of inheritance: None
Mendeliome v1.3153 TBX2 Zornitza Stark reviewed gene: TBX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 20206336, 22052739, 21271665, https://doi.org/10.1101/2024.07.18.24310488; Phenotypes: Hearing loss disorder, MONDO:0005365, TBX2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3153 NTN1 Zornitza Stark Phenotypes for gene: NTN1 were changed from Mirror movements 4 MIM#618264 to Mirror movements 4 MIM#618264; Hearing loss disorder, MONDO:0005365, NTN1-related
Mendeliome v1.3152 NTN1 Zornitza Stark Publications for gene: NTN1 were set to 25763452; 28945198; 33472083
Mendeliome v1.3151 NTN1 Zornitza Stark reviewed gene: NTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39648562; Phenotypes: Hearing loss disorder, MONDO:0005365, NTN1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3151 GNAI2 Zornitza Stark Phenotypes for gene: GNAI2 were changed from Pituitary adenoma, ACTH-secreting, somatic; Ventricular tachycardia, idiopathic 192605; Syndromic developmental disorder to Syndromic disease MONDO:0002254, GNAI2-related
Mendeliome v1.3150 GNAI2 Zornitza Stark Publications for gene: GNAI2 were set to PMID: 31036916
Mendeliome v1.3149 GNAI2 Zornitza Stark Classified gene: GNAI2 as Green List (high evidence)
Mendeliome v1.3149 GNAI2 Zornitza Stark Gene: gnai2 has been classified as Green List (High Evidence).
Mendeliome v1.3148 TRPC5 Zornitza Stark Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Mendeliome v1.3147 BMPR1A Zornitza Stark Phenotypes for gene: BMPR1A were changed from Polyposis, juvenile intestinal, MIM# 174900 to BMPR1A-related juvenile polyposis syndrome MONDO:0700348
Mendeliome v1.3146 CDK5 Zornitza Stark Publications for gene: CDK5 were set to 25560765; 32273484; 32097629; 28854363; 7490100
Mendeliome v1.3145 CDK5 Zornitza Stark Classified gene: CDK5 as Green List (high evidence)
Mendeliome v1.3145 CDK5 Zornitza Stark Gene: cdk5 has been classified as Green List (High Evidence).
Mendeliome v1.3144 PACSIN3 Zornitza Stark Phenotypes for gene: PACSIN3 were changed from Myopathy, MONDO:0005336, PACSIN3-related to Congenital myopathy 27, MIM# 621343
Mendeliome v1.3143 PACSIN3 Zornitza Stark edited their review of gene: PACSIN3: Changed phenotypes: Congenital myopathy 27, MIM# 621343
Mendeliome v1.3143 GNAI2 Rylee Peters reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40926810, 39298586; Phenotypes: Syndromic disease MONDO:0002254, GNAI2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3143 TRPC5 Rylee Peters reviewed gene: TRPC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 40907672; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TRPC5-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3143 BMPR1A Leah Frajman reviewed gene: BMPR1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: BMPR1A-related juvenile polyposis syndrome MONDO:0700348; Mode of inheritance: None
Mendeliome v1.3143 PRKCI Sangavi Sivagnanasundram edited their review of gene: PRKCI: Changed rating: GREEN
Mendeliome v1.3143 PRKCI Sangavi Sivagnanasundram changed review comment from: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

The gene is not constrained for LoF in gnomAD and there are no pathogenic SNVs reported in ClinVar at this present time. Amber until further evidence is published in support of this gene-disease association.
Sources: Literature; to: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

Sources: Literature
Mendeliome v1.3143 CDK5 Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40186457; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3143 ANLN Zornitza Stark Publications for gene: ANLN were set to 24676636; 30002222
Mendeliome v1.3142 ANLN Zornitza Stark edited their review of gene: ANLN: Added comment: Further reports but evidence is conflicting, including variants with implausibly high pop frequency.

Gbadegesin et al (2014); Hall et al (2018) 2 x families reported with FSGS (USA) and missense variants G618C (v4: absent) and R431C (v4: 63 hets, 0 hom). R431C was identified in 6 affected family members and absent in 6 unaffected family members. G618C was present in the proband and absent in 4 unaffected family members, the other 2 affected individuals from this family were not genotyped (deceased). Missense demostrated as LoF with both in vitro and in vivo (zebrafish). R431C was shown to disrupt interaction with CD2AP (primarily LoF effect), causing downstream hyperactivation of the PI3K/AKT/mTOR/Rac1 signaling pathway, which drives podocytes hypermotility.

Geminiganesan et al (2021) 1 x 2 year old child (India) with early-onset steroid resistant nephrotic syndrome, whole-exome sequencing and genome-wide linkage studies, a missense variant in ANLN was identified p.Thr821Met (v4: 508 hets, 0 hom).

Zhang et al (2023) 3 x children with steroid resistant nephrotic syndrome (China). 2 x missense (p.M1099I - LP (v4:1 het, 0 hom), p.S140T - VUS (v4: 6 hets, 0 hom) and 1 x stop gain reported p.R39X - LP ( v4: 1 het, 0 hom).

Lin et al (2023) 3 x unrelated individuals with missense E841K (China, v4: 618 hets, 2 hom). In famly A the variant was de novo, in family 2 only the proband as tested, in family 3 the variant was inherited from an affected father. 4 x unaffected individuals did not have the variant. Knockout mouse model inconclusive, did not show any effect until 36 weeks. Zebrafish model was also inconclusive.; Changed publications: 24676636, 30002222, 34819827, 38322629, 37957688
Mendeliome v1.3142 COL4A3BP Zornitza Stark Phenotypes for gene: COL4A3BP were changed from Intellectual developmental disorder 34 (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3141 COL4A3BP Zornitza Stark edited their review of gene: COL4A3BP: Changed phenotypes: Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3141 COL4A3BP Zornitza Stark Phenotypes for gene: COL4A3BP were changed from Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351) to Intellectual developmental disorder 34 (MIM#616351)
Mendeliome v1.3140 PRKCI Zornitza Stark Marked gene: PRKCI as ready
Mendeliome v1.3140 PRKCI Zornitza Stark Gene: prkci has been classified as Green List (High Evidence).
Mendeliome v1.3140 PRKCI Zornitza Stark Phenotypes for gene: PRKCI were changed from Van der Woude syndrome MONDO:0019508 to Van der Woude syndrome MONDO:0019508, PRKCI-related
Mendeliome v1.3139 PRKCI Zornitza Stark Classified gene: PRKCI as Green List (high evidence)
Mendeliome v1.3139 PRKCI Zornitza Stark Gene: prkci has been classified as Green List (High Evidence).
Mendeliome v1.3138 PRKCI Zornitza Stark reviewed gene: PRKCI: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Van der Woude syndrome MONDO:0019508, PRKCI-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3138 TMEM167A Zornitza Stark Marked gene: TMEM167A as ready
Mendeliome v1.3138 TMEM167A Zornitza Stark Gene: tmem167a has been classified as Green List (High Evidence).
Mendeliome v1.3138 BAIAP3 Zornitza Stark Marked gene: BAIAP3 as ready
Mendeliome v1.3138 BAIAP3 Zornitza Stark Gene: baiap3 has been classified as Red List (Low Evidence).
Mendeliome v1.3138 BAIAP3 Zornitza Stark gene: BAIAP3 was added
gene: BAIAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BAIAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BAIAP3 were set to 40943168
Phenotypes for gene: BAIAP3 were set to Retinitis pigmentosa MONDO:0019200, BAIAP3-related
Review for gene: BAIAP3 was set to RED
Added comment: 1 individual with retinitis pigmentosa with onset at 18yrs. Trio WGS identified biallelic missense variants in BAIAP3 gene (c.556C>G [p.Arg186Gly] and c.3099C>G [p.His1033Gln]). Both variants were very rare in gnomAD, and the healthy brother was heterozygous for one variant. BAIAP3 interacts with SNARE proteins, whose function is essential for endosome-mediated retrograde trafficking. Single-cell RNA sequencing profiling showed enhanced expression of the BAIAP3 gene in ciliated cells, astrocytes, excitatory and inhibitory neurons, and enteroendocrine cells. Confocal microscopy analysis showed elongated cilia in patient-derived and BAIAP3-depleted fibroblasts compared to control cells.
Sources: Literature
Mendeliome v1.3137 KDM5A Rylee Peters reviewed gene: KDM5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 33350388; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), KDM5A-related, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3137 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Congenital hydrocephalus 4 (MIM#618667) to Congenital hydrocephalus 4 (MIM#618667)
Mendeliome v1.3137 TRIM71 Elena Savva Phenotypes for gene: TRIM71 were changed from Hydrocephalus, congenital communicating, 1 618667 to Congenital hydrocephalus 4 (MIM#618667)
Mendeliome v1.3136 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3135 COL4A3BP Elena Savva Phenotypes for gene: COL4A3BP were changed from Intellectual developmental disorder 34 (MIM#616351) to Neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (MIM#616351)
Mendeliome v1.3134 PRKCI Sangavi Sivagnanasundram gene: PRKCI was added
gene: PRKCI was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKCI was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRKCI were set to 40902599
Phenotypes for gene: PRKCI were set to Van der Woude syndrome MONDO:0019508
Review for gene: PRKCI was set to AMBER
Added comment: Multiple reported variants in affected individuals mainly presenting with lower lip pits and orofacial clefts (OFCs). Some individuals presented with a more severe phenotype inclusing seizures, ID/DD and urogenital anomalies. Supportive zebrafish model supporting a loss-of-function mechanism was performed on three recurrent variants [c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe)] however there is not enough evidence to show that LoF is the mechanism of disease.

The gene is not constrained for LoF in gnomAD and there are no pathogenic SNVs reported in ClinVar at this present time. Amber until further evidence is published in support of this gene-disease association.
Sources: Literature
Mendeliome v1.3134 TMEM167A Chirag Patel Classified gene: TMEM167A as Green List (high evidence)
Mendeliome v1.3134 TMEM167A Chirag Patel Gene: tmem167a has been classified as Green List (High Evidence).
Mendeliome v1.3133 TMEM167A Chirag Patel gene: TMEM167A was added
gene: TMEM167A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to PMID: 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome MONDO:0100328, TMEM167A-related
Review for gene: TMEM167A was set to GREEN
Added comment: 6 individuals from 6 unrelated families (4/6 consanguineous) presenting with neonatal diabetes onset <4mths (6/6), severe microcephaly (6/6), epilepsy (5/6), and developmental delay (4/6).

Whole genome sequencing identified biallelic variants in TMEM167A gene. Variants were homozygous in 5/6 families, and variant types were missense (4), frameshift (1), and splice (1), and all variants were rare/unreported in gnomAD. Segregation studies not reported in paper.

Microcephaly, epilepsy and diabetes syndrome has 2 known associated genes (IER3IP1 and YIPF5) which encode proteins involved in endoplasmic reticulum to Golgi trafficking. TMEM167A is highly expressed in developing and adult human pancreas and brain. Both TMEM167A depletion in EndoC-βH1 cells and knock‑in of p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction.
Sources: Literature
Mendeliome v1.3132 QRSL1 Zornitza Stark Phenotypes for gene: QRSL1 were changed from Combined oxidative phosphorylation deficiency 40 to Combined oxidative phosphorylation deficiency 40 MIM#618835
Mendeliome v1.3131 RAB11A Zornitza Stark Phenotypes for gene: RAB11A were changed from Intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, RAB11A-related
Mendeliome v1.3130 CETN3 Zornitza Stark Marked gene: CETN3 as ready
Mendeliome v1.3130 CETN3 Zornitza Stark Gene: cetn3 has been classified as Red List (Low Evidence).
Mendeliome v1.3130 CETN3 Zornitza Stark Classified gene: CETN3 as Red List (low evidence)
Mendeliome v1.3130 CETN3 Zornitza Stark Gene: cetn3 has been classified as Red List (Low Evidence).
Mendeliome v1.3129 PYGM Zornitza Stark Phenotypes for gene: PYGM were changed from McArdle disease, MIM# 232600; Glycogen storage disease, autosomal dominant to McArdle disease, MIM# 232600; Disorder of glycogen metabolism MONDO:0002412, PYGM-related, AD
Mendeliome v1.3128 ZNF865 Zornitza Stark Marked gene: ZNF865 as ready
Mendeliome v1.3128 ZNF865 Zornitza Stark Gene: znf865 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3128 ZNF865 Zornitza Stark Classified gene: ZNF865 as Amber List (moderate evidence)
Mendeliome v1.3128 ZNF865 Zornitza Stark Gene: znf865 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3127 ZNF865 Zornitza Stark reviewed gene: ZNF865: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ZNF865‑associated neurodevelopmental disorder MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3127 PTPRC Zornitza Stark Phenotypes for gene: PTPRC were changed from Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive MIM# 608971; Hepatitis C virus, susceptibility to MIM# 609532 to Immunodeficiency 105, severe combined MIM#619924; Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive MIM# 608971; Hepatitis C virus, susceptibility to MIM# 609532
Mendeliome v1.3126 PTPN22 Zornitza Stark Phenotypes for gene: PTPN22 were changed from to Autoimmune disease MONDO:0007179, PTPN22-related
Mendeliome v1.3125 PTPA Zornitza Stark Phenotypes for gene: PTPA were changed from Intellectual disability, MONDO: 36073231, PTPA-related to Intellectual disability, MONDO: 36073231, PTPA-related; Parkinson disease MONDO:0005180, PTPA-related
Mendeliome v1.3124 PTGS1 Zornitza Stark Phenotypes for gene: PTGS1 were changed from Platelet dysfunction; bleeding to Platelet-type bleeding disorder 12 MONDO:0011588
Mendeliome v1.3123 PTCH1 Zornitza Stark Phenotypes for gene: PTCH1 were changed from Holoprosencephaly 7, MIM# 610828; Bladder exstrophy and epispadias complex (BEEC) to Holoprosencephaly 7, MIM# 610828; Exstrophy-epispadias complex MONDO:0017919, PTCH1-related
Mendeliome v1.3122 PTCD1 Zornitza Stark Phenotypes for gene: PTCD1 were changed from Cardiomyopathy to Cardiomyopathy MONDO:0004994, PTCD1-related
Mendeliome v1.3121 PSMC1 Zornitza Stark Phenotypes for gene: PSMC1 were changed from Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss , MIM# 620071 to Birk-Aharoni syndrome MIM# 620071
Mendeliome v1.3120 SRP72 Zornitza Stark Publications for gene: SRP72 were set to 22541560; 31254415
Mendeliome v1.3119 CETN3 Rylee Peters gene: CETN3 was added
gene: CETN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CETN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CETN3 were set to 40926052
Phenotypes for gene: CETN3 were set to microcephaly, MONDO:0001149, CETN3-related
Review for gene: CETN3 was set to RED
Added comment: PMID: 40926052: 1x cHet individual with primary microcephaly (-2 SD at birth and -3 SD at 5yo), motor delay, enlarged bilateral ventricles on MRI, horizontal nystagmus. Two frameshift variants identified, p.Lys15Glufs*9 (5’ NMD-escape; 432 hets, 2 homs in gnomAD v4) and p.Asp40Lysfs*5 (NMD-predicted; filtered out in v4).

CETN3-KO hCOs (human cerebral organoids) were significantly smaller than control hCOs.
The identified patient variants were introduced into WT iPSCs. Western blot analysis demonstrated a complete loss of CETN3 protein in both CETN3-KO cells and CETN3-mutant iPSCs. These were then used to generate hCOs, both of which exhibited reduced size compared to their respective controls.

Forebrain-specific Cetn3-ablated mice were also generated. At embryonic day 13.5 a significant but subtle reduction in forebrain size was detected in Cetn3-KO mice compared to control, while no difference was observed at P0.
Sources: Literature
Mendeliome v1.3119 TOM1 Zornitza Stark Publications for gene: TOM1 were set to 31263572; 40936361
Mendeliome v1.3118 RAB11A Lucy Spencer reviewed gene: RAB11A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, RAB11A-related; Mode of inheritance: None
Mendeliome v1.3118 TOM1 Zornitza Stark Publications for gene: TOM1 were set to 31263572
Mendeliome v1.3117 TOM1 Zornitza Stark Classified gene: TOM1 as Amber List (moderate evidence)
Mendeliome v1.3117 TOM1 Zornitza Stark Gene: tom1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3116 QRSL1 Lucy Spencer reviewed gene: QRSL1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 40 MIM#618835; Mode of inheritance: None
Mendeliome v1.3116 PYGM Lucy Spencer reviewed gene: PYGM: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Disorder of glycogen metabolism MONDO:0002412, PYGM-related, AD; Mode of inheritance: None
Mendeliome v1.3116 SNAPIN Zornitza Stark Marked gene: SNAPIN as ready
Mendeliome v1.3116 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Mendeliome v1.3116 SNAPIN Zornitza Stark Classified gene: SNAPIN as Green List (high evidence)
Mendeliome v1.3116 SNAPIN Zornitza Stark Gene: snapin has been classified as Green List (High Evidence).
Mendeliome v1.3115 PSMB8 Zornitza Stark Publications for gene: PSMB8 were set to 21129723; 21881205; 21852578; 21953331
Mendeliome v1.3114 PSMB8 Zornitza Stark Mode of inheritance for gene: PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3113 ZNF865 Sangavi Sivagnanasundram gene: ZNF865 was added
gene: ZNF865 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to ZNF865‑associated neurodevelopmental disorder MONDO:0700092
Review for gene: ZNF865 was set to AMBER
Added comment: PMID: 40936200
18 patients reported with DD, hypotonia and six individuals were reported with some dysmorphic features (frontal bossing, a broad nasal bridge, hypertelorism, and low-set ears)
All 18 individuals were reported with de novo truncating variants in ZNF865. All variants were rare/absent in gnomAD v4.1.

The mechanism of disease for this gene is unknown. No pathogenic SNVs have been reported in ClinVar at this stage however there are reports of VUS’s and pathogenic CNVs.
Sources: Literature
Mendeliome v1.3113 PTPRC Lucy Spencer reviewed gene: PTPRC: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 105, severe combined MIM#619924; Mode of inheritance: None
Mendeliome v1.3113 PTPN22 Lucy Spencer reviewed gene: PTPN22: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoimmune disease MONDO:0007179, PTPN22-related; Mode of inheritance: None
Mendeliome v1.3113 PTPA Lucy Spencer reviewed gene: PTPA: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Parkinson disease MONDO:0005180, PTPA-related; Mode of inheritance: None
Mendeliome v1.3113 PTGS1 Lucy Spencer reviewed gene: PTGS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Platelet-type bleeding disorder 12 MONDO:0011588; Mode of inheritance: None
Mendeliome v1.3113 PTCH1 Lucy Spencer reviewed gene: PTCH1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Exstrophy-epispadias complex MONDO:0017919, PTCH1-related; Mode of inheritance: None
Mendeliome v1.3113 PTCD1 Lucy Spencer reviewed gene: PTCD1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy MONDO:0004994, PTCD1-related; Mode of inheritance: None
Mendeliome v1.3113 PSMC1 Lucy Spencer reviewed gene: PSMC1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Birk-Aharoni syndrome MIM# 620071; Mode of inheritance: None
Mendeliome v1.3113 PSMB8 Lucy Spencer reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3113 SRP72 Lucy Spencer reviewed gene: SRP72: Rating: AMBER; Mode of pathogenicity: None; Publications: 40922878; Phenotypes: Bone marrow failure syndrome 1, MIM#614675; Mode of inheritance: None
Mendeliome v1.3113 TOM1 Lucy Spencer reviewed gene: TOM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 40936361, 33864888; Phenotypes: Immunodeficiency 85 and autoimmunity MIM#619510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3113 SNAPIN Lucy Spencer gene: SNAPIN was added
gene: SNAPIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097; 26539891
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder (MONDO:0700092), SNAPIN-related
Review for gene: SNAPIN was set to GREEN
Added comment: PMID: 40930097 6 patients from 5 families with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI, all homozygous for variants in SNAPIN. 2 stopgain, 1 canonical splice, 5 missense. common phenotypes: ventriculomegaly 5/6, cerebellar hypoplasia/atrophy 5/6, clubfeet 4/6, corpus callosum agenesis 4/6, flexion contractures 4/6, microcephaly 3/6, micrognathia/retrognathia 4/6. The patients with the nonsense or splice variants did not survive the perinatal period, while those with missense survived into early childhood.

This paper also mentions a 7th patient reported in PMID: 26539891, who has ID, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy, and hypotonia. They are homozygous for a missense variant Asn55Tyr. Of note, the other paper report this as Arg55Trp and one of their patients also has this variant, based off the transcript information provided in both papers Arg55Trp is correct.

PMID: 40930097 Knockout zebrafish models recapitulated the human phenotype. This phenotype was rescued by injecting WT human SNAPIN RNA. Injection with the 2 missense variants observed in patients in this study was able to partially rescue the phenotype but it was significantly worse than the rescue with WT injection. One of these missense variants is absent from gnomad (Arg55Trp) while the other (Glu49Asp) has 167 hets and 1 hom.
Sources: Literature
Mendeliome v1.3113 PSMB8 Rylee Peters reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40666351, https://dx.doi.org/10.2139/ssrn.5370606; Phenotypes: Proteosome-associated autoinflammatory syndrome MONDO:0009726, PSMB8-related, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3113 HK1 Chirag Patel reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40033430; Phenotypes: Hyperinsulinism MONDO:0002177, HK1-related; Mode of inheritance: None
Mendeliome v1.3113 MCMDC2 Zornitza Stark Marked gene: MCMDC2 as ready
Mendeliome v1.3113 MCMDC2 Zornitza Stark Gene: mcmdc2 has been classified as Green List (High Evidence).
Mendeliome v1.3113 MCMDC2 Zornitza Stark Publications for gene: MCMDC2 were set to PMID: 40897906, 35172124, 39789727, 36732629
Mendeliome v1.3112 MCMDC2 Zornitza Stark Classified gene: MCMDC2 as Green List (high evidence)
Mendeliome v1.3112 MCMDC2 Zornitza Stark Gene: mcmdc2 has been classified as Green List (High Evidence).
Mendeliome v1.3111 TGFB2 Zornitza Stark Phenotypes for gene: TGFB2 were changed from Loeys-Dietz syndrome 4, MIM# 614816 to Loeys-Dietz syndrome 4, MIM# 614816; Camurati-Engelmann disease 2, MIM# 606631
Mendeliome v1.3110 TGFB2 Zornitza Stark Publications for gene: TGFB2 were set to
Mendeliome v1.3109 TGFB2 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen.; to: DEFINITIVE by ClinGen for LDS.
Mendeliome v1.3109 TGFB2 Zornitza Stark edited their review of gene: TGFB2: Added comment: Second skeletal phenotype associated with variants in this gene: Camurati-Engelmann disease-2 (CAEND2). This is an autosomal dominant disorder characterized by progressive diaphyseal dysplasia, associated with a waddling gait, muscle weakness, and severe leg pain. Bone striations are present in the spine, pelvis, and long tubular bones, with epiphyseal sclerosis. Coarse sclerotic trabeculae are observed in the short tubular bones. Skull involvement may be minimal. Four unrelated families reported in PMIDs 39014191 and 40204055. Variants were de novo in 3 of the families, and segregated with disease in the fourth.; Changed publications: 39014191, 40204055; Changed phenotypes: Loeys-Dietz syndrome 4, MIM# 614816, Camurati-Engelmann disease 2, MIM# 606631
Mendeliome v1.3109 PLD4 Zornitza Stark Marked gene: PLD4 as ready
Mendeliome v1.3109 PLD4 Zornitza Stark Gene: pld4 has been classified as Green List (High Evidence).
Mendeliome v1.3109 PLD4 Krithika Murali Classified gene: PLD4 as Green List (high evidence)
Mendeliome v1.3109 PLD4 Krithika Murali Gene: pld4 has been classified as Green List (High Evidence).
Mendeliome v1.3108 PLD4 Krithika Murali gene: PLD4 was added
gene: PLD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD4 were set to PMID:40931063
Phenotypes for gene: PLD4 were set to Systemic lupus erythematosus - MONDO:0007915, PLD4-related
Review for gene: PLD4 was set to GREEN
Added comment: PMID:40931063 Wang et al 2025 (Nature) - report 5 unrelated individuals with SLE and biallelic variants in PLD4. Variants were either PTC or missense variants that localised to the catalytic domain. Functional evidence supported LoF mechanism with the variants impairing PLD4 exonuclease activity resulting in aberrant type I IFN signalling activation. pld4-deficient mice had an autoimmune phenotype.
Sources: Literature
Mendeliome v1.3107 MCMDC2 Sarah Milton gene: MCMDC2 was added
gene: MCMDC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCMDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCMDC2 were set to PMID: 40897906, 35172124, 39789727, 36732629
Phenotypes for gene: MCMDC2 were set to Azoospermia, MONDO:0100459, MCMDC2-related
Review for gene: MCMDC2 was set to GREEN
Added comment: MCMDC2 encodes minichromosome maintenance domain-containing 2. It is involved in meiotic recombination and double stranded break repair for maintenance of fertility.

6 male individuals have been described thus far with homozygous missense/nonsense/fs variants with non obstructive azoospermia. Loss of function is the proposed mechanism of disease.

MCMDC2 knockout mice have issues with double stranded break repair in meiosis and subsequent aberrant gametogenesis.

1 female individual has been described with a homozygous nonsense variant with premature ovarian insufficiency, in the same publication a heterozygous female was also described to have the same phenotype. Functional studies on variants in these two individuals demonstrated homologous repair efficiency to be reduced compared to wild type.

Homozygous LOF variants are absent in gnomAD v4.
Sources: Literature
Mendeliome v1.3107 SKOR2 Zornitza Stark Marked gene: SKOR2 as ready
Mendeliome v1.3107 SKOR2 Zornitza Stark Gene: skor2 has been classified as Green List (High Evidence).
Mendeliome v1.3107 BNIP1 Zornitza Stark Phenotypes for gene: BNIP1 were changed from spondyloepiphyseal dysplasia MONDO:0016761 to Spondylopeiphyseal dysplasia, Holling type, MIM# 621345
Mendeliome v1.3106 BNIP1 Zornitza Stark reviewed gene: BNIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondylopeiphyseal dysplasia, Holling type, MIM# 621345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3106 SKOR2 Bryony Thompson Classified gene: SKOR2 as Green List (high evidence)
Mendeliome v1.3106 SKOR2 Bryony Thompson Gene: skor2 has been classified as Green List (High Evidence).
Mendeliome v1.3105 SKOR2 Bryony Thompson gene: SKOR2 was added
gene: SKOR2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 40890458; 29997391; 21937600
Phenotypes for gene: SKOR2 were set to complex neurodevelopmental disorder with motor features MONDO:0100516
Review for gene: SKOR2 was set to GREEN
Added comment: 3 unrelated families with consistent phenotypes and a supportive mouse model:
PMID: 40890458 - 2 unrelated consanguineous Iranian families with a combination of learning disability, facial dysmorphisms, and motor and speech impairments with homozygous variants (c.374 G>C: p.Arg125Pro & c.1271_1274del: p.K424Rfs*71). The homozygous missense variant segregated with disease in 8 individuals (no unaffected individuals tested were homozygous).

PMID: 29997391 - proband with neurodevelopmental delay, hypotonia, ataxia, cerebellar dysplasia from a consanguineous Turkish family with a homozygous null variant (NM_001278063.1:c.2750C>G; p.Ser917*). None of the 4 healthy siblings were homozygous for the variant.

PMID: 21937600 - Skor2 -/- mouse model had defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Mouse had unstable gait.
Sources: Literature
Mendeliome v1.3104 SLC38A6 Bryony Thompson Marked gene: SLC38A6 as ready
Mendeliome v1.3104 SLC38A6 Bryony Thompson Gene: slc38a6 has been classified as Red List (Low Evidence).
Mendeliome v1.3104 SLC38A6 Bryony Thompson edited their review of gene: SLC38A6: Changed rating: RED
Mendeliome v1.3104 SLC38A6 Bryony Thompson gene: SLC38A6 was added
gene: SLC38A6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC38A6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC38A6 were set to 40931016
Phenotypes for gene: SLC38A6 were set to essential tremor MONDO:0003233
Review for gene: SLC38A6 was set to AMBER
Added comment: The study identified SLC38A6 variants in 71 unrelated Chinese ET families (≈9.2% of families) and 47 unrelated sporadic cases, with 15 distinct protein‑altering variants. However, many of the 15 variants are >2% in the East Asian population, which is inconsistent with the incidence of essential tremor in the population (~1%). The study does not contain any statistical enrichment analyses or case-control analyses. It also reports incomplete segregation and non-segregation of variants (called a phenocopy by the authors). A null mouse model (Slc38a6-/-) displays tremor and delineated cerebellar cellular abnormalities. In vitro assessment of 3 of the most common missense variants (p.Y108F [gnomAD total 0.0002; East Asian 0.006, p.M281T [gnomAD total 0.0015; East Asian 0.0227] and p.G318S [gnomAD total 0.0021; East Asian 0.0278]) significantly impaired L-arginine (L-Arg) uptake in HeLa cells. Given the prevalence of the reported variants in the East Asian population, the genetic evidence for this gene-disease association is limited.
Sources: Literature
Mendeliome v1.3103 PATJ Zornitza Stark Marked gene: PATJ as ready
Mendeliome v1.3103 PATJ Zornitza Stark Gene: patj has been classified as Red List (Low Evidence).
Mendeliome v1.3103 PATJ Zornitza Stark Classified gene: PATJ as Red List (low evidence)
Mendeliome v1.3103 PATJ Zornitza Stark Gene: patj has been classified as Red List (Low Evidence).
Mendeliome v1.3102 PATJ Sarah Milton changed review comment from: PATJ encodes PALS1-associated tight junction protein.

PMID: 40931526 describes 1 affected fetus with hydrocephalus and polycystic kidney disease with a homozygous NMD predicted variant.

Some supportive zebrafish functional data.

Homozygous NMD predicted variants rare in gnomAD v4.
Sources: Literature; to: PATJ encodes PALS1-associated tight junction protein.

PMID: 40931526 describes 1 affected fetus with hydrocephalus and polycystic kidney disease with a homozygous NMD predicted variant.

Some supportive zebrafish functional data.

Homozygous NMD predicted variants are rare in gnomAD v4.
Sources: Literature
Mendeliome v1.3102 PATJ Sarah Milton gene: PATJ was added
gene: PATJ was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PATJ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PATJ were set to PMID: 40931526
Phenotypes for gene: PATJ were set to Ciliopathy, MONDO:0005308, PATJ-related
Review for gene: PATJ was set to RED
Added comment: PATJ encodes PALS1-associated tight junction protein.

PMID: 40931526 describes 1 affected fetus with hydrocephalus and polycystic kidney disease with a homozygous NMD predicted variant.

Some supportive zebrafish functional data.

Homozygous NMD predicted variants rare in gnomAD v4.
Sources: Literature
Mendeliome v1.3102 DHRS9 Zornitza Stark Marked gene: DHRS9 as ready
Mendeliome v1.3102 DHRS9 Zornitza Stark Gene: dhrs9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3102 DHRS9 Zornitza Stark Classified gene: DHRS9 as Amber List (moderate evidence)
Mendeliome v1.3102 DHRS9 Zornitza Stark Gene: dhrs9 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3101 DHRS9 Zornitza Stark gene: DHRS9 was added
gene: DHRS9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS9 were set to 40945732; 32752300; 38256219
Phenotypes for gene: DHRS9 were set to Genetic epilepsy, MONDO:0100575, DHRS9
Review for gene: DHRS9 was set to AMBER
Added comment: PMID 40945732: Single individual reported with compound heterozygous missense variants, c.605C>T (p.S202L); c.856G>C (p.D286H) and early onset epilepsy. Functional studies conducted on both variants separately, demonstrating loss of function.

PMID 32752300: compound het missense variants in an individual with epilepsy.

PMID 38256219: put forward as a candidate gene in an epilepsy cohort, compound het missense variants identified c.785C>T (p.Ser262Leu) and c.1036G>C (p.Asp346His).
Sources: Literature
Mendeliome v1.3100 MAP3K6 Zornitza Stark Marked gene: MAP3K6 as ready
Mendeliome v1.3100 MAP3K6 Zornitza Stark Gene: map3k6 has been classified as Red List (Low Evidence).
Mendeliome v1.3100 MAP3K6 Zornitza Stark gene: MAP3K6 was added
gene: MAP3K6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAP3K6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K6 were set to 33728376; 40947452
Phenotypes for gene: MAP3K6 were set to Neurovascular disorder, MONDO:0043218, MAP3K6-related
Review for gene: MAP3K6 was set to RED
Added comment: PMID 33728376: large multiplex family segregating a missense variant, p.Asp108Asn and stroke episodes, cognitive impairment and tremor. Same family reported in PMID 40947452, with additional feature of basal ganglia calcification.
Sources: Literature
Mendeliome v1.3099 ELFN1 Zornitza Stark Marked gene: ELFN1 as ready
Mendeliome v1.3099 ELFN1 Zornitza Stark Gene: elfn1 has been classified as Green List (High Evidence).
Mendeliome v1.3099 ELFN1 Zornitza Stark Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092, ELFN1-related to Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344
Mendeliome v1.3098 ELFN1 Zornitza Stark reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dursun-Ozgul neurodevelopmental syndrome, MIM# 621344; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3098 TRPC4AP Zornitza Stark Marked gene: TRPC4AP as ready
Mendeliome v1.3098 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3098 TRPC4AP Zornitza Stark Classified gene: TRPC4AP as Amber List (moderate evidence)
Mendeliome v1.3098 TRPC4AP Zornitza Stark Gene: trpc4ap has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3097 TRPC4AP Zornitza Stark gene: TRPC4AP was added
gene: TRPC4AP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC4AP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPC4AP were set to 32428920; 26786105
Phenotypes for gene: TRPC4AP were set to Thyroid hypoplasia, MONDO:0019861, TRPC4AP-related
Review for gene: TRPC4AP was set to AMBER
Added comment: De novo LoF TRPC4AP variant identified on WES in a child with thyroid dyshormonogenesis.
179 patients with CHTD sequenced using a panel of target genes identifying four variants in TRPC4AP. During development, Choukair et al. showed that Trpc4ap is expressed in the brain, the thyroid bud, and the kidney of the African clawed frog (Xenopus laevis). This team showed that disabling Trpc4ap in the African clawed frog leads to thyroid hypoplasia during development. It was also shown that TRPC4AP interacted with IKBKG which activates the NF-κB signaling pathway and regulates the genes involved in the growth and survival of thyrocytes. Furthermore, the NF-kB would control the expression of NKX2-1, PAX8, TPO, NIS, and TG.18 The authors conclude that TRPC4AP would be a new candidate gene for TDs. Insufficient clinical cases for green. Candidate gene.
Sources: Literature
Mendeliome v1.3096 PSMB1 Zornitza Stark Phenotypes for gene: PSMB1 were changed from Intellectual disability; microcephaly to Neurodevelopmental disorder MONDO:0700092, PSMB1-related
Mendeliome v1.3095 PSAT1 Zornitza Stark Phenotypes for gene: PSAT1 were changed from Phosphoserine aminotransferase deficiency 610992; Neu-Laxova syndrome 2 616038 to Neurometabolic disorder due to serine deficiency MONDO:0018162, PSAT1-related
Mendeliome v1.3094 PRX Zornitza Stark Phenotypes for gene: PRX were changed from Charcot-Marie-Tooth disease, type 4F, MIM# 614895; Dejerine-Sottas disease, MIM# 145900 to Charcot-Marie-Tooth disease type 4 MONDO:0018995
Mendeliome v1.3093 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751 to PRRT2-associated paroxysmal movement disorder MONDO:0100556
Mendeliome v1.3092 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from Arts syndrome MIM#301835; Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070; Deafness, X-linked 1 MIM#304500; Gout, PRPS-related MIM#300661; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661 to PRPS1 deficiency disorder MONDO:0100061; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661
Mendeliome v1.3091 PRPH2 Zornitza Stark Phenotypes for gene: PRPH2 were changed from Leber congenital amaurosis 18, MIM#608133; Macular dystrophy, vitelliform, 3, MIM#608161; Retinitis pigmentosa 7 and digenic form, MIM#608133; Choroidal dystrophy, central areolar 2, MIM#613105; Macular dystrophy, patterned, 1, MIM#169150; Retinitis punctata albescens, MIM#136880 to PRPH2-related retinopathy MONDO:1040055
Mendeliome v1.3090 PROM1 Zornitza Stark Phenotypes for gene: PROM1 were changed from 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 to PROM1-related dominant retinopathy MONDO:1040053; Cone-rod dystrophy 12, MIM# 612657; Retinitis pigmentosa 41, MIM# 612095
Mendeliome v1.3089 PRKAG3 Zornitza Stark Phenotypes for gene: PRKAG3 were changed from increased glycogen content in skeletal muscle to Skeletal muscle glycogen content and metabolism QTL MIM#619030
Mendeliome v1.3088 PSMB1 Lucy Spencer reviewed gene: PSMB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PSMB1-related; Mode of inheritance: None
Mendeliome v1.3088 PSAT1 Lucy Spencer reviewed gene: PSAT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurometabolic disorder due to serine deficiency MONDO:0018162, PSAT1-related; Mode of inheritance: None
Mendeliome v1.3088 PRX Lucy Spencer reviewed gene: PRX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease type 4 MONDO:0018995; Mode of inheritance: None
Mendeliome v1.3088 PRRT2 Lucy Spencer reviewed gene: PRRT2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRRT2-associated paroxysmal movement disorder MONDO:0100556; Mode of inheritance: None
Mendeliome v1.3088 PRPS1 Lucy Spencer reviewed gene: PRPS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPS1 deficiency disorder MONDO:0100061; Mode of inheritance: None
Mendeliome v1.3088 PRPH2 Lucy Spencer reviewed gene: PRPH2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PRPH2-related retinopathy MONDO:1040055; Mode of inheritance: None
Mendeliome v1.3088 PROM1 Lucy Spencer reviewed gene: PROM1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: PROM1-related dominant retinopathy MONDO:1040053; Mode of inheritance: None
Mendeliome v1.3088 PRKAG3 Lucy Spencer reviewed gene: PRKAG3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal muscle glycogen content and metabolism QTL MIM#619030; Mode of inheritance: None
Mendeliome v1.3088 PRDX3 Zornitza Stark Phenotypes for gene: PRDX3 were changed from cerebellar ataxia (early onset, mild to moderate, progressive) to Cerebellar ataxia MONDO:0000437, PRDX3-related
Mendeliome v1.3087 PRDX3 Lucy Spencer reviewed gene: PRDX3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar ataxia MONDO:0000437, PRDX3-related; Mode of inheritance: None
Mendeliome v1.3087 HEY2 Zornitza Stark Phenotypes for gene: HEY2 were changed from congenital heart disease MONDO:0005453; thoracic aortic aneurysms to Congenital heart disease, MONDO:0005453, HEY2-related; thoracic aortic aneurysms
Mendeliome v1.3086 HEY2 Zornitza Stark Publications for gene: HEY2 were set to 32820247
Mendeliome v1.3085 HEY2 Zornitza Stark Deleted their comment
Mendeliome v1.3085 HEY2 Zornitza Stark commented on gene: HEY2: Further family reported segregating a missense variant and Tetralogy of Fallot.
Mendeliome v1.3085 HEY2 Zornitza Stark edited their review of gene: HEY2: Added comment: Further family reported segregating a missense variant and Tetralogy of Fallot.; Changed publications: 32820247, 40481234; Changed phenotypes: Congenital heart disease, MONDO:0005453, HEY2-related
Mendeliome v1.3085 ENPP5 Zornitza Stark Marked gene: ENPP5 as ready
Mendeliome v1.3085 ENPP5 Zornitza Stark Gene: enpp5 has been classified as Red List (Low Evidence).
Mendeliome v1.3085 ENPP5 Zornitza Stark gene: ENPP5 was added
gene: ENPP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ENPP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENPP5 were set to 40457511
Phenotypes for gene: ENPP5 were set to Skeletal dysplasia, MONDO:0018230, ENPP5-related
Review for gene: ENPP5 was set to RED
Added comment: Single affected individual reported distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis and a homozygous missense variant p.Gly58Val, affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts.
Sources: Literature
Mendeliome v1.3084 AXDND1 Zornitza Stark Marked gene: AXDND1 as ready
Mendeliome v1.3084 AXDND1 Zornitza Stark Gene: axdnd1 has been classified as Red List (Low Evidence).
Mendeliome v1.3084 AXDND1 Zornitza Stark gene: AXDND1 was added
gene: AXDND1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AXDND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AXDND1 were set to 40457935
Phenotypes for gene: AXDND1 were set to Spermatogenic failure, MONDO:0004983, AXDND1-related
Review for gene: AXDND1 was set to RED
Added comment: Single family reported with bi-allelic LoF variant.
Sources: Literature
Mendeliome v1.3083 KDF1 Zornitza Stark Marked gene: KDF1 as ready
Mendeliome v1.3083 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Mendeliome v1.3083 KDF1 Zornitza Stark Classified gene: KDF1 as Green List (high evidence)
Mendeliome v1.3083 KDF1 Zornitza Stark Gene: kdf1 has been classified as Green List (High Evidence).
Mendeliome v1.3082 KDF1 Zornitza Stark gene: KDF1 was added
gene: KDF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDF1 were set to 27838789; 40463401; 38501196
Phenotypes for gene: KDF1 were set to Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MIM# 617337
Review for gene: KDF1 was set to GREEN
Added comment: Three families reported.
Sources: Literature
Mendeliome v1.3081 KCNA4 Zornitza Stark Marked gene: KCNA4 as ready
Mendeliome v1.3081 KCNA4 Zornitza Stark Gene: kcna4 has been classified as Red List (Low Evidence).
Mendeliome v1.3081 KCNA4 Zornitza Stark gene: KCNA4 was added
gene: KCNA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA4 were set to 40472070
Phenotypes for gene: KCNA4 were set to Epilepsy, MONDO:0005027, KCNA4-related
Review for gene: KCNA4 was set to RED
Added comment: Single individual with de novo missense variant reported.
Sources: Literature
Mendeliome v1.3080 LIMK1 Zornitza Stark Marked gene: LIMK1 as ready
Mendeliome v1.3080 LIMK1 Zornitza Stark Gene: limk1 has been classified as Red List (Low Evidence).
Mendeliome v1.3080 LIMK1 Zornitza Stark gene: LIMK1 was added
gene: LIMK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LIMK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LIMK1 were set to 40491492
Phenotypes for gene: LIMK1 were set to Endocrine system disorder, MONDO:0005151, LIMK1-related
Review for gene: LIMK1 was set to RED
Added comment: Two individuals reported with divergent phenotypes and divergent underlying mechanisms postulated.

One individual exhibited epileptic encephalopathy and developmental delay, while the other showed common variable immune deficiency and glucose dysregulation. Actin polymerization was significantly decreased in individual 1, whereas it was increased in individual 2. Insulin-secreting cell lines expressing the LIMK1 variant of individual 1 exhibited significantly slower exocytosis, contrasting the rapid and uncontrolled exocytosis in individual 2. Intriguingly, both variants led to increased overall insulin secretion.

Hold off further panel distribution until phenotypic associations clarified through further case reports.
Sources: Literature
Mendeliome v1.3079 GBX1 Zornitza Stark Marked gene: GBX1 as ready
Mendeliome v1.3079 GBX1 Zornitza Stark Gene: gbx1 has been classified as Red List (Low Evidence).
Mendeliome v1.3079 GBX1 Zornitza Stark gene: GBX1 was added
gene: GBX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBX1 were set to 40519143
Phenotypes for gene: GBX1 were set to Neurodevelopmental disorder, MONDO:0700092, GBX1-related
Review for gene: GBX1 was set to RED
Added comment: Single individual with de novo LoF variant with DD and focal epilepsy. Zebrafish model had abnormal morphology of the interocular area. Furthermore, the zebrafish larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.
Sources: Literature
Mendeliome v1.3078 DHRS3 Zornitza Stark Marked gene: DHRS3 as ready
Mendeliome v1.3078 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3078 DHRS3 Zornitza Stark Classified gene: DHRS3 as Amber List (moderate evidence)
Mendeliome v1.3078 DHRS3 Zornitza Stark Gene: dhrs3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3077 DHRS3 Zornitza Stark gene: DHRS3 was added
gene: DHRS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRS3 were set to 40519748
Phenotypes for gene: DHRS3 were set to Syndromic disease, MONDO:0002254, DHRS3-related
Review for gene: DHRS3 was set to AMBER
Added comment: Five homozygotes from 3 families (1 family segregating a deletion of the promoter and 5'-untranslated region of DHRS3, the other 2 a missense variant p.(Val171Met)), manifested a congruent phenotype, including coronal craniosynostosis, dysmorphic facial features, congenital heart disease (4/5 individuals), and scoliosis (5/5 individuals). Transcription of DHRS3 in whole blood cells from 2 homozygotes for the promoter/5'-untranslated region deletion was 90% to 98% reduced. Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA; correspondingly, plasma from homozygous patients had significantly reduced retinol and elevated RA (exceeding the normal range), compared with controls and heterozygous relatives.

Three additional homozygous missense variants of DHRS3 (p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln)) were shown to reduce catalytic activity in vitro and/or in vivo but were associated with normal or different phenotypes that did not meet the threshold to assign likely pathogenicity.
Sources: Literature
Mendeliome v1.3076 DMRTA2 Zornitza Stark Marked gene: DMRTA2 as ready
Mendeliome v1.3076 DMRTA2 Zornitza Stark Gene: dmrta2 has been classified as Red List (Low Evidence).
Mendeliome v1.3076 DMRTA2 Zornitza Stark gene: DMRTA2 was added
gene: DMRTA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DMRTA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMRTA2 were set to 40541527; 26757254
Phenotypes for gene: DMRTA2 were set to Microcephaly, MONDO:0001149, DMRTA2-related
Review for gene: DMRTA2 was set to RED
Added comment: Single family reported with three affected siblings and bi-allelic LoF variant. Newly published functional data but no further reports.
Sources: Literature
Mendeliome v1.3075 RCC1 Zornitza Stark Phenotypes for gene: RCC1 were changed from Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related to Infection-induced acute-onset axonal neuropathy, MIM# 621333
Mendeliome v1.3074 RCC1 Zornitza Stark edited their review of gene: RCC1: Changed phenotypes: Infection-induced acute-onset axonal neuropathy, MIM# 621333
Mendeliome v1.3074 ICK Chirag Patel reviewed gene: ICK: Rating: ; Mode of pathogenicity: None; Publications: PMID: 40615527; Phenotypes: Cranioectodermal dysplasia MONDO:0009032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3074 MTERF3 Zornitza Stark Marked gene: MTERF3 as ready
Mendeliome v1.3074 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3074 MTERF3 Zornitza Stark Classified gene: MTERF3 as Amber List (moderate evidence)
Mendeliome v1.3074 MTERF3 Zornitza Stark Gene: mterf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3073 MTERF3 Zornitza Stark gene: MTERF3 was added
gene: MTERF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTERF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTERF3 were set to 40543543
Phenotypes for gene: MTERF3 were set to Mitochondrial disease (MONDO:0044970), MTERF3-related
Review for gene: MTERF3 was set to AMBER
Added comment: Two individuals reported from unrelated families, presenting with DD/ID, intermittent hypoglycaemia and metabolic acidosis. Genetic testing identified compound heterozygous variants c.635dup p.(Asn212Lysfs*7) and c.1055C > T p.(Pro352Leu) in Patient 1, and a homozygous variant c.943A > Gp.(Met315Val) in Patient 2. Patient's fibroblasts and MTERF3 knockdown cells showed impaired mitochondrial respiration and reduced levels of OXPHOS complexes I, III, and IV. Transcription of MT-ND5, ND6, COII, and COIII was reduced, while other mitochondrial genes were upregulated. Wild-type MTERF3 expression restored these defects, but the variant Pro352Leu from patient failed to rescue mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.3072 KCNJ15 Zornitza Stark Marked gene: KCNJ15 as ready
Mendeliome v1.3072 KCNJ15 Zornitza Stark Gene: kcnj15 has been classified as Red List (Low Evidence).
Mendeliome v1.3072 KCNJ15 Zornitza Stark gene: KCNJ15 was added
gene: KCNJ15 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNJ15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ15 were set to 40566643
Phenotypes for gene: KCNJ15 were set to Parkinson disease, MONDO:0005180, KCNJ15-related
Review for gene: KCNJ15 was set to RED
Added comment: Single multiplex family reported with a missense variant and functional data.
Sources: Literature
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Marked gene: TFCP2L1 as ready
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Classified gene: TFCP2L1 as Amber List (moderate evidence)
Mendeliome v1.3071 TFCP2L1 Zornitza Stark Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3070 TFCP2L1 Zornitza Stark gene: TFCP2L1 was added
gene: TFCP2L1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFCP2L1 were set to 40569305; 33097957
Phenotypes for gene: TFCP2L1 were set to CAKUT, MONDO:0019719, TFGP2L1-related
Review for gene: TFCP2L1 was set to AMBER
Added comment: PMID 40569305: consanguineous preterm male infant with a clinical picture of advanced kidney dysfunction and severe renal salt-wasting, highly suggestive of prenatal onset Bartter syndrome. Patient's follow-up was characterized by severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. Homozygous variant in the TFCP2L1 gene identified. TFCP2L1 is a transcription factor required for normal kidney development, that regulates acid-base and salt-water homeostasis.

PMID 33097957: infant who developed CKD by the age of 2 months and had episodes of severe hypochloraemic, hyponatraemic and hypokalaemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. Homozygous LoF variant.

TFCP2L1 is localized throughout kidney development particularly in the distal nephron. TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.
Sources: Literature
Mendeliome v1.3069 PIH1D3 Zornitza Stark Tag new gene name tag was added to gene: PIH1D3.
Mendeliome v1.3069 BCAS2 Zornitza Stark Marked gene: BCAS2 as ready
Mendeliome v1.3069 BCAS2 Zornitza Stark Gene: bcas2 has been classified as Red List (Low Evidence).
Mendeliome v1.3069 BCAS2 Zornitza Stark gene: BCAS2 was added
gene: BCAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BCAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCAS2 were set to 40585763
Phenotypes for gene: BCAS2 were set to Hyper IgM syndrome, MONDO:0003947, BCAS2-related
Review for gene: BCAS2 was set to RED
Added comment: Extensive functional work, however a single individual reported with non-coding variant, 3'UTR.
Sources: Literature
Mendeliome v1.3068 RSG1 Zornitza Stark Marked gene: RSG1 as ready
Mendeliome v1.3068 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Mendeliome v1.3068 RSG1 Zornitza Stark Classified gene: RSG1 as Green List (high evidence)
Mendeliome v1.3068 RSG1 Zornitza Stark Gene: rsg1 has been classified as Green List (High Evidence).
Mendeliome v1.3067 RSG1 Zornitza Stark gene: RSG1 was added
gene: RSG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 40593758
Phenotypes for gene: RSG1 were set to Ciliopathy, MONDO:0005308, RSG1-related
Review for gene: RSG1 was set to GREEN
Added comment: Three individuals from unrelated families reported with bi-allelic variants and displaying cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. Variants were shown to disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins.
Sources: Literature
Mendeliome v1.3066 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Red List (low evidence)
Mendeliome v1.3066 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Red List (Low Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark edited their review of gene: TMBIM4: Changed rating: RED
Mendeliome v1.3065 PPP1R12A Lucy Spencer reviewed gene: PPP1R12A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Genitourinary and/or/brain malformation syndrome MIM#618820; Mode of inheritance: None
Mendeliome v1.3065 PPM1F Lucy Spencer reviewed gene: PPM1F: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis MONDO:0001751, PPM1F-related; Mode of inheritance: None
Mendeliome v1.3065 ICK Zornitza Stark Marked gene: ICK as ready
Mendeliome v1.3065 ICK Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is CILK1
Mendeliome v1.3065 ICK Zornitza Stark Gene: ick has been classified as Green List (High Evidence).
Mendeliome v1.3065 ICK Zornitza Stark Tag new gene name tag was added to gene: ICK.
Mendeliome v1.3065 TMBIM4 Zornitza Stark Marked gene: TMBIM4 as ready
Mendeliome v1.3065 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3065 TMBIM4 Zornitza Stark Classified gene: TMBIM4 as Amber List (moderate evidence)
Mendeliome v1.3065 TMBIM4 Zornitza Stark Gene: tmbim4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3064 TMBIM4 Zornitza Stark gene: TMBIM4 was added
gene: TMBIM4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMBIM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMBIM4 were set to 40744297; 21282601; 28991257
Phenotypes for gene: TMBIM4 were set to Visceral heterotaxy MONDO:0018677, TMBIM4-related
Review for gene: TMBIM4 was set to AMBER
Added comment: Rare deleterious variants enriched in CHD cohorts, supportive functional data.
Sources: Literature
Mendeliome v1.3063 ZNF319 Zornitza Stark Marked gene: ZNF319 as ready
Mendeliome v1.3063 ZNF319 Zornitza Stark Gene: znf319 has been classified as Red List (Low Evidence).
Mendeliome v1.3063 ZNF319 Zornitza Stark gene: ZNF319 was added
gene: ZNF319 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF319 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF319 were set to 40820230
Phenotypes for gene: ZNF319 were set to Leukodystrophy, MONDO:0019046, ZNF319-related
Review for gene: ZNF319 was set to RED
Added comment: Single individual with homozygous missense variant reported, p.Phe267Ser.

18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the variant disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319's role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy.
Sources: Literature
Mendeliome v1.3062 POMT1 Zornitza Stark Phenotypes for gene: POMT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 1 613155; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308 to Myopathy caused by variation in POMT1 MONDO:0700070
Mendeliome v1.3061 POMT1 Zornitza Stark edited their review of gene: POMT1: Changed phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070
Mendeliome v1.3061 POMGNT2 Zornitza Stark Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, MIM# 614830; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, MIM# 618135 to Myopathy caused by variation in POMGNT2 MONDO:0700069
Mendeliome v1.3060 POMGNT1 Zornitza Stark Phenotypes for gene: POMGNT1 were changed from 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 to Myopathy caused by variation in POMGNT1 MONDO:0700068; Retinitis pigmentosa 76 617123
Mendeliome v1.3059 NR6A1 Zornitza Stark Publications for gene: NR6A1 were set to 39606382
Mendeliome v1.3058 ARID3A Zornitza Stark Phenotypes for gene: ARID3A were changed from Cornelia de Lange syndrome - MONDO:0016033 to Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related; Cornelia de Lange syndrome - MONDO:0016033
Mendeliome v1.3057 ARID3A Zornitza Stark Publications for gene: ARID3A were set to PMID: 40677927
Mendeliome v1.3056 ARID3A Zornitza Stark Classified gene: ARID3A as Amber List (moderate evidence)
Mendeliome v1.3056 ARID3A Zornitza Stark Gene: arid3a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3055 MED14 Zornitza Stark Marked gene: MED14 as ready
Mendeliome v1.3055 MED14 Zornitza Stark Gene: med14 has been classified as Red List (Low Evidence).
Mendeliome v1.3055 MED14 Zornitza Stark Classified gene: MED14 as Red List (low evidence)
Mendeliome v1.3055 MED14 Zornitza Stark Gene: med14 has been classified as Red List (Low Evidence).
Mendeliome v1.3054 NXT2 Zornitza Stark Marked gene: NXT2 as ready
Mendeliome v1.3054 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3054 NXT2 Zornitza Stark Classified gene: NXT2 as Amber List (moderate evidence)
Mendeliome v1.3054 NXT2 Zornitza Stark Gene: nxt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3053 ATP5A1 Zornitza Stark Phenotypes for gene: ATP5A1 were changed from Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Combined oxidative phosphorylation deficiency 22 616045; Mitochondrial complex V (ATP synthase) deficiency nuclear type 4, 615228
Mendeliome v1.3052 ATP5A1 Zornitza Stark Publications for gene: ATP5A1 were set to 23599390, 34954817, 34483339
Mendeliome v1.3051 ATP5A1 Zornitza Stark Mode of inheritance for gene: ATP5A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 ATP5A1 Zornitza Stark changed review comment from: Two unrelated families.; to: Two unrelated families with biallelic disease. Evidence for bi-allelic disease is limited. In one of the families, PMID 23599390, only a paternally inherited variant was identified, maternal variant presumed based on functional studies but not actually identified. In the other family, PMID 23596069, the variant identified is a homozygous missense.
Mendeliome v1.3050 POMT2 Lucy Spencer reviewed gene: POMT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMT2 MONDO:0700071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMT1 Lucy Spencer reviewed gene: POMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMT1 MONDO:0700070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMGNT2 Lucy Spencer reviewed gene: POMGNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMGNT2 MONDO:0700069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 POMGNT1 Lucy Spencer reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy caused by variation in POMGNT1 MONDO:0700068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3050 NR6A1 Rylee Peters reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40774958; Phenotypes: Oculovertebral syndrome MIM# 621277; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 ARID3A Rylee Peters reviewed gene: ARID3A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40774958; Phenotypes: Congenital anomaly of kidney and urinary tract, MONDO:0019719, ARID3A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 MED14 Rylee Peters gene: MED14 was added
gene: MED14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED14 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MED14 were set to PMID: 40597352
Phenotypes for gene: MED14 were set to Neurodevelopmental disorder (MONDO:0700092), MED14-related
Review for gene: MED14 was set to RED
Added comment: PMID: 40597352: 1x male with clinical VLCAD, developmental delay, microcephaly, hypotonia and brain anomalies. Identified a hemizygous, maternally inherited splice variant c.2365+2T>C, classified as VUS. RNA studies show that the variant results in an out-of-frame loss of the C-terminal end of exon 18 due to novel splice donor use in 1.72 percent of reads.
Sources: Literature
Mendeliome v1.3050 NXT2 Rylee Peters gene: NXT2 was added
gene: NXT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NXT2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NXT2 were set to PMID: 40624043; 35013161
Phenotypes for gene: NXT2 were set to Spermatogenic failure, MONDO:0004983, NXT2-related
Review for gene: NXT2 was set to AMBER
Added comment: PMID: 40624043
- 1x hemi male with maternally inherited p.(Asp119*) – (p.Asp64* in MANE transcript) – absent from v4. Variant also present in two infertile brothers with azoospermia; absent in fertile father and brother. Over expression of the variant in HEK293T cells resulted in the complete absence of the truncated protein according to Western blot analysis.
- 1x hemi male with p.(Ala90Ser) – (p.Ala35Ser in MANE transcript) – 85 hets, 42 hemis in v4. Variant is located near the start of an exon, minigene assay showed exon 4 skipping resulting in a PTC, but no quantification of aberrant transcript expression was performed. Over expression of the variant in HEK293T cells showed comparable protein expression to WT, and NXT2 staining was present in SOX9-positive Sertoli cells in the patient’s testis.
- Above article also refers to an individual described in PMID: 35013161 – 1x male individual with a de novo 42 kb large deletion on the X chromosome encompassing the entire NXT2 gene.
Sources: Literature
Mendeliome v1.3050 ATP5A1 Rylee Peters reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40672495; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3050 LDHD Zornitza Stark Marked gene: LDHD as ready
Mendeliome v1.3050 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Mendeliome v1.3050 LDHD Zornitza Stark Classified gene: LDHD as Green List (high evidence)
Mendeliome v1.3050 LDHD Zornitza Stark Gene: ldhd has been classified as Green List (High Evidence).
Mendeliome v1.3049 CREB3 Zornitza Stark Marked gene: CREB3 as ready
Mendeliome v1.3049 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3049 CREB3 Zornitza Stark Classified gene: CREB3 as Amber List (moderate evidence)
Mendeliome v1.3049 CREB3 Zornitza Stark Gene: creb3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3048 CREB3 Zornitza Stark Tag founder tag was added to gene: CREB3.
Mendeliome v1.3048 CREB3 Zornitza Stark reviewed gene: CREB3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3048 XPO1 Zornitza Stark Marked gene: XPO1 as ready
Mendeliome v1.3048 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Mendeliome v1.3048 XPO1 Zornitza Stark Classified gene: XPO1 as Green List (high evidence)
Mendeliome v1.3048 XPO1 Zornitza Stark Gene: xpo1 has been classified as Green List (High Evidence).
Mendeliome v1.3047 NPPA Zornitza Stark Publications for gene: NPPA were set to 18614783; 20064500; 31034774; 31077706
Mendeliome v1.3046 NPPA Zornitza Stark Mode of inheritance for gene: NPPA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3045 NPPA Zornitza Stark changed review comment from: PMID 40838933: young adult with AF and homozygous missense variant in this gene. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; to: PMID 40838933: young adult with AF and homozygous missense variant in this gene p.Arg150Gln. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.
Mendeliome v1.3045 NPPA Zornitza Stark edited their review of gene: NPPA: Added comment: PMID 40838933: young adult with AF and homozygous missense variant in this gene. Another 14 cases with same homozygous variant identified in literature, PMIDs 23275345. Biallelic disease may be specific to this variant.; Changed publications: 18614783, 20064500, 31034774, 31077706, 40838933, 23275345; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3045 PNLIP Zornitza Stark Publications for gene: PNLIP were set to 31977950; 25862608; 24262094; 27604308
Mendeliome v1.3044 PNLIP Zornitza Stark Classified gene: PNLIP as Green List (high evidence)
Mendeliome v1.3044 PNLIP Zornitza Stark Gene: pnlip has been classified as Green List (High Evidence).
Mendeliome v1.3043 PNLIP Zornitza Stark reviewed gene: PNLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 40840699; Phenotypes: Pancreatic lipase deficiency MIM#614338; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3043 ATP5A1 Zornitza Stark Classified gene: ATP5A1 as Green List (high evidence)
Mendeliome v1.3043 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Green List (High Evidence).
Mendeliome v1.3042 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Added comment: PMID 40859057: 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. Functional data.; Changed rating: GREEN; Changed publications: 23599390, 40859057
Mendeliome v1.3042 ATP5A1 Zornitza Stark edited their review of gene: ATP5A1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3042 PLCG1 Zornitza Stark Publications for gene: PLCG1 were set to 37422272
Mendeliome v1.3041 PLCG1 Zornitza Stark Classified gene: PLCG1 as Green List (high evidence)
Mendeliome v1.3041 PLCG1 Zornitza Stark Gene: plcg1 has been classified as Green List (High Evidence).
Mendeliome v1.3040 PLCG1 Zornitza Stark edited their review of gene: PLCG1: Added comment: PMID 40862571: seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] presenting with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). Further functional work in Drosophila on some of the variants investigating GoF effect.; Changed rating: GREEN; Changed publications: 37422272, 40862571
Mendeliome v1.3040 KNG1 Zornitza Stark Classified gene: KNG1 as Green List (high evidence)
Mendeliome v1.3040 KNG1 Zornitza Stark Gene: kng1 has been classified as Green List (High Evidence).
Mendeliome v1.3039 KNG1 Zornitza Stark edited their review of gene: KNG1: Added comment: PMID 40848077: Two more individuals reported with LoF variants as part of a large angioedema cohort.; Changed rating: GREEN; Changed publications: 31087670, 33114181, 40848077
Mendeliome v1.3039 MYOF Zornitza Stark Classified gene: MYOF as Amber List (moderate evidence)
Mendeliome v1.3039 MYOF Zornitza Stark Gene: myof has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3038 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: PMID 40848077: four more missense variants reported as part of a cohort, no further supportive data. Upgrade to Amber.; Changed rating: AMBER; Changed publications: 32542751, 40797221, 40848077
Mendeliome v1.3038 ETS1 Zornitza Stark Phenotypes for gene: ETS1 were changed from Neurodevelopmental disorder, MONDO:0700092, ETS1-related to Neurodevelopmental disorder, MONDO:0700092, ETS1-related; Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Mendeliome v1.3037 ETS1 Zornitza Stark edited their review of gene: ETS1: Added comment: PMID 40870883: Single multiplex family reported with LoF variant and DCM.; Changed publications: 31160359, 40870883; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ETS1-related, Familial dilated cardiomyopathy, MONDO:0016333, ETS1-related
Mendeliome v1.3037 SCN3B Zornitza Stark Marked gene: SCN3B as ready
Mendeliome v1.3037 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3037 SCN3B Zornitza Stark Classified gene: SCN3B as Amber List (moderate evidence)
Mendeliome v1.3037 SCN3B Zornitza Stark Gene: scn3b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3036 POLR3H Zornitza Stark Phenotypes for gene: POLR3H were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR3H-related
Mendeliome v1.3035 POU5F1 Zornitza Stark Phenotypes for gene: POU5F1 were changed from Premature ovarian failure to Primary ovarian insufficiency MONDO:0005387, POU5F1-related
Mendeliome v1.3034 PPARA Zornitza Stark Phenotypes for gene: PPARA were changed from {Hyperapobetalipoproteinemia, susceptibility to} to Cholesterol metabolism disease MONDO:0045008, PPARA-related
Mendeliome v1.3033 TCFL5 Zornitza Stark Marked gene: TCFL5 as ready
Mendeliome v1.3033 TCFL5 Zornitza Stark Gene: tcfl5 has been classified as Red List (Low Evidence).
Mendeliome v1.3033 TCFL5 Zornitza Stark Phenotypes for gene: TCFL5 were changed from Oligoasthenoteratozoospermia MONDO:0850098 to Oligoasthenoteratozoospermia MONDO:0850098, TCFL5-related
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Marked gene: ADAMTS6 as ready
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Gene: adamts6 has been classified as Green List (High Evidence).
Mendeliome v1.3032 ADAMTS6 Zornitza Stark Phenotypes for gene: ADAMTS6 were changed from Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 to Connective tissue disorder MONDO:0003900, ADAMTS6-related
Mendeliome v1.3031 UPF1 Zornitza Stark Phenotypes for gene: UPF1 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092, UPF1-related
Mendeliome v1.3030 UPF1 Zornitza Stark Publications for gene: UPF1 were set to 33057194
Mendeliome v1.3029 UPF1 Zornitza Stark Classified gene: UPF1 as Green List (high evidence)
Mendeliome v1.3029 UPF1 Zornitza Stark Gene: upf1 has been classified as Green List (High Evidence).
Mendeliome v1.3028 UPF1 Achchuthan Shanmugasundram reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 28539120, 39571789, 39993774; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3028 COMMD9 Krithika Murali Marked gene: COMMD9 as ready
Mendeliome v1.3028 COMMD9 Krithika Murali Gene: commd9 has been classified as Red List (Low Evidence).
Mendeliome v1.3028 COMMD9 Krithika Murali gene: COMMD9 was added
gene: COMMD9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COMMD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD9 were set to PMID: 40601774
Phenotypes for gene: COMMD9 were set to Neurodevelopmental disorder, MONDO:0700092, COMMD9-related
Review for gene: COMMD9 was set to RED
Added comment: PMID: 40601774 report a cohort ascertained through GeneMatcher with phenotypic features overlapping with Ritscher-Schinzel syndrome.

Homozygous fs variant in COMMD9 [NM_014186.3:c.208_209del, p.Leu70Glyfs*5] identified in a 4 yo M with dev delay, dysmorphism, skeletal changes including brachydactyly and radioulnar dysostosis, hypotonia, MRI-B anomalies - dysgyria, dilated
lateral ventricles, deep white matter periventricular demyelination, thin corpus callosum, cerebellar vermis hypoplasia and malrotation.

Consanguineous parents confirmed to be heterozygous carriers. No information provided regarding segregation of these variants in unaffected siblings.
Sources: Literature
Mendeliome v1.3027 TBCB Krithika Murali Marked gene: TBCB as ready
Mendeliome v1.3027 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3027 TBCB Krithika Murali Classified gene: TBCB as Amber List (moderate evidence)
Mendeliome v1.3027 TBCB Krithika Murali Gene: tbcb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3026 TBCB Krithika Murali gene: TBCB was added
gene: TBCB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to PMID: 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092, TBCB-related
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 Bratman, S. et al 2025 (Genetics in Medicine) report 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with a homozygous missense founder variant in TBCB (c.589T>A, p.Tyr197Asn) identified through exome sequencing. This variant is present at 1.3% carrier frequency in the AJ population in gnomAD v4 with 0 homozygotes. Variant is reasonably well-conserved, REVEL 0.9 and in the Cap-Gly domain. No other homozygous missense variants in this region in gnomAD v4 and homozygous variants rare, overall.

Phenotypic features included:
- Motor/speech delays in infancy (almost all)
- ASD (8/10)
- ADHD (5/10)
- Mild ID - formal cognitive evaluation (5/8).
- Spastic paraparesis in late childhood (9-12y) with slowly progressive gait difficulties and lower limb spasticity. Urinary abnormalities were not reported.
- Brain MRI was performed on five individuals - three displayed a thin corpus callosum,
and two had decreased white matter.

No prenatal features reported.

Supportive Drosophilia models.
Sources: Literature
Mendeliome v1.3025 NPSR1 Zornitza Stark Phenotypes for gene: NPSR1 were changed from {Asthma, susceptibility to, 2} 608584 to Short sleep, familial natural, 3, MIM# 621336; {Asthma, susceptibility to, 2} 608584
Mendeliome v1.3024 NPSR1 Zornitza Stark Publications for gene: NPSR1 were set to
Mendeliome v1.3023 NPSR1 Zornitza Stark reviewed gene: NPSR1: Rating: RED; Mode of pathogenicity: None; Publications: 31619542; Phenotypes: Short sleep, familial natural, 3, MIM# 621336; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3023 KRT32 Bryony Thompson Marked gene: KRT32 as ready
Mendeliome v1.3023 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Mendeliome v1.3023 KRT32 Bryony Thompson Classified gene: KRT32 as Green List (high evidence)
Mendeliome v1.3023 KRT32 Bryony Thompson Gene: krt32 has been classified as Green List (High Evidence).
Mendeliome v1.3022 KRT32 Bryony Thompson gene: KRT32 was added
gene: KRT32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KRT32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KRT32 were set to 40814173; 39048559
Phenotypes for gene: KRT32 were set to loose anagen syndrome MONDO:0010908; Pityriasis rubra pilaris MONDO:0100017
Review for gene: KRT32 was set to GREEN
Added comment: Sufficient evidence for Pityriasis rubra pilaris association, but limited for association with loose anagen syndrome.
PMID: 39048559 - Significant enrichment of KRT32 variants (p=3.06e-4) in 58 PRP cases vs 364 healthy controls (4 variants - individual 1: c.344G>A (p.Arg115Gln - 10 hets gnomAD v4.1), individual 2: c.477_478del (p.Thr160fs), individual 3: c.607C>T (p.Arg203Cys - 71 hets gnomAD v4.1), and individual 4: c.685T>C (p.Cys229Arg - 18 hets gnomAD v4.1). Validation cohort of 44 PRP cases vs 436 healthy controls identified an additional 2 variants (individual 5: c.907G>A (p.Glu303Lys - 3 hets gnomAD v4.1), individual 6: c.937A>G (p.Ile313Val - 30 hets gnomAD v4.1). A combined analysis of the KRT32 gene in both the discovery and validation cohorts revealed a significant p value of 1.73 e-6. The KRT32 expression patterns (location of protein expression) were altered in PRP cases with the KRT32 variants. In vitro analysis demonstrated that the 6 variants (all located in the IF rod domain) exhibited varying degrees of attenuation in inhibiting the NF-κB signaling pathway. A Krt32 knockout mouse model recapitulates the human PRP-like phenotype.
PMID: 40814173 - a single family with loose anagen hair syndrome co-segregating (c.296C>T; p.Thr99Ile) in a large family; however, the AF in the European population is 0.3% in gnomAD v4.1 (6 homozygotes), which is higher than expected for a dominant condition. In vitro functional assay showing the variant alters interaction with KRT82, however, only WT & the variant were assessed (no positive control).
Sources: Literature
Mendeliome v1.3021 CCDC89 Bryony Thompson Marked gene: CCDC89 as ready
Mendeliome v1.3021 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3021 CCDC89 Bryony Thompson Classified gene: CCDC89 as Amber List (moderate evidence)
Mendeliome v1.3021 CCDC89 Bryony Thompson Gene: ccdc89 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3020 CCDC89 Bryony Thompson gene: CCDC89 was added
gene: CCDC89 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC89 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC89 were set to 40591933
Phenotypes for gene: CCDC89 were set to spermatogenic failure MONDO:0004983
Review for gene: CCDC89 was set to AMBER
Added comment: 2 missense identified in 3 males with non-obstructive azoospermia (2 homozygous for c.903G>T p.E301D, NFE AF 0.7% in gnomAD v4.1 & 1 chet for c.903G>T & c.1024G>A p.D342N - NFE AF 0.0086%). A homozygous knock-in mouse model for p.E301D (Ccdc89E297D/E297D) was fertile, their testis weights and germ cell content were reduced, and male knockouts (Ccdc89−/−) were sub-fertile.
Sources: Literature
Mendeliome v1.3019 TULP2 Bryony Thompson Marked gene: TULP2 as ready
Mendeliome v1.3019 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3019 TULP2 Bryony Thompson Classified gene: TULP2 as Amber List (moderate evidence)
Mendeliome v1.3019 TULP2 Bryony Thompson Gene: tulp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3018 TULP2 Bryony Thompson gene: TULP2 was added
gene: TULP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TULP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TULP2 were set to 35619658: 33763418; 40613306
Phenotypes for gene: TULP2 were set to male infertility MONDO:0005372
Review for gene: TULP2 was set to AMBER
Added comment: Tulp2 -/- mouse model is sterile. Only one individual with asthenoteratozoospermia reported with a homozygous missense variant (c.832C>T p.R278W) that present in at AF of ~1% in the East Asian population in gnomAD v4.1 (455/44,880 alleles, 4 homozygotes). This AF doesn’t rule it out as a possible cause of male sterility.
Sources: Literature
Mendeliome v1.3017 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; Wiedemann-Rautenstrauch syndrome, MIM# 264090; Susceptibility to severe VZV infection; POLR3A-related spastic ataxia to POLR3A-related disorder MONDO:0700276; Susceptibility to severe VZV infection; POLR3A-related spastic ataxia
Mendeliome v1.3016 POLR2C Zornitza Stark Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to Primary ovarian insufficiency MONDO:0005387, POLR2C-related
Mendeliome v1.3015 ZPR1 Zornitza Stark Classified gene: ZPR1 as Amber List (moderate evidence)
Mendeliome v1.3015 ZPR1 Zornitza Stark Gene: zpr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.3014 COMMD4 Zornitza Stark Marked gene: COMMD4 as ready
Mendeliome v1.3014 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Mendeliome v1.3014 COMMD4 Zornitza Stark Classified gene: COMMD4 as Red List (low evidence)
Mendeliome v1.3014 COMMD4 Zornitza Stark Gene: commd4 has been classified as Red List (Low Evidence).
Mendeliome v1.3013 ADAMTS6 Chirag Patel Classified gene: ADAMTS6 as Green List (high evidence)
Mendeliome v1.3013 ADAMTS6 Chirag Patel Gene: adamts6 has been classified as Green List (High Evidence).
Mendeliome v1.3012 ADAMTS6 Chirag Patel gene: ADAMTS6 was added
gene: ADAMTS6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTS6 were set to PMID: 40657314
Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453
Review for gene: ADAMTS6 was set to GREEN
Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4).

WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder.

Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts.

Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome.
Sources: Literature
Mendeliome v1.3011 TCFL5 Chirag Patel gene: TCFL5 was added
gene: TCFL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCFL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCFL5 were set to PMID: 40711600
Phenotypes for gene: TCFL5 were set to Oligoasthenoteratozoospermia MONDO:0850098
Review for gene: TCFL5 was set to RED
Added comment: 2 brothers from non-consanguineous family with oligoasthenoteratozoospermia (OAT). WES identified missense variant in TCFL5 gene (c.1207G>A, p.E403K). Western blotting and immunofluorescence showed no significant effect on the expression of 'mutant' TCFL5. Dual-luciferase reporter assay revealed a serious impact on its transcriptional regulatory function.
The variant disrupted the normal transcription of crucial genes involved in spermatogenesis (DMRT1, DAZL, SYCE1, SPACA1, CNTROB, IFT88, HOOK1 and SPATA6). Tcfl5+/- male mice manifest infertile due to OAT, while Tcfl5-/- mice can not be generated.
Sources: Literature
Mendeliome v1.3010 PPARA Lucy Spencer reviewed gene: PPARA: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholesterol metabolism disease MONDO:0045008, PPARA-related; Mode of inheritance: None
Mendeliome v1.3010 POU5F1 Lucy Spencer reviewed gene: POU5F1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POU5F1-related; Mode of inheritance: None
Mendeliome v1.3010 POPDC2 Lucy Spencer reviewed gene: POPDC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39006410, 32535041; Phenotypes: Cardiac conduction defect MONDO:0100042, POPDC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3010 POLR3H Lucy Spencer reviewed gene: POLR3H: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR3H-related; Mode of inheritance: None
Mendeliome v1.3010 POLR3A Lucy Spencer reviewed gene: POLR3A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: POLR3A-related disorder MONDO:0700276; Mode of inheritance: None
Mendeliome v1.3010 POLR2C Lucy Spencer reviewed gene: POLR2C: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency MONDO:0005387, POLR2C-related; Mode of inheritance: None
Mendeliome v1.3010 ZPR1 Lucy Spencer reviewed gene: ZPR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 40776660; Phenotypes: Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies MIM#619321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3010 COMMD4 Lucy Spencer gene: COMMD4 was added
gene: COMMD4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COMMD4 were set to 40601774
Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel syndrome, MONDO:0019078, COMMD4-related
Review for gene: COMMD4 was set to RED
Added comment: PMID: 40601774 3 siblings with Ritscher-Schinzel syndrome and a homozygous missense in COMMD4 NM_017828.5:c.122T>G; p.Leu41Arg. All three individuals died in infancy and the authors suggest there could be a dual diagnosis to explain the severity.

This variant was expressed in a H4 neuroglioma cell line with COMMD4 knocked out, and showed an enhanced degradative turnover compared to WT when treated with cyclohexamide. Western blot in HEK293T cells showed a decrease in the steady-state abundance of COMMD4.

Knock out of COMMD4 protein leads to destabilization of the Commander complex.
Sources: Literature
Mendeliome v1.3010 TMEM184B Zornitza Stark Marked gene: TMEM184B as ready
Mendeliome v1.3010 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3010 TMEM184B Zornitza Stark Classified gene: TMEM184B as Green List (high evidence)
Mendeliome v1.3010 TMEM184B Zornitza Stark Gene: tmem184b has been classified as Green List (High Evidence).
Mendeliome v1.3009 C4orf26 Zornitza Stark Marked gene: C4orf26 as ready
Mendeliome v1.3009 C4orf26 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is ODAPH.
Mendeliome v1.3009 C4orf26 Zornitza Stark Gene: c4orf26 has been classified as Green List (High Evidence).
Mendeliome v1.3009 C4orf26 Zornitza Stark Tag new gene name tag was added to gene: C4orf26.
Mendeliome v1.3009 TMEM184B Lucy Spencer gene: TMEM184B was added
gene: TMEM184B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM184B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM184B were set to 39006436
Phenotypes for gene: TMEM184B were set to Neurodevelopmental disorder (MONDO:0700092), TMEM184B-related
Review for gene: TMEM184B was set to GREEN
Added comment: A cohort of 6 patients with developmental delay (5/6), corpus callosum hypoplasia (4/6), microcephaly (1/6), seizures (3/6), and ID (2/6). 2 patients also had gastrointestinal motility disruption. All 6 have de novo variants in TMEM184B, 5 missense 1 canonical splice. 1 of the missense variants has 35 hets in gnomad but the rest are absent. The authors also say they are aware of a 7th patient with overlapping features by personal communication.

A knockout zebrafish model showed a dose dependent reduction in head size and body length in larvae. Knock-in of 2 of the missense variants also showed head size and body length reduction, but the other missense did not. However the other three missense failed to rescue the phenotype of a knockout zebrafish while WT and a negative control did. The authors suggest the first 2 variants are dominant negative while the latter three and loss of function.

The splice variant was shown to cause exon 7 skipping which is out of frame.

Transfection of the missense and splice variants in HEK293T cells showed that all but 1 had reduced TMEM184B protein levels.
Sources: Literature
Mendeliome v1.3009 PHLPP2 Zornitza Stark Marked gene: PHLPP2 as ready
Mendeliome v1.3009 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Mendeliome v1.3009 PHLPP2 Zornitza Stark Classified gene: PHLPP2 as Red List (low evidence)
Mendeliome v1.3009 PHLPP2 Zornitza Stark Gene: phlpp2 has been classified as Red List (Low Evidence).
Mendeliome v1.3008 MYO19 Zornitza Stark Marked gene: MYO19 as ready
Mendeliome v1.3008 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3008 MYO19 Zornitza Stark Classified gene: MYO19 as Red List (low evidence)
Mendeliome v1.3008 MYO19 Zornitza Stark Gene: myo19 has been classified as Red List (Low Evidence).
Mendeliome v1.3007 C4orf26 Sangavi Sivagnanasundram reviewed gene: C4orf26: Rating: GREEN; Mode of pathogenicity: Other; Publications: 40680053; Phenotypes: Amelogenesis imperfecta, type IIA4 MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3007 MYO19 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Mendeliome v1.3007 PHLPP2 Lucy Spencer changed review comment from: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature; to: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also had variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature
Mendeliome v1.3007 PHLPP2 Lucy Spencer gene: PHLPP2 was added
gene: PHLPP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHLPP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHLPP2 were set to 40634996; 29628444
Phenotypes for gene: PHLPP2 were set to Hypertrophic cardiomyopathy MONDO:0005045, PHLPP2-related
Review for gene: PHLPP2 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy PMID: 29628444
Sources: Literature
Mendeliome v1.3007 MYO19 Lucy Spencer gene: MYO19 was added
gene: MYO19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYO19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO19 were set to 40634996
Phenotypes for gene: MYO19 were set to Hypertrophic cardiomyopathy MONDO:0005045, MYO19-related
Review for gene: MYO19 was set to RED
Added comment: 1 month old baby with severe HCM found to have compound heterozygous variants in MYO19 (missense and frameshift). The patients mother, maternal aunt and maternal grandfather also had HCM and were diagnosed as teenagers or adults. The MYO19 frameshift variant was maternally inherited, but was not present in the affected aunt or grandfather.

MYO19 is a myosin located in the mitochondria, its role in cardiac function has not bene investigated.

All 4 affected individuals in this family also has variants in PHLPP2 (stop gain), CAPN1 (canonical splice) and ADAMTS8 (missense). CAPN1 is associated with biallelic HSP while the other 2 genes are not yet associated with disease. the CAPN1 and ADAMTS8 variants are present with over 10 hets in gnomad while PHLPP2 is absent.

It has previously been shown that inhibiting PHLPP2 activity increases cardiomyocyte hypertrophy.
Sources: Literature
Mendeliome v1.3007 POLR3D Zornitza Stark Marked gene: POLR3D as ready
Mendeliome v1.3007 POLR3D Zornitza Stark Gene: polr3d has been classified as Red List (Low Evidence).
Mendeliome v1.3007 POLR3D Zornitza Stark gene: POLR3D was added
gene: POLR3D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR3D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3D were set to 37915380
Phenotypes for gene: POLR3D were set to Leukodystrophy, MONDO:0019046, POLR3D-related
Review for gene: POLR3D was set to RED
Added comment: PMID 37915380: single individual with compound het variants in POLR3D and childhood onset leukodystrophy manifesting as DD/ID.

Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient's fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation.
Sources: Literature
Mendeliome v1.3006 STAB2 Zornitza Stark Marked gene: STAB2 as ready
Mendeliome v1.3006 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Mendeliome v1.3006 STAB2 Zornitza Stark Classified gene: STAB2 as Red List (low evidence)
Mendeliome v1.3006 STAB2 Zornitza Stark Gene: stab2 has been classified as Red List (Low Evidence).
Mendeliome v1.3005 LDHD Lucy Spencer gene: LDHD was added
gene: LDHD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LDHD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDHD were set to 40678184
Phenotypes for gene: LDHD were set to D-lactic aciduria with susceptibility to gout MIM#245450
Review for gene: LDHD was set to GREEN
Added comment: 8 patients summarized in PMID: 40678184 with D-Lactate Dehydrogenase Deficiency. 5 homozygous missense, 1 homozygous frameshift, 1 compound heterozygous canonical splice and missense, and 1 homozygous deletion encompassing CTRB2, ZFP1 (neither of which have a disease association) and the first 7 exons of LDHD. Three of these patients had additional variants of interest in other genes that were thought to explain extra phenotypes they had out of the typical spectrum for this disorder.

Some patients only have increased plasma urate/gout however 4 also had delayed development, ataxia or epilepsy. 2 of these individuals had other genetic variants that likely explained the neurodevelopmental phenotype (11p deletion syndrome, CACNA1B), and 1 had the deletion that also affected 2 other genes of uncertain significance. So its unclear whether this gene is actually associated with a neurodevelopmental phenotype.
Sources: Literature
Mendeliome v1.3005 STAB2 Lucy Spencer changed review comment from: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 100 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature; to: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 1000 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Mendeliome v1.3005 STAB2 Lucy Spencer gene: STAB2 was added
gene: STAB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STAB2 were set to 40726512
Phenotypes for gene: STAB2 were set to Chronic thromboembolic pulmonary hypertension MONDO:0013024, STAB2-related
Review for gene: STAB2 was set to RED
Added comment: In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 100 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Mendeliome v1.3005 ARHGEF15 Zornitza Stark Phenotypes for gene: ARHGEF15 were changed from to Brain small vessel disease 5 with osteoporosis, MIM# 621331
Mendeliome v1.3004 ARHGEF15 Zornitza Stark Publications for gene: ARHGEF15 were set to
Mendeliome v1.3003 ARHGEF15 Zornitza Stark Mode of inheritance for gene: ARHGEF15 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3002 ARHGEF15 Zornitza Stark Classified gene: ARHGEF15 as Green List (high evidence)
Mendeliome v1.3002 ARHGEF15 Zornitza Stark Gene: arhgef15 has been classified as Green List (High Evidence).
Mendeliome v1.3001 ARHGEF15 Zornitza Stark edited their review of gene: ARHGEF15: Added comment: 7 individuals, ranging from 42 to 60 years of age and from 4 unrelated Chinese families, who presented between 38 and 46 years of age, with cognitive and memory decline, psychiatric disturbances, and small-vessel cerebral infarction and/or intracerebral hemorrhage on brain imaging. Features included irritability, mania, anxiety, depression, and suicidal tendencies.

Four different missense variants identified. Supportive functional data, including mouse model.; Changed rating: GREEN; Changed publications: 36929019; Changed phenotypes: Brain small vessel disease 5 with osteoporosis, MIM# 621331; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.3001 TDRD9 Bryony Thompson Classified gene: TDRD9 as Green List (high evidence)
Mendeliome v1.3001 TDRD9 Bryony Thompson Gene: tdrd9 has been classified as Green List (High Evidence).
Mendeliome v1.3000 TDRD9 Bryony Thompson gene: TDRD9 was added
gene: TDRD9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TDRD9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD9 were set to 28536242; 40645105; 20059948; 39267058; 39174853; 35172124
Phenotypes for gene: TDRD9 were set to spermatogenic failure MONDO:0004983
Review for gene: TDRD9 was set to GREEN
Added comment: At least 5 families with biallelic variants (homozygous and compound heterozygous) were identified in males with spermatogenic failure (azoospermia and oligoazoospermia). Also, supporting infertile mouse model.
Sources: Literature
Mendeliome v1.2999 HS6ST2 Bryony Thompson Marked gene: HS6ST2 as ready
Mendeliome v1.2999 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Mendeliome v1.2999 HS6ST2 Bryony Thompson Classified gene: HS6ST2 as Green List (high evidence)
Mendeliome v1.2999 HS6ST2 Bryony Thompson Gene: hs6st2 has been classified as Green List (High Evidence).
Mendeliome v1.2998 HS6ST2 Bryony Thompson gene: HS6ST2 was added
gene: HS6ST2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HS6ST2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: HS6ST2 were set to 40686562; 30471091; 36993824; 38015989
Phenotypes for gene: HS6ST2 were set to X-linked syndromic intellectual disability MONDO:0020119
Review for gene: HS6ST2 was set to GREEN
Added comment: 4 males with a neurodevelopmental phenotype from 3 families (1 set monozygotic twins) hemizygous for rare missense variants and a supporting mouse model.
PMID: 40686562 - a Chinese male child with a syndromic neurodevelopmental phenotype hemizygous c.764C>A (p.Pro255Glu) and in vitro assays showing the variant alters function. Parents were unaffected and variant was maternally inherited.

PMID: 38015989 - knockout mouse model impairs dendritic spines of hippocampal neurons, and affects memory.

PMID: 36993824 - an Iranian male child with a syndromic neurodevelopmental phenotype hemizygouc.979C>T p.Pro327Ser.

PMID: 30471091 - Italian monozygotic male twins with a syndromic neurodevelopmental phenotype hemizygous c.916G>C (p.G306R - inherited from unaffected mother) and functional assay showing altered enzyme activity.
Sources: Literature
Mendeliome v1.2997 SPNS1 Zornitza Stark Marked gene: SPNS1 as ready
Mendeliome v1.2997 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2997 SPNS1 Zornitza Stark Classified gene: SPNS1 as Amber List (moderate evidence)
Mendeliome v1.2997 SPNS1 Zornitza Stark Gene: spns1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2996 TMEM17 Zornitza Stark Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Mendeliome v1.2995 TMEM17 Zornitza Stark reviewed gene: TMEM17: Rating: AMBER; Mode of pathogenicity: None; Publications: 40841990; Phenotypes: Meckel syndrome MONDO:0018921, TMEM17-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2995 TEX44 Zornitza Stark Marked gene: TEX44 as ready
Mendeliome v1.2995 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Mendeliome v1.2995 TEX44 Zornitza Stark Classified gene: TEX44 as Green List (high evidence)
Mendeliome v1.2995 TEX44 Zornitza Stark Gene: tex44 has been classified as Green List (High Evidence).
Mendeliome v1.2994 TEX44 Zornitza Stark gene: TEX44 was added
gene: TEX44 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEX44 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEX44 were set to 40849303
Phenotypes for gene: TEX44 were set to Spermatogenic failure, MONDO:0004983, TEX44-related
Review for gene: TEX44 was set to GREEN
Added comment: Six individuals with biallelic variants, mouse model and other functional data support this gene-disease relationship.
Sources: Literature
Mendeliome v1.2993 ADA2 Zornitza Stark Publications for gene: ADA2 were set to 24552284; 24552285; 33791889
Mendeliome v1.2992 ADA2 Zornitza Stark Mode of inheritance for gene: ADA2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2991 ADA2 Zornitza Stark edited their review of gene: ADA2: Added comment: PMID 40864493 : Ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. Studies involving ADA2 protein expression, secretion, and enzymatic activity indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. New MOI and mechanism.; Changed publications: 24552284, 24552285, 33791889, 40864493; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2991 FSCN1 Zornitza Stark Marked gene: FSCN1 as ready
Mendeliome v1.2991 FSCN1 Zornitza Stark Gene: fscn1 has been classified as Red List (Low Evidence).
Mendeliome v1.2991 FSCN1 Zornitza Stark gene: FSCN1 was added
gene: FSCN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FSCN1 were set to 40874942
Phenotypes for gene: FSCN1 were set to Neurodevelopmental disorder, MONDO:0700092, FSCN1-related
Review for gene: FSCN1 was set to RED
Added comment: Two individuals reported in an Iranian cohort with same missense variant, c.665C>A; p.Ala222Asp, plus other circumstantial data.
Sources: Literature
Mendeliome v1.2990 TTC1 Zornitza Stark Marked gene: TTC1 as ready
Mendeliome v1.2990 TTC1 Zornitza Stark Gene: ttc1 has been classified as Red List (Low Evidence).
Mendeliome v1.2990 TTC1 Zornitza Stark gene: TTC1 was added
gene: TTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC1 were set to 40879651
Phenotypes for gene: TTC1 were set to Pontocerebellar hypoplasia, MONDO:0020135, TTC1-related
Review for gene: TTC1 was set to RED
Added comment: Four individuals from two families reported with the same homozygous missense variant, NM_003314.3: c.784 T > G, p.Phe262Val. No other supporting data.
Sources: Literature
Mendeliome v1.2989 MAEA Zornitza Stark Marked gene: MAEA as ready
Mendeliome v1.2989 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2989 MAEA Zornitza Stark Classified gene: MAEA as Amber List (moderate evidence)
Mendeliome v1.2989 MAEA Zornitza Stark Gene: maea has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2988 MAEA Zornitza Stark gene: MAEA was added
gene: MAEA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAEA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAEA were set to 40880485
Phenotypes for gene: MAEA were set to Neurodevelopmental disorder, MONDO:0700092, MAEA-related
Review for gene: MAEA was set to AMBER
Added comment: At least 4 individuals with de novo missense variants in this gene reported as part of large DDD papers. PMID 40880485 presents extensive data showing that loss of MAEA impairs RAD51 recruitment at stalled replication forks, leading to increased sensitivity to replication stress-inducing agents and excessive degradation of nascent DNA strands. Amber rating as scant detail on the affected individuals.
Sources: Literature
Mendeliome v1.2987 NIN Zornitza Stark Publications for gene: NIN were set to 22933543
Mendeliome v1.2986 NIN Zornitza Stark edited their review of gene: NIN: Added comment: PMID 40751525: second affected individual but homozygous inframe deletion.; Changed publications: 22933543, 40751525
Mendeliome v1.2986 SYNE2 Zornitza Stark Publications for gene: SYNE2 were set to 32184094; 17761684
Mendeliome v1.2985 SYNE2 Zornitza Stark Mode of inheritance for gene: SYNE2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2984 SYNE2 Zornitza Stark reviewed gene: SYNE2: Rating: RED; Mode of pathogenicity: None; Publications: 40757551; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2984 EMP2 Zornitza Stark Phenotypes for gene: EMP2 were changed from nephrotic syndrome, type 10 MONDO:0014373 to nephrotic syndrome, type 10 MONDO:0014373; Ichthyosis, MONDO:0019269, EMP2-related
Mendeliome v1.2983 EMP2 Zornitza Stark Mode of inheritance for gene: EMP2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2982 EMP2 Zornitza Stark reviewed gene: EMP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 40758889; Phenotypes: Ichthyosis, MONDO:0019269, EMP2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2982 C4A Zornitza Stark Publications for gene: C4A were set to 22387014; 22737222; 15998580; 10529130; 15294999; 32048120
Mendeliome v1.2981 C4A Zornitza Stark reviewed gene: C4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 40788338; Phenotypes: C4a deficiency MIM#614380; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2981 NDNF Zornitza Stark Publications for gene: NDNF were set to 31883645
Mendeliome v1.2980 NDNF Zornitza Stark edited their review of gene: NDNF: Added comment: PMID 40788466: two sisters with compound het variants and CHH. RED for this MOI.; Changed rating: AMBER; Changed publications: 31883645, 40788466
Mendeliome v1.2980 REPS1 Zornitza Stark Publications for gene: REPS1 were set to 29395073
Mendeliome v1.2979 REPS1 Zornitza Stark edited their review of gene: REPS1: Added comment: Additional family reported in PMID 40788509, but homozygous missense variant with no further supporting information.; Changed publications: 29395073, 40788509
Mendeliome v1.2979 MYOF Zornitza Stark Publications for gene: MYOF were set to 32542751
Mendeliome v1.2978 MYOF Zornitza Stark edited their review of gene: MYOF: Added comment: Two further families reported but with missense variants, which did not completely segregate with disease. No other supportive information provided.; Changed publications: 32542751, 40797221
Mendeliome v1.2978 CDK6 Zornitza Stark Publications for gene: CDK6 were set to 23918663
Mendeliome v1.2977 CDK6 Zornitza Stark edited their review of gene: CDK6: Added comment: Report of a second family, but same homozygous missense variant, suggestive of founder effect.; Changed publications: 23918663, 40801391
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected/affected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4. In addition, no information about unaffected siblings and segregation testing has been provided.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Mendeliome v1.2977 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals of Han Chinese descent with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

Phenotypic features
- age of onset 1.5-10 years old
- complex partial seizures (4), secondary GTCS (2)
- Normal MRI-B (3), focal cortical dysplasia (1)
- mild ID (1).

The variants were noted to be rare in EXAC-East Asian cohort, most located in CUB/Sushi domains. The gene has some evidence of missense and LoF constraint in gnomAD v4. There was also enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents). Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity. LoF is the postulated disease mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype associated with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Review of the missense variants in this study highlighted issues in a number of them including poor-moderate conservation, conflicting or benign in silicos including REVEL, non-coding in an alternative transcript, Case 4 p.Val1547Ile homozygote – this variant has been noted in an East Asian male homozygote aged between 45-50 in gnomAD v4.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries and variant-specific functional evidence is required to support this proposed gene-disease association.
Mendeliome v1.2977 CSMD2 Krithika Murali Marked gene: CSMD2 as ready
Mendeliome v1.2977 CSMD2 Krithika Murali Gene: csmd2 has been classified as Red List (Low Evidence).
Mendeliome v1.2977 CSMD2 Krithika Murali reviewed gene: CSMD2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 40632521, 31068362, 38649688; Phenotypes: Focal epilepsy - MONDO:0005384, CSMD2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2977 NSF Zornitza Stark Classified gene: NSF as Green List (high evidence)
Mendeliome v1.2977 NSF Zornitza Stark Gene: nsf has been classified as Green List (High Evidence).
Mendeliome v1.2976 NSF Zornitza Stark edited their review of gene: NSF: Added comment: Personal communication of additional cases with de novo variants and epilepsy; internal case at VCGS.; Changed rating: GREEN
Mendeliome v1.2976 CSMD2 Krithika Murali Deleted their review
Mendeliome v1.2976 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and 3631 amino acids. The true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2976 CSMD2 Krithika Murali changed review comment from: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature; to: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed some to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2976 CSMD2 Krithika Murali gene: CSMD2 was added
gene: CSMD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD2 were set to PMID: 40632521; 38649688; 31068362
Phenotypes for gene: CSMD2 were set to Focal epilepsy - MONDO:0005384, CSMD1-related
Review for gene: CSMD2 was set to AMBER
Added comment: PMID: 40632521 Li et al 2025 (Epilepsia) reported 6 unrelated individuals with biallelic CSMD2 missense variants (NM_052896) and focal epilepsy. 5 individuals were compound heterozygous and one was homozygous. These individuals were ascertained through trio WES analysis of 420 unrelated individuals of Han Chinese descent with focal epilepsy enrolled in the China Epilepsy Gene 1.0 project.

The age of onset was 1.5-10 years old, complex partial seizures (4 individuals), secondary GTCS (2 individuals), normal MRI (3), focal cortical dysplasia (1), mild ID (1).

The variants were noted to be rare, most located in CUB/Sushi domains, none reported in EXAC - East Asian population in homozygotes, and none predicted to have co-occurred as compound hets. There was also a significant enrichment of biallelic CSMD2 variants in affected individuals versus a control cohort of unaffected parents (5/420 compound hets affected individuals, 3/1942 compound hets in unaffected parents).

Previous mouse Csmd2 knockdown models demonstrated reduction in dendritic spine density and complexity and LoF is the postulated mechanism.

Closely related gene paralog CSMD1 has a definitive association with autosomal recessive complex neurodevelopmental disorder with a more severe phenotype. Different expression profiles during developmental stages between CSMD1 and CSMD2 postulated for the comparatively milder phenotype with the latter.

CSMD2 has 71 exons and true prevalence of biallelic missense variants in healthy individuals across diverse ancestries has not been ascertained. Closer review of the missense variants in this study showed a number of them to be moderately conserved residues with conflicting or benign in silicos.

Given prevalence of focal epilepsy, stronger case-control evidence required from diverse ancestries required to support gene-disease association in conjunction with variant-specific functional evidence.
Sources: Literature
Mendeliome v1.2975 PTCH2 Zornitza Stark Phenotypes for gene: PTCH2 were changed from Basal cell carcinoma, somatic 605462; Basal cell nevus syndrome, 109400; Medulloblastoma, somatic to Duplication of pituitary gland; Basal cell carcinoma, somatic 605462; Basal cell nevus syndrome, 109400; Medulloblastoma, somatic
Mendeliome v1.2974 PTCH2 Zornitza Stark Publications for gene: PTCH2 were set to 30820324; 23479190; 18285427
Mendeliome v1.2973 PTCH2 Zornitza Stark edited their review of gene: PTCH2: Added comment: PMID 40803816: novel splice site PTCH2 variant, c.1590+1G>A, leading to exon 12 skipping and an in-frame deletion of 44 amino acids identified in individual with duplication of the pituitary gland. Unclear how this relates to previously reported variants and phenotypes.; Changed publications: 30820324, 23479190, 18285427, 40803816; Changed phenotypes: Basal cell nevus syndrome, MIM#109400, Duplication of pituitary gland
Mendeliome v1.2973 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Amber List (moderate evidence)
Mendeliome v1.2973 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2972 SLC10A2 Zornitza Stark edited their review of gene: SLC10A2: Added comment: Second individual reported homozygous missense, but quite a specific phenotype so upgrade to Amber.; Changed rating: AMBER; Changed publications: 9109432, 40814585
Mendeliome v1.2972 KLHL9 Zornitza Stark Publications for gene: KLHL9 were set to 20554658
Mendeliome v1.2971 KLHL9 Zornitza Stark reviewed gene: KLHL9: Rating: AMBER; Mode of pathogenicity: None; Publications: 40818927; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2971 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982; 36458887
Mendeliome v1.2970 UHRF1 Zornitza Stark Classified gene: UHRF1 as Amber List (moderate evidence)
Mendeliome v1.2970 UHRF1 Zornitza Stark Gene: uhrf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2969 UHRF1 Zornitza Stark edited their review of gene: UHRF1: Added comment: Second family reported with homozygous missense variant.; Changed rating: AMBER; Changed publications: 29574422, 28976982, 40825131; Changed phenotypes: Imprinting disorder
Mendeliome v1.2969 RNF2 Zornitza Stark Publications for gene: RNF2 were set to 33864376
Mendeliome v1.2968 RNF2 Zornitza Stark Classified gene: RNF2 as Green List (high evidence)
Mendeliome v1.2968 RNF2 Zornitza Stark Gene: rnf2 has been classified as Green List (High Evidence).
Mendeliome v1.2967 RNF2 Zornitza Stark edited their review of gene: RNF2: Added comment: PMID 40831499 is a preprint which identifies additional individuals with de novo variants. p.S82R is recurrent. Functional data to support gene-disease association.; Changed rating: GREEN; Changed publications: 40831499
Mendeliome v1.2967 CCDC93 Zornitza Stark Marked gene: CCDC93 as ready
Mendeliome v1.2967 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Mendeliome v1.2967 CCDC93 Zornitza Stark Classified gene: CCDC93 as Red List (low evidence)
Mendeliome v1.2967 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Mendeliome v1.2966 COX18 Zornitza Stark Publications for gene: COX18 were set to PMID:37468577
Mendeliome v1.2965 COX18 Zornitza Stark Classified gene: COX18 as Green List (high evidence)
Mendeliome v1.2965 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Mendeliome v1.2964 SPNS1 Sangavi Sivagnanasundram changed review comment from: Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature; to: Patient 1 and 2 - Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature
Mendeliome v1.2964 SPNS1 Sangavi Sivagnanasundram gene: SPNS1 was added
gene: SPNS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPNS1 were set to 40608416
Phenotypes for gene: SPNS1 were set to Lysosomal disorder, SPNS1-related, MONDO:0002561
Review for gene: SPNS1 was set to AMBER
Added comment: Proband and younger brother prolonged, transient neonatal unconjugated hyperbilirubinemia followed by persistently elevated transaminases, serum creatine kinase and myoglobin levels since 6 months and 12 months of age
Compound het - Ser416Cys; Ile50Alafs*48 confirmed in trans - both absent from gnomAD v4.1

Patient 3 - 8M from consanguineous parents with elevated transaminase and failure to thrive at 2.5years. Liver transaminase, serum creatinine kinase were elevated. Diagnosed with DD and presented with neonatal cardiac abnormalities
Homozygous variant - Thr287Met - NFE PopMax AF 0.0008474%

Supportive functional assay conducted on patient fibroblasts showed accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens.
Sources: Literature
Mendeliome v1.2964 MIS18BP1 Krithika Murali Marked gene: MIS18BP1 as ready
Mendeliome v1.2964 MIS18BP1 Krithika Murali Gene: mis18bp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2964 WDR18 Krithika Murali Marked gene: WDR18 as ready
Mendeliome v1.2964 WDR18 Krithika Murali Gene: wdr18 has been classified as Red List (Low Evidence).
Mendeliome v1.2964 WDR18 Krithika Murali gene: WDR18 was added
gene: WDR18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR18 were set to PMID: 40677927
Phenotypes for gene: WDR18 were set to Cornelia de Lange syndrome (MONDO:0016033)
Review for gene: WDR18 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2963 MIS18BP1 Krithika Murali gene: MIS18BP1 was added
gene: MIS18BP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIS18BP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIS18BP1 were set to PMID: 40677927
Phenotypes for gene: MIS18BP1 were set to Cornelia de Lange syndrome (MONDO:0016033)
Review for gene: MIS18BP1 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2962 MED29 Zornitza Stark Marked gene: MED29 as ready
Mendeliome v1.2962 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2962 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Mendeliome v1.2962 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2961 GLYAT Zornitza Stark Marked gene: GLYAT as ready
Mendeliome v1.2961 GLYAT Zornitza Stark Gene: glyat has been classified as Red List (Low Evidence).
Mendeliome v1.2961 GLYAT Zornitza Stark gene: GLYAT was added
gene: GLYAT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GLYAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLYAT were set to 40747359
Phenotypes for gene: GLYAT were set to Neurodevelopmental disorder, MONDO:0700092, GLYAT-related
Review for gene: GLYAT was set to RED
Added comment: Single individual reported with homozygous LoF variant, p.Q108Ter. The individual was treated with pantothenic acid and a mitochondrial cocktail consisting of coenzyme Q10, vitamins B1, B2, B6, B12, C, folate, and carnitine, together with a low-protein diet, which led to the alleviation of oedema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature
Mendeliome v1.2960 TDRD12 Zornitza Stark Marked gene: TDRD12 as ready
Mendeliome v1.2960 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2960 TDRD12 Zornitza Stark Classified gene: TDRD12 as Amber List (moderate evidence)
Mendeliome v1.2960 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2959 TDRD12 Zornitza Stark gene: TDRD12 was added
gene: TDRD12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TDRD12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDRD12 were set to 40750267
Phenotypes for gene: TDRD12 were set to Spermatogenic failure, MONDO:0004983, TDRD12-related
Review for gene: TDRD12 was set to AMBER
Added comment: Two novel homozygous TDRD12 variants (c.3378dupG and c.2463C>G) reported in two unrelated infertile men, respectively. Patient 1 had a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This individual presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 had a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This individual exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage.
Sources: Literature
Mendeliome v1.2958 CCDC189 Zornitza Stark Marked gene: CCDC189 as ready
Mendeliome v1.2958 CCDC189 Zornitza Stark Gene: ccdc189 has been classified as Red List (Low Evidence).
Mendeliome v1.2958 CCDC189 Zornitza Stark gene: CCDC189 was added
gene: CCDC189 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: CCDC189.
Mode of inheritance for gene: CCDC189 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC189 were set to 40759592
Phenotypes for gene: CCDC189 were set to Spermatogenic failure, MONDO:0004983, CCDC189-related
Review for gene: CCDC189 was set to RED
Added comment: Single individual with biallelic variants. Limited functional data.

New HGNC approved name CFAP119.
Sources: Literature
Mendeliome v1.2957 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Mendeliome v1.2957 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Mendeliome v1.2957 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Mendeliome v1.2957 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Mendeliome v1.2956 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C1orf109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf109 were set to 40760247
Phenotypes for gene: C1orf109 were set to Neurodevelopmental disorder, MONDO:0700092, C1orf109-related
Review for gene: C1orf109 was set to GREEN
Added comment: Cohort of 11 unrelated families, encompassing 18 individuals with bi-allelic variants in C1orf109, 17 liveborn. Affected individuals presented with moderate-to-severe or severe global developmental delay/intellectual disability (17 of 17) and never achieved developmental milestones. Microcephaly and seizures were other common features. Reduced ribosome activity demonstrated during early brain development.
Sources: Literature
Mendeliome v1.2955 ASAP2 Zornitza Stark Marked gene: ASAP2 as ready
Mendeliome v1.2955 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2955 ASAP2 Zornitza Stark Classified gene: ASAP2 as Amber List (moderate evidence)
Mendeliome v1.2955 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2954 ASAP2 Zornitza Stark gene: ASAP2 was added
gene: ASAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASAP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ASAP2 were set to 40770811; 28191890; 33057194; 35982160
Phenotypes for gene: ASAP2 were set to Neurodevelopmental disorder, MONDO:0700092, ASAP2-related
Review for gene: ASAP2 was set to AMBER
Added comment: One individual reported with compound het missense variants. Identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811. Another individual with biallelic variants identified in the DDD cohort. Several others found with de novo variants through retrospective literature review of large cohort studies reporting multiple gene candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of ASAP2 in brain development. Rated AMBER as only two families with bi-allelic variants and minimal information on the cases with mono-allelic variants.
Sources: Literature
Mendeliome v1.2953 RTF1 Zornitza Stark changed review comment from: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates.
Sources: Literature; to: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 in brain development.
Sources: Literature
Mendeliome v1.2953 RTF1 Zornitza Stark Marked gene: RTF1 as ready
Mendeliome v1.2953 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Mendeliome v1.2953 RTF1 Zornitza Stark Classified gene: RTF1 as Green List (high evidence)
Mendeliome v1.2953 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Mendeliome v1.2952 RTF1 Zornitza Stark gene: RTF1 was added
gene: RTF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RTF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RTF1 were set to 40770811; 33057194; 35982160; 31038196
Phenotypes for gene: RTF1 were set to Neurodevelopmental disorder, MONDO:0700092, RTF1-related
Review for gene: RTF1 was set to GREEN
Added comment: Two individuals with de novo missense variants identified in a cohort of individuals presenting with ID/microcephaly, PMID 40770811, and further 8 identified through retrospective literature review of large cohort studies reporting multiple candidates.
Sources: Literature
Mendeliome v1.2951 PIK3C3 Krithika Murali Marked gene: PIK3C3 as ready
Mendeliome v1.2951 PIK3C3 Krithika Murali Gene: pik3c3 has been classified as Red List (Low Evidence).
Mendeliome v1.2951 PIK3C3 Krithika Murali gene: PIK3C3 was added
gene: PIK3C3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIK3C3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C3 were set to PMID:40677927
Phenotypes for gene: PIK3C3 were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: PIK3C3 was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2950 ARID3A Krithika Murali Marked gene: ARID3A as ready
Mendeliome v1.2950 ARID3A Krithika Murali Gene: arid3a has been classified as Red List (Low Evidence).
Mendeliome v1.2950 ARID3A Krithika Murali gene: ARID3A was added
gene: ARID3A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID3A were set to PMID: 40677927
Phenotypes for gene: ARID3A were set to Cornelia de Lange syndrome - MONDO:0016033
Review for gene: ARID3A was set to RED
Added comment: PMID: 40677927 Ansari et al 2025 (Hum Mut) - performed short-read WGS on 108 individuals with suspected CdLS with no causative variant identified on previous genetic testing.

In addition to variants in genes with known gene-disease associations, 5 de novo variants absent in gnomAD in 5 novel genes also identified in 5 unrelated individuals:

- ARID3A (missense variant, REVEL 0.72)
- PIK3C3 (missense, mechanistically not thought to be an obvious candidate gene for CdLS)
- MCM7 (LoF variant, gene linked with cohesin complex)
- MIS18BP1 (LoF variant, this individual also had a de novo intragenic deletion in PUF60)
- WDR18 (missense variant, weak in silico, REVEL 0.268)
Sources: Literature
Mendeliome v1.2949 DDX39A Krithika Murali Marked gene: DDX39A as ready
Mendeliome v1.2949 DDX39A Krithika Murali Gene: ddx39a has been classified as Red List (Low Evidence).
Mendeliome v1.2949 DDX39A Krithika Murali gene: DDX39A was added
gene: DDX39A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX39A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX39A were set to PMID: 40726340
Phenotypes for gene: DDX39A were set to Neurodevelopmental disorder, MONDO:0700092, DDX39A-related
Review for gene: DDX39A was set to RED
Added comment: PMID: 40726340 Ahmed et al 2025 (Clinical Genetics) report a 7 month old F with GDD, seizures, microcephaly, hypotonia, corpus callosum thinning and homozygous missense variant (p.Lys137Gln) in DDX39A on trio WES with both non-consanguineous parents confirmed to be heterozygous carriers. DDX39A is involved in mRNA splicing and export. Patient-derived fibroblast studies showed that mutant protein resulted in aberrant nuclear clumping and failure to interact with the TREX complex.

Of note, closely-related paralogue DDX39B is also a component of the TREX complex and has a definitive monoallelic association with neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.2948 HYPK Krithika Murali Marked gene: HYPK as ready
Mendeliome v1.2948 HYPK Krithika Murali Gene: hypk has been classified as Red List (Low Evidence).
Mendeliome v1.2948 HYPK Krithika Murali gene: HYPK was added
gene: HYPK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HYPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HYPK were set to Clinical Genetics Early View
Phenotypes for gene: HYPK were set to Neurodevelopmental disorder, MONDO:0700092, HYPK-related
Review for gene: HYPK was set to RED
Added comment: Single case report - Patel, R. et al 2025 Clinical Genetics Early View

Male proband with developmental delay, autism and facial dysmorphism with a de novo missense HYPK variant (p. R70I). Variant-specific biochemical analyses demonstrates enhanced inhibitory activity of HYPK on NatA-mediated N-terminal protein acetylation.

GestaltMatcher analysis indicates that the proband's facial phenotype closely resembles Ogden syndrome (NAA10) and some resemblance to NAA15-NDS - both associated genes are also involved in the N-terminal acetylation pathway.
Sources: Literature
Mendeliome v1.2947 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED29 were set to PMID: 40745490
Phenotypes for gene: MED29 were set to Pontocerebellar hypoplasia, MONDO:0020135, MED29-related
Review for gene: MED29 was set to AMBER
Added comment: MED29 encodes part of the mediator (MED) complex which has role in RNA polymerase II (Poll II) gene transcription.

PMID: 40745490 describes 2 siblings from one consanguineous family affected with pontocerebellar hypoplasia, profound GDD, severe microcephaly, cataracts and variable seizures.
Both shared the same homozygous missense variant with presumed LOF mechanism.

No homozygous LOF variants in gnomAD v4.

Extensive functional studies performed with morpholino knockdown of MED29 having marked reduction of GABAergic neurons and abnormal touch response.
Studies of hippocampal neurons from mice with knockdown MED29 showed impaired development.
Mouse embryos that had knockdown of MED29 during development demonstrated abnormal neuronal migration.
Sources: Literature
Mendeliome v1.2947 COX18 Sangavi Sivagnanasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 40830826; Phenotypes: Mitochondrial disease (MONDO:0044970), COX18-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2947 CCDC93 Sarah Milton reviewed gene: CCDC93: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 40601774; Phenotypes: Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2947 CCDC93 Sarah Milton Deleted their review
Mendeliome v1.2947 CCDC93 Sarah Milton gene: CCDC93 was added
gene: CCDC93 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC93 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC93 were set to PMID: 40601774
Phenotypes for gene: CCDC93 were set to Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related
Review for gene: CCDC93 was set to AMBER
Added comment: CCDC93 encodes the coiled coil domain containing subunit of commander complex involved in recycling of integral membrane proteins.

PMID: 40601774 describes 1 affected individual with compound heterozygous variants in CCDC93 who presented with Ritscher Schinzel like phenotype. Features included hypoplasia of cerebellar hemispheres, hypoplasia of the brainstem and of the corpus callosum, distinctive facial features and multiple small renal cysts.
Variants were missense and nonsense.

No homozygous LOF variants in gnomAD v4.

Some supportive functional data.
Sources: Literature
Mendeliome v1.2947 ATP13A3 Zornitza Stark Mode of inheritance for gene: ATP13A3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2946 ATP13A3 Zornitza Stark edited their review of gene: ATP13A3: Added comment: Biallelic variants reported in childhood onset. DEFINITIVE by ClinGen.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2946 DLGAP5 Zornitza Stark Marked gene: DLGAP5 as ready
Mendeliome v1.2946 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Mendeliome v1.2946 DLGAP5 Zornitza Stark Classified gene: DLGAP5 as Green List (high evidence)
Mendeliome v1.2946 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Mendeliome v1.2945 DLGAP5 Zornitza Stark gene: DLGAP5 was added
gene: DLGAP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DLGAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLGAP5 were set to 40796344
Phenotypes for gene: DLGAP5 were set to Infertility disorder, MONDO:0005047, DLGAP5-related
Review for gene: DLGAP5 was set to GREEN
Added comment: 3 individuals with biallelic variants identified as part of a large cohort (N=488) of women experiencing recurrent early embryonic arrest. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.
Sources: Literature
Mendeliome v1.2944 CREB3 Sarah Milton gene: CREB3 was added
gene: CREB3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CREB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CREB3 were set to PMID: 40674075
Phenotypes for gene: CREB3 were set to Retinal degeneration, MONDO:0004580, CREB3-related
Review for gene: CREB3 was set to GREEN
Added comment: CREB3 encodes Cyclic AMP response element binding protein-3 which is an endoplasmic reticulum–membrane-bound transcription factor.

PMID: 40674075 describes 13 individuals from 4 families with the same homozygous nonsense variant (CREB:c.881G>A|p.Trp294). Affected individuals had retinal degeneration presenting initially with slowly progressive decreased visual acuity – significant variability in age of onset and severity – age 8-65.
2 different haplotypes identified on which the variant was found.

Homozygous LOF variants not present in CREB3 in gnomad v4.

Functional studies performed only demonstrated that mRNA transcript doesn't undergo NMD and that protein is expressed in retina. No variant specific or downstream effects investigated.
Sources: Literature
Mendeliome v1.2944 ISPD Zornitza Stark Marked gene: ISPD as ready
Mendeliome v1.2944 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Mendeliome v1.2944 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Mendeliome v1.2944 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Mendeliome v1.2944 TRIM72 Zornitza Stark Marked gene: TRIM72 as ready
Mendeliome v1.2944 TRIM72 Zornitza Stark Gene: trim72 has been classified as Red List (Low Evidence).
Mendeliome v1.2944 TRIM72 Zornitza Stark gene: TRIM72 was added
gene: TRIM72 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM72 were set to 40804694
Phenotypes for gene: TRIM72 were set to Limb girdle muscular dystrophy MONDO:0016971, TRIM72-related
Review for gene: TRIM72 was set to RED
Added comment: Single affected individual, homozygous LoF variant, c.891delT; p.Ala298ArgfsTer64. However note two homozygous individuals are present in gnomAD.
Sources: Literature
Mendeliome v1.2943 TRIM74 Zornitza Stark Marked gene: TRIM74 as ready
Mendeliome v1.2943 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Mendeliome v1.2943 TRIM74 Zornitza Stark Classified gene: TRIM74 as Red List (low evidence)
Mendeliome v1.2943 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Mendeliome v1.2942 ZNF496 Zornitza Stark Marked gene: ZNF496 as ready
Mendeliome v1.2942 ZNF496 Zornitza Stark Gene: znf496 has been classified as Red List (Low Evidence).
Mendeliome v1.2942 ZNF496 Zornitza Stark gene: ZNF496 was added
gene: ZNF496 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF496 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF496 were set to 40806714
Phenotypes for gene: ZNF496 were set to Neurodevelopmental disorder, MONDO:0700092, ZNF496-related
Review for gene: ZNF496 was set to RED
Added comment: Single individual with NDD and de novo LoF variant, no other supportive data.
Sources: Literature
Mendeliome v1.2941 SCN3B Sarah Milton gene: SCN3B was added
gene: SCN3B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCN3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN3B were set to PMID: 40879121
Phenotypes for gene: SCN3B were set to Neurodevelopmental disorder, MONDO:0700092, SCN3B-related
Review for gene: SCN3B was set to AMBER
Added comment: SCN3B Encodes b3 auxiliary subunit of the sodium channel.

4 affected individuals from 2 consanguineous families reported in PMID: 40879121 with biallelic variants in this gene with neurodevelopmental phenotypes. Presentation included GDD, ID of variable severity, autism, seizures.
One variant was nonsense, one canonical splice site in the penultimate exon.

No homozygous LOF variants in gnomAD v4.

Some functional studies performed with loss of function of channel demonstrated for one variant.
Sources: Literature
Mendeliome v1.2941 XPO1 Sangavi Sivagnanasundram gene: XPO1 was added
gene: XPO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: XPO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: XPO1 were set to 40819229
Phenotypes for gene: XPO1 were set to Neurodevelopmental disorder, XPO1-related, MONDO:0700092
Review for gene: XPO1 was set to GREEN
Added comment: Established gene-disease association
22 probands with de novo XPO1 variants presenting with phenotypes associated with NDD (DD, ID, motor delay, behavioral problems, facial dysmorphisms, microcephaly and organ anomalies) along with supportive Drosophila knockdown model reported.
Sources: Literature
Mendeliome v1.2941 MKL1 Zornitza Stark Phenotypes for gene: MKL1 were changed from Neutropaenia with combined immune deficiency to Inborn error of immunity, MONDO:0003778, MKL1-related
Mendeliome v1.2940 MKL1 Zornitza Stark Publications for gene: MKL1 were set to 32128589; 26224645
Mendeliome v1.2939 MKL1 Zornitza Stark Classified gene: MKL1 as Green List (high evidence)
Mendeliome v1.2939 MKL1 Zornitza Stark Gene: mkl1 has been classified as Green List (High Evidence).
Mendeliome v1.2938 MKL1 Zornitza Stark edited their review of gene: MKL1: Added comment: Third individual reported with compound het LoF variants and some supportive functional data. Neutrophils from the affected individual showed impaired F-actin polymerization, decreased migration ability, reduced ROS production, increased apoptosis, diminished NETs formation, and decreased MPO levels. Transcriptome profiling revealed neutrophil-specific downregulation of cytoskeletal genes with concomitant upregulation of antimicrobial peptide/inflammatory pathways, while PBMCs presented upregulated adhesion/migration-related genes.; Changed rating: GREEN; Changed publications: 32128589, 26224645, 40808667; Changed phenotypes: Inborn error of immunity, MONDO:0003778, MKL1-related
Mendeliome v1.2938 MARS Zornitza Stark Publications for gene: MARS were set to 23729695; 24354524; 29655802; 24103465; 25913036; 33909043; 24482476; 34585293
Mendeliome v1.2937 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Second individual with homozygous variant and trichothiodystorphy reported in PMID 40820264; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036, 24482476, 34585293, 40820264, 33909043
Mendeliome v1.2937 TECTB Zornitza Stark Marked gene: TECTB as ready
Mendeliome v1.2937 TECTB Zornitza Stark Gene: tectb has been classified as Red List (Low Evidence).
Mendeliome v1.2937 TECTB Zornitza Stark gene: TECTB was added
gene: TECTB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TECTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TECTB were set to 40832383
Phenotypes for gene: TECTB were set to Hearing loss disorder, MONDO:0005365, TECTB-related
Review for gene: TECTB was set to RED
Added comment: Single multigenerational family segregating a missense variant and a mouse model.
Sources: Literature
Mendeliome v1.2936 TRIM74 Sangavi Sivagnanasundram gene: TRIM74 was added
gene: TRIM74 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TRIM74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM74 were set to 40735933
Phenotypes for gene: TRIM74 were set to Neurodevelopmental disorder, TRIM74-related, MONDO:0700092
Review for gene: TRIM74 was set to RED
Added comment: Only one reported case with supportive functional assay

PMID: 40735933
5yr M presenting from non consanguineous parents with global developmental delay, hypotonia, seizures, and diffuse cerebral atrophy with mega cisterna magna. Parents of the proband were found to be carriers of the variant.
Homozygous variant c.562C > T (p.Pro121Leu) - NFE AF 0.0188% - rare enough for AR

Supportive functional analysis on human fibroblast showed protein function disruption leading to protein aggregation, proteostasis collapse, and cell death.
Sources: Other
Mendeliome v1.2936 BAZ2B Zornitza Stark Classified gene: BAZ2B as Amber List (moderate evidence)
Mendeliome v1.2936 BAZ2B Zornitza Stark Gene: baz2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2935 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Added comment: Classified as LIMITED by ClinGen.; Changed rating: AMBER; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Mendeliome v1.2935 BAZ2B Zornitza Stark Phenotypes for gene: BAZ2B were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Mendeliome v1.2934 BBS2 Sarah Milton reviewed gene: BBS2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: BBS2-related ciliopathy, MONDO:1040048; Mode of inheritance: None
Mendeliome v1.2934 BAZ2B Sarah Milton reviewed gene: BAZ2B: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related; Mode of inheritance: None
Mendeliome v1.2934 TRAP1 Zornitza Stark Phenotypes for gene: TRAP1 were changed from CAKUT; VACTERL to Syndromic disease, MONDO:0002254, TRAP1-related
Mendeliome v1.2933 TRAP1 Zornitza Stark edited their review of gene: TRAP1: Changed phenotypes: Syndromic disease, MONDO:0002254, TRAP1-related
Mendeliome v1.2933 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from 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 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Premature ovarian failure 21, MIM#620311
Mendeliome v1.2932 TP63 Zornitza Stark edited their review of gene: TP63: Added comment: DEFINITIVE by ClinGen.

Lumped EEC3 syndrome (MIM:604292), ADULT syndrome (MIM:103285), AEC syndrome (MIM:106260), Rapp-Hodgkin syndrome (MIM:129400), Limb-mammary syndrome (MIM:603543), Split-hand/foot malformation 4 (MIM:605289), and Orofacial cleft 8 (MIM:618149).

Association with POF considered separate.; Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001, Premature ovarian failure 21, MIM#620311
Mendeliome v1.2932 TOMM70 Zornitza Stark Phenotypes for gene: TOMM70 were changed from Severe anaemia, lactic acidosis, developmental delay; White matter abnormalities, developmental delay, regression, movement disorder to Mitochondrial disease, MONDO:0044970, TOMM70-related; Leukodystrophy, MONDO:0019046, TOMM70-related
Mendeliome v1.2931 TOMM70 Zornitza Stark edited their review of gene: TOMM70: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TOMM70-related, Leukodystrophy, MONDO:0019046, TOMM70-related
Mendeliome v1.2931 ARNTL Zornitza Stark Marked gene: ARNTL as ready
Mendeliome v1.2931 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Mendeliome v1.2931 ARNTL Zornitza Stark Classified gene: ARNTL as Green List (high evidence)
Mendeliome v1.2931 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Mendeliome v1.2930 ARNTL Zornitza Stark Tag new gene name tag was added to gene: ARNTL.
Mendeliome v1.2930 CSMD3 Zornitza Stark Marked gene: CSMD3 as ready
Mendeliome v1.2930 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Mendeliome v1.2930 CSMD3 Zornitza Stark Classified gene: CSMD3 as Green List (high evidence)
Mendeliome v1.2930 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Mendeliome v1.2929 TMPRSS7 Zornitza Stark Marked gene: TMPRSS7 as ready
Mendeliome v1.2929 TMPRSS7 Zornitza Stark Gene: tmprss7 has been classified as Red List (Low Evidence).
Mendeliome v1.2929 TMPRSS7 Zornitza Stark gene: TMPRSS7 was added
gene: TMPRSS7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMPRSS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS7 were set to 40796295
Phenotypes for gene: TMPRSS7 were set to Neurodevelopmental disorder, TMPRSS7-related
Review for gene: TMPRSS7 was set to RED
Added comment: PMID 40796295: individual with compound het variants, p.R479H and p.S685Kfs*26 and neurodevelopmental disorder. Tmprss7 homozygous knockout (KO) mice exhibited dysregulated synaptic dendritic spine density, function, and dendritic elongation in the cerebral cortex and hippocampus. In addition, the KO animals displayed neurobehavioral deficits, including impairments in spatial learning, anxiety-like behavior, and a reduced preference for social novelty. Multi-omics analysis discovered enrichment of pathways related to synaptic signaling disruptions in both the cerebral cortex and hippocampus.
Sources: Literature
Mendeliome v1.2928 PPP1R2 Zornitza Stark gene: PPP1R2 was added
gene: PPP1R2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP1R2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R2 were set to 40597352; 26558779
Phenotypes for gene: PPP1R2 were set to Neurodevelopmental disorder, PPP1R2-related
Review for gene: PPP1R2 was set to RED
Added comment: Single individual reported with homozygous splicing variant c.403 + 3 A >T. Abnormal splicing demonstrated but leaky. Clinical features included pre and postnatal growth restriction, ventricular septal defect, dysmorphic features (proptosis, long eye lashes, thick eyebrows, low-set ears), microcephaly, sensorineural hearing loss, cortical cataracts, retinal defects, intellectual disability with limited speech, and autism spectrum disorder. Note mouse model is embryonically lethal, leading the authors to speculate survival may be due to fraction of normally spliced transcripts.
Sources: Literature
Mendeliome v1.2927 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Mendeliome v1.2927 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Mendeliome v1.2927 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Mendeliome v1.2927 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Mendeliome v1.2926 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Mendeliome v1.2925 CSMD3 Sarah Milton gene: CSMD3 was added
gene: CSMD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD3 were set to PMID: 40632521
Phenotypes for gene: CSMD3 were set to Epilepsy, MONDO:0005027, CSMD3-related
Review for gene: CSMD3 was set to GREEN
Added comment: CSMD3 encodes a synaptic membrane proteins and play a role in neuronal maturation/growth dendrites. A related protein CSMD1 has been previously associated with a complex neurodevelopmental disorder.

PMID: 40632521 describes 8 individuals with seizures. 4 with focal epilepsy, 3 with febrile seizures and 1 individual with infantile spasms. 1 individual described had a de novo missense variant with remainder having comp het/biallelic variants. Mild ID in 1 individual only.

Variant type mostly missense variants with 1 nonsense, all appropriately rare in gnomAD v4 for recessive disorder.

No variant specific functional studies performed, no clear discussion in paper about postulated mechanism for disease. No discussion around difference in mechanism for de novo monoallelic variant.

Previous studies showed homozygous knockout mice display abnormal neuronal proliferation and growth retardation.
Sources: Literature
Mendeliome v1.2925 MMD2 Zornitza Stark Marked gene: MMD2 as ready
Mendeliome v1.2925 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2925 MMD2 Zornitza Stark Classified gene: MMD2 as Amber List (moderate evidence)
Mendeliome v1.2925 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2924 MMD2 Zornitza Stark gene: MMD2 was added
gene: MMD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMD2 were set to 40663042
Phenotypes for gene: MMD2 were set to Periodontitis, MONDO:0005076, MMD2-related
Review for gene: MMD2 was set to AMBER
Added comment: Two multigenerational families with aggressive periodontitis segregating missense variants, plus supportive functional data. Abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients' neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 variants.
Sources: Literature
Mendeliome v1.2923 ARNTL Sarah Milton gene: ARNTL was added
gene: ARNTL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARNTL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARNTL were set to PMID: 40720646
Phenotypes for gene: ARNTL were set to Neurodevelopmental disorder, MONDO:0700092, BMAL1-related
Review for gene: ARNTL was set to GREEN
Added comment: Note has new HGNC approved name - BMAL1

BMAL1 encodes a transcription factor that plays a role in the mammalian molecular clock, binds to promoter of PER and CRY family genes to promote transcription. Other circardian genes have sleep phase disorder assoc but not neurodevelopmental phenotype.

10 affected individuals described in PMID: 40455867 with variable developmental delay/ID from average IQ to severe ID, seizures in 50%, autism, some had sleep disturbance and marfanoid habitus.
Variants were LOF & missense and very rare or absent in gnomAD v4.
5 confirmed de novo, 2 confirmed inherited (one from apparently unaffected mother).

Functional studies using luciferase reporter assay of downstream target PER showed reduced luminescence for most variants with presumed LOF mechanism. One variant p.(Ile201Thr) led to increased luminescence with author's postulating GOF mechanism for this variant. Drosophilia studies for 2 of the variants demonstrated altered circadian rhythm. ?needs more studies to further define mechanism.
Sources: Literature
Mendeliome v1.2923 FAM136A Zornitza Stark Marked gene: FAM136A as ready
Mendeliome v1.2923 FAM136A Zornitza Stark Gene: fam136a has been classified as Red List (Low Evidence).
Mendeliome v1.2923 FAM136A Zornitza Stark gene: FAM136A was added
gene: FAM136A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM136A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FAM136A were set to 40714634
Phenotypes for gene: FAM136A were set to Meniere's disease
Review for gene: FAM136A was set to RED
Added comment: Single family reported with high impact variant, supportive functional data.
Sources: Literature
Mendeliome v1.2922 NCOA7 Zornitza Stark Marked gene: NCOA7 as ready
Mendeliome v1.2922 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Mendeliome v1.2922 NCOA7 Zornitza Stark Classified gene: NCOA7 as Green List (high evidence)
Mendeliome v1.2922 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Mendeliome v1.2921 NCOA7 Zornitza Stark gene: NCOA7 was added
gene: NCOA7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCOA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NCOA7 were set to 40745099
Phenotypes for gene: NCOA7 were set to Inherited premature ovarian failure MONDO:0019852, NCOA7-related
Review for gene: NCOA7 was set to GREEN
Added comment: 7 individuals with POI and heterozygous variants in this gene. Two of the variants led to NMD; 3 were missense. Functional data supports role in cell senescence.
Sources: Literature
Mendeliome v1.2920 DNAH6 Zornitza Stark Phenotypes for gene: DNAH6 were changed from Spermatogenic failure, MONDO:0004983, DNAH6-related; situs inversus, MONDO:0010029 to Spermatogenic failure, MONDO:0004983, DNAH6-related
Mendeliome v1.2919 DNAH6 Zornitza Stark Publications for gene: DNAH6 were set to PMID: 26918822
Mendeliome v1.2918 DNAH6 Zornitza Stark Classified gene: DNAH6 as Green List (high evidence)
Mendeliome v1.2918 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Green List (High Evidence).
Mendeliome v1.2917 DNAH6 Zornitza Stark Deleted their comment
Mendeliome v1.2917 DNAH6 Zornitza Stark edited their review of gene: DNAH6: Added comment: More than 5 unrelated individuals reported with spermatogenic failure and bi-allelic variants in this gene.; Changed rating: GREEN; Changed publications: 37594300, 39192248, 37424858, 31676830, 29356036, 40592014
Mendeliome v1.2917 DNAH6 Zornitza Stark Phenotypes for gene: DNAH6 were changed from Heterotaxy, Azoospermia to Spermatogenic failure, MONDO:0004983, DNAH6-related; situs inversus, MONDO:0010029
Mendeliome v1.2916 DNAH6 Zornitza Stark reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 40592014; Phenotypes: Spermatogenic failure, MONDO:0004983, DNAH6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2916 PAX4 Zornitza Stark edited their review of gene: PAX4: Changed phenotypes: Maturity-onset diabetes of the young, type IX MIM#612225, Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Mendeliome v1.2916 PAX4 Zornitza Stark Phenotypes for gene: PAX4 were changed from Maturity-onset diabetes of the young, type IX MIM#612225; Diabetes mellitus, type 2, MIM# 125853 to Maturity-onset diabetes of the young, type IX MIM#612225; Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Mendeliome v1.2915 PAX4 Zornitza Stark Publications for gene: PAX4 were set to 17426099; 14561778; 25951767; 21263211
Mendeliome v1.2914 PAX4 Zornitza Stark Mode of inheritance for gene: PAX4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2913 PAX4 Zornitza Stark edited their review of gene: PAX4: Added comment: Homozygous PAX4 loss-of-function variants in 2 individuals with transient NDM: a p.(Arg126∗) stop-gain variant and a c.-352_104del deletion affecting the first 4 PAX4 exons. This is a separate association to the refuted association with MODY but maintaining the RED rating overall.; Changed rating: RED; Changed publications: 17426099, 14561778, 25951767, 21263211, 40614820; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2913 MAN2A2 Zornitza Stark Publications for gene: MAN2A2 were set to 36357165
Mendeliome v1.2912 MAN2A2 Zornitza Stark Classified gene: MAN2A2 as Amber List (moderate evidence)
Mendeliome v1.2912 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2911 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Added comment: PMID 40628855: second unrelated individual reported, presenting with ID/autism and with bi-allelic variants, one missense and the other LoF. Abnormal glycosylation patterns observed consistent with CDG.; Changed rating: AMBER; Changed publications: 36357165, 40628855
Mendeliome v1.2911 CCDC186 Zornitza Stark Phenotypes for gene: CCDC186 were changed from Epileptic encephalopathy to Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Mendeliome v1.2910 CCDC186 Zornitza Stark Publications for gene: CCDC186 were set to 33259146
Mendeliome v1.2909 CCDC186 Zornitza Stark Classified gene: CCDC186 as Green List (high evidence)
Mendeliome v1.2909 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Changed rating: GREEN
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Added comment: PMID 40633195: Individual with another bi-allelic LoF variant reported, NM_018017.4:c.535C>T (p.Arg179Ter), presenting with seizures, ID and microcephaly.; Changed publications: 33259146, 37569695, 40633195
Mendeliome v1.2908 CCDC186 Zornitza Stark changed review comment from: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter; to: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter. EE was part of the phenotype, although the phenotype was broader.
Mendeliome v1.2908 CCDC186 Zornitza Stark changed review comment from: One individual reported with bi-allelic truncating variant and EE.
Sources: Literature; to: One individual reported with bi-allelic truncating variant p.(Ser256Ter) and EE.
Sources: Literature
Mendeliome v1.2908 CCDC186 Zornitza Stark edited their review of gene: CCDC186: Added comment: PMID: two Gypsy families reported, with same homozygous variant, c.2215C>T, p.Arg739Ter; Changed publications: 33259146, 37569695
Mendeliome v1.2908 VWA8 Zornitza Stark Publications for gene: VWA8 were set to PMID: 37012052
Mendeliome v1.2907 VWA8 Zornitza Stark Classified gene: VWA8 as Green List (high evidence)
Mendeliome v1.2907 VWA8 Zornitza Stark Gene: vwa8 has been classified as Green List (High Evidence).
Mendeliome v1.2906 VWA8 Zornitza Stark edited their review of gene: VWA8: Added comment: PMID 40638000: additional individual reported with LoF variant and RP, upgrade to Green.; Changed rating: GREEN; Changed publications: 37012052, 40638000
Mendeliome v1.2906 PCLO Zornitza Stark Publications for gene: PCLO were set to 25832664
Mendeliome v1.2905 PCLO Zornitza Stark Classified gene: PCLO as Green List (high evidence)
Mendeliome v1.2905 PCLO Zornitza Stark Gene: pclo has been classified as Green List (High Evidence).
Mendeliome v1.2904 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 40661989: additional case report of a Thai patient with PCH and compound het LoF variants in this gene.
PMID 32122952: rat model consistent with human phenotype.
PMID 30287594: additional family with 5 affected sibs, compound het for LoF variants and PCH. Upgrade to GREEN.; Changed rating: GREEN; Changed publications: 25832664, 40661989, 32122952, 30287594
Mendeliome v1.2904 LSR Zornitza Stark Phenotypes for gene: LSR were changed from transient neonatal cholestasis; intellectual disability; short stature to Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related; transient neonatal cholestasis; intellectual disability; short stature
Mendeliome v1.2903 LSR Zornitza Stark Publications for gene: LSR were set to 30250217; 32303357
Mendeliome v1.2902 LSR Zornitza Stark Classified gene: LSR as Green List (high evidence)
Mendeliome v1.2902 LSR Zornitza Stark Gene: lsr has been classified as Green List (High Evidence).
Mendeliome v1.2901 LSR Zornitza Stark edited their review of gene: LSR: Added comment: PMID 40846272: further two patients with homozygous missense variants.
PMID 40679108: additional case report, compound het LoF and missense variant in a 4yo with cholestasis and mild liver fibrosis.
We are aware of a further case internally, upgrade to GREEN.; Changed rating: GREEN; Changed publications: 32303357, 30250217, 40679108, 40846272; Changed phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related, transient neonatal cholestasis, intellectual disability, short stature
Mendeliome v1.2901 TAF13 Zornitza Stark Phenotypes for gene: TAF13 were changed from Mental retardation, autosomal recessive 60, MIM# 617432 to Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Mendeliome v1.2900 TAF13 Zornitza Stark Publications for gene: TAF13 were set to 28257693
Mendeliome v1.2899 TAF13 Zornitza Stark edited their review of gene: TAF13: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Mendeliome v1.2899 TAF13 Zornitza Stark edited their review of gene: TAF13: Added comment: Two more families reported, but with same homozygous missense variant as previous, c.119T>A p.Met40Lys, suggestive of founder effect. In addition to ID and microcephaly, DSD reported.; Changed publications: 28257693, 40679298
Mendeliome v1.2899 IGSF10 Zornitza Stark Phenotypes for gene: IGSF10 were changed from delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency to Disorder of sex differentiation, MONDO:0002145, IGSF10-related
Mendeliome v1.2898 IGSF10 Zornitza Stark Publications for gene: IGSF10 were set to 27137492; 31042289
Mendeliome v1.2897 IGSF10 Zornitza Stark Mode of inheritance for gene: IGSF10 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2896 IGSF10 Zornitza Stark reviewed gene: IGSF10: Rating: AMBER; Mode of pathogenicity: None; Publications: 27137492, 31042289, 40700020; Phenotypes: Disorder of sex differentiation, MONDO:0002145, IGSF10-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2896 TXNRD2 Zornitza Stark Classified gene: TXNRD2 as Green List (high evidence)
Mendeliome v1.2896 TXNRD2 Zornitza Stark Gene: txnrd2 has been classified as Green List (High Evidence).
Mendeliome v1.2895 TXNRD2 Zornitza Stark edited their review of gene: TXNRD2: Added comment: PMID 40726908: further family reported with compound het missense variants, some supportive data (reduced protein levels).

Two further case reports identified in PMIDs 38011841 and 39097530. Upgrade to GREEN.; Changed rating: GREEN; Changed publications: 34258490, 40726908, 38011841, 39097530
Mendeliome v1.2895 FAAH2 Zornitza Stark Phenotypes for gene: FAAH2 were changed from autism spectrum disorder MONDO:0005258 to Neurodevelopmental disorder, MONDO:0700092, FAAH2-related
Mendeliome v1.2894 FAAH2 Zornitza Stark Publications for gene: FAAH2 were set to 34645488; 25885783
Mendeliome v1.2893 FAAH2 Zornitza Stark edited their review of gene: FAAH2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2893 FAAH2 Zornitza Stark reviewed gene: FAAH2: Rating: RED; Mode of pathogenicity: None; Publications: 40744325; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, FAAH2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2893 TNFSF12 Zornitza Stark Phenotypes for gene: TNFSF12 were changed from Recurrent infections, poor antibody responses, decreased immunoglobulins to Inborn error of immunity, MONDO:0003778, TNFSF12-related
Mendeliome v1.2892 TNFSF12 Zornitza Stark edited their review of gene: TNFSF12: Changed phenotypes: Inborn error of immunity, MONDO:0003778, TNFSF12-related
Mendeliome v1.2892 NDC1 Zornitza Stark Phenotypes for gene: NDC1 were changed from triple-A syndrome MONDO:0009279 to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328
Mendeliome v1.2891 NDC1 Zornitza Stark reviewed gene: NDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MIM# 621328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2891 SEPHS1 Zornitza Stark Phenotypes for gene: SEPHS1 were changed from Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related to Ververi-Brady syndrome 2, MIM# 621325
Mendeliome v1.2890 SEPHS1 Zornitza Stark edited their review of gene: SEPHS1: Changed phenotypes: Ververi-Brady syndrome 2, MIM# 621325
Mendeliome v1.2890 TNFRSF21 Zornitza Stark Phenotypes for gene: TNFRSF21 were changed from high myopia to Myopia, MONDO:0001384, TNFRSF21-related
Mendeliome v1.2889 TNFRSF21 Zornitza Stark reviewed gene: TNFRSF21: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopia, MONDO:0001384, TNFRSF21-related; Mode of inheritance: None
Mendeliome v1.2889 TMTC2 Zornitza Stark Classified gene: TMTC2 as Red List (low evidence)
Mendeliome v1.2889 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Red List (Low Evidence).
Mendeliome v1.2888 TMTC2 Zornitza Stark Tag disputed tag was added to gene: TMTC2.
Mendeliome v1.2888 TMTC2 Zornitza Stark edited their review of gene: TMTC2: Added comment: Note the homozygous variant reported in PMID 27311106 is present in a high number of homozygotes in gnomAD.; Changed rating: RED
Mendeliome v1.2888 TMEM65 Zornitza Stark Phenotypes for gene: TMEM65 were changed from Mitochondrial encephalomyopathy to Mitochondrial disease, MONDO:0044970, TMEM65-related
Mendeliome v1.2887 TMEM65 Zornitza Stark edited their review of gene: TMEM65: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TMEM65-related
Mendeliome v1.2887 POLE2 Zornitza Stark Phenotypes for gene: POLE2 were changed from Combined immunodeficiency; Lymphopaenia; Lack of TRECS, absent proliferation in response to antigens; Hypoglobulinaemia; Recurrent infections, disseminated BCG infections; Autoimmunity; Facial dysmorphism to Combined immunodeficiency MONDO:0015131, POLE2-related
Mendeliome v1.2886 PNPLA6 Zornitza Stark Phenotypes for gene: PNPLA6 were changed from Boucher-Neuhauser syndrome, 215470; ?Laurence-Moon syndrome, 245800; Oliver-McFarlane syndrome, 275400; Spastic paraplegia 39, autosomal recessive, 612020 to Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155; Spastic paraplegia 39, autosomal recessive MIM#612020
Mendeliome v1.2885 PNPLA4 Zornitza Stark Phenotypes for gene: PNPLA4 were changed from to Mitochondrial disease (MONDO:0044970), PNPLA4-related
Mendeliome v1.2884 PNPLA3 Zornitza Stark Phenotypes for gene: PNPLA3 were changed from Susceptibility to nonalcoholic fatty liver disease to Metabolic dysfunction-associated steatotic liver disease MONDO:0013209, PNPLA3-related
Mendeliome v1.2883 POLE2 Lucy Spencer reviewed gene: POLE2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined immunodeficiency MONDO:0015131, POLE2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PNPLA6 Lucy Spencer reviewed gene: PNPLA6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155, Spastic paraplegia 39, autosomal recessive MIM#612020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PNPLA4 Lucy Spencer reviewed gene: PNPLA4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial disease (MONDO:0044970), PNPLA4-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2883 PNPLA3 Lucy Spencer reviewed gene: PNPLA3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metabolic dysfunction-associated steatotic liver disease MONDO:0013209, PNPLA3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2883 TMEM173 Zornitza Stark Marked gene: TMEM173 as ready
Mendeliome v1.2883 TMEM173 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is STING1
Mendeliome v1.2883 TMEM173 Zornitza Stark Gene: tmem173 has been classified as Green List (High Evidence).
Mendeliome v1.2883 TMEM173 Zornitza Stark Tag new gene name tag was added to gene: TMEM173.
Mendeliome v1.2883 PMM2 Lucy Spencer changed review comment from: Adding HIPKD MONDO term specific for this gene; to: Adding HIPKD MONDO term specific for this gene
Mendeliome v1.2883 PMM2 Lucy Spencer reviewed gene: PMM2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinaemic Hypoglycaemia with polycystic kidney disease MONDO:1030000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PMFBP1 Lucy Spencer reviewed gene: PMFBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 31 MIM#618112; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2883 PLXNC1 Lucy Spencer reviewed gene: PLXNC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral cortical dysplasia MONDO:0017094, PLXNC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2883 PLXNA3 Lucy Spencer reviewed gene: PLXNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0018555, PLXNA3-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2883 TIMM22 Zornitza Stark Phenotypes for gene: TIMM22 were changed from mitochondrial myopathy; hypotonia; gastroesophageal reflux disease to Mitochondrial disease, MONDO:0044970, TIMM22-related
Mendeliome v1.2882 TIMM22 Zornitza Stark edited their review of gene: TIMM22: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TIMM22-related
Mendeliome v1.2882 THOC1 Zornitza Stark Phenotypes for gene: THOC1 were changed from Nonsyndromic hearing loss to Hearing loss disorder, MONDO:0005365, THOC1-related
Mendeliome v1.2881 THOC1 Zornitza Stark reviewed gene: THOC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hearing loss disorder, MONDO:0005365, THOC1-related; Mode of inheritance: None
Mendeliome v1.2881 TDGF1 Zornitza Stark Phenotypes for gene: TDGF1 were changed from Forebrain abnormalities to Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Mendeliome v1.2880 TDGF1 Zornitza Stark Tag disputed tag was added to gene: TDGF1.
Mendeliome v1.2880 TDGF1 Zornitza Stark edited their review of gene: TDGF1: Changed phenotypes: Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Mendeliome v1.2880 TCF7L2 Zornitza Stark Phenotypes for gene: TCF7L2 were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system to Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Mendeliome v1.2879 TCF7L2 Zornitza Stark edited their review of gene: TCF7L2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCF7L2-related
Mendeliome v1.2879 TCF7L1 Zornitza Stark Phenotypes for gene: TCF7L1 were changed from Congenital hypopituitarism to Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related
Mendeliome v1.2878 TCF7L1 Zornitza Stark reviewed gene: TCF7L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2878 NIT1 Zornitza Stark Phenotypes for gene: NIT1 were changed from Cerebrovascular disorder, NIT1-related (MONDO:0011057) to Brain small vessel disease 4, MIM# 621313
Mendeliome v1.2877 NIT1 Zornitza Stark reviewed gene: NIT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 4, MIM# 621313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2877 PLEKHG5 Zornitza Stark Phenotypes for gene: PLEKHG5 were changed from Charcot-Marie-Tooth disease, recessive intermediate C, MIM# 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, MIM# 611067 to hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related
Mendeliome v1.2876 PLEKHN1 Zornitza Stark Phenotypes for gene: PLEKHN1 were changed from Sensory Neuropathy to Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related
Mendeliome v1.2875 CYP3A4 Zornitza Stark Publications for gene: CYP3A4 were set to 29461981
Mendeliome v1.2874 SYP Zornitza Stark Phenotypes for gene: SYP were changed from Mental retardation, X-linked 96 MIM#300802 to Intellectual developmental disorder, X-linked 96, MIM# 300802
Mendeliome v1.2873 SYP Zornitza Stark reviewed gene: SYP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 96, MIM# 300802; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2873 SYNCRIP Zornitza Stark Phenotypes for gene: SYNCRIP were changed from Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology to Neurodevelopmental disorder, MONDO:0700092, SYNCRIP-related
Mendeliome v1.2872 SYNCRIP Zornitza Stark edited their review of gene: SYNCRIP: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SYNCRIP-related
Mendeliome v1.2872 SYCP2 Zornitza Stark Phenotypes for gene: SYCP2 were changed from Male infertility to Spermatogenic failure 1, MIM# 258150
Mendeliome v1.2871 SYCP2 Zornitza Stark edited their review of gene: SYCP2: Changed phenotypes: Spermatogenic failure 1, MIM# 258150
Mendeliome v1.2871 SUFU Zornitza Stark Phenotypes for gene: SUFU were changed from Joubert syndrome 32, MIM#617757; SUFU-related neurodevelopmental syndrome; Basal cell nevus syndrome, MIM# 109400 to Joubert syndrome 32, MIM#617757; Neurodevelopmental disorder, MONDO:0700092, SUFU-related; Basal cell nevus syndrome, MIM# 109400
Mendeliome v1.2870 SUFU Zornitza Stark edited their review of gene: SUFU: Changed phenotypes: Joubert syndrome 32, MIM#617757, Neurodevelopmental disorder, MONDO:0700092, SUFU-related, Basal cell nevus syndrome, MIM# 109400
Mendeliome v1.2870 SUCO Zornitza Stark Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta to Osteogenesis imperfecta, MONDO:0019019, SUCO-related
Mendeliome v1.2869 SUCO Zornitza Stark reviewed gene: SUCO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteogenesis imperfecta, MONDO:0019019, SUCO-related; Mode of inheritance: None
Mendeliome v1.2869 STXBP3 Zornitza Stark Phenotypes for gene: STXBP3 were changed from Very Early Onset Inflammatory Bowel Disease; Bilateral Sensorineural Hearing Loss; Immune Dysregulation to Inborn error of immunity, MONDO:0003778, STXBP3-related
Mendeliome v1.2868 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Mendeliome v1.2868 SRGAP1 Zornitza Stark Phenotypes for gene: SRGAP1 were changed from CAKUT to CAKUT, MONDO:0019719, SRGAP1-related
Mendeliome v1.2867 SRGAP1 Zornitza Stark edited their review of gene: SRGAP1: Changed rating: AMBER; Changed phenotypes: CAKUT, MONDO:0019719, SRGAP1-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2867 COPZ1 Zornitza Stark Marked gene: COPZ1 as ready
Mendeliome v1.2867 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2867 COPZ1 Zornitza Stark Classified gene: COPZ1 as Amber List (moderate evidence)
Mendeliome v1.2867 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2866 COPZ1 Zornitza Stark gene: COPZ1 was added
gene: COPZ1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COPZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPZ1 were set to 39642330
Phenotypes for gene: COPZ1 were set to Severe congenital neutropenia, autosomal recessive, MONDO:0028226, COPZ1-related
Review for gene: COPZ1 was set to AMBER
Added comment: 3 individuals from 2 unrelated families reported. A pair of siblings with homozygous LoF variant and a more severe phenotype, comprising other immune defects, neurological and skeletal features. An additional individual with homozygous missense variant and a milder phenotype of isolated neutropenia. Some supportive functional data. AMBER rating as only two families and homozygous variants.
Sources: Literature
Mendeliome v1.2865 CYP3A4 Chirag Patel Classified gene: CYP3A4 as Amber List (moderate evidence)
Mendeliome v1.2865 CYP3A4 Chirag Patel Gene: cyp3a4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2864 CYP3A4 Chirag Patel reviewed gene: CYP3A4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38179381, 29461981, 36656330; Phenotypes: Vitamin D-dependent rickets, type 3, MIM#619073; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2864 PLEKHN1 Lucy Spencer reviewed gene: PLEKHN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2864 PLEKHG5 Lucy Spencer changed review comment from: ClinGen has now lumped the 2 OMIM conditions under the general term "neuromuscular disease MONDO:0019056" however, "hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related" is a better description of the condition; to: ClinGen has now lumped the 2 OMIM conditions under the general term "neuromuscular disease MONDO:0019056" however, "hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related" is a better description of the condition
Mendeliome v1.2864 PLEKHG5 Lucy Spencer reviewed gene: PLEKHG5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2864 TRIM33 Zornitza Stark Phenotypes for gene: TRIM33 were changed from to Developmental dysplasia of the hip 4, MIM# 621311
Mendeliome v1.2863 TRIM33 Zornitza Stark Publications for gene: TRIM33 were set to
Mendeliome v1.2862 TRIM33 Zornitza Stark Mode of inheritance for gene: TRIM33 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2861 TRIM33 Zornitza Stark edited their review of gene: TRIM33: Added comment: Four siblings with homozygous single aa insertion reported.; Changed publications: 39054052; Changed phenotypes: Developmental dysplasia of the hip 4, MIM# 621311; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2861 SPOP Zornitza Stark Phenotypes for gene: SPOP were changed from Intellectual disability; dysmorphism; microcephaly; macrocephaly to Nabais Sa-de Vries syndrome, type 1 MIM#618828; Nabais Sa-de Vries syndrome, type 2, MIM#618829
Mendeliome v1.2860 SPOP Zornitza Stark edited their review of gene: SPOP: Changed phenotypes: Nabais Sa-de Vries syndrome, type 1 MIM#618828, Nabais Sa-de Vries syndrome, type 2, MIM#618829
Mendeliome v1.2860 SPATC1L Zornitza Stark Phenotypes for gene: SPATC1L were changed from Deafness to Hearing loss disorder, MONDO:0005365 SPATC1L-related
Mendeliome v1.2859 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed phenotypes: Hearing loss disorder, MONDO:0005365 SPATC1L-related
Mendeliome v1.2859 SOHLH2 Zornitza Stark Phenotypes for gene: SOHLH2 were changed from Premature ovarian failure to Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Mendeliome v1.2858 SOHLH2 Zornitza Stark edited their review of gene: SOHLH2: Changed phenotypes: Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Mendeliome v1.2858 SOD2 Zornitza Stark Phenotypes for gene: SOD2 were changed from {Microvascular complications of diabetes 6} 612634; Lethal neonatal dilated cardiomyopathy to {Microvascular complications of diabetes 6} 612634; Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related
Mendeliome v1.2857 SOBP Zornitza Stark Phenotypes for gene: SOBP were changed from Mental retardation, anterior maxillary protrusion, and strabismus, MIM# 613671 to Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: mpaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
Mendeliome v1.2856 SNX27 Zornitza Stark Phenotypes for gene: SNX27 were changed from intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, SNX27-related
Mendeliome v1.2855 SNX27 Zornitza Stark edited their review of gene: SNX27: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SNX27-related
Mendeliome v1.2855 SMPDL3A Zornitza Stark Phenotypes for gene: SMPDL3A were changed from Sensory Neuropathy to Sensory Neuropathy MONDO:0002321, SMPDL3A-related
Mendeliome v1.2854 SMPDL3A Zornitza Stark reviewed gene: SMPDL3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sensory Neuropathy MONDO:0002321, SMPDL3A-related; Mode of inheritance: None
Mendeliome v1.2854 SMPD4 Zornitza Stark Phenotypes for gene: SMPD4 were changed from Severe neurodevelopmental delay, microcephaly, arthrogryposis to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (MIM#618622)
Mendeliome v1.2853 SMPD4 Zornitza Stark edited their review of gene: SMPD4: Changed phenotypes: Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (MIM#618622)
Mendeliome v1.2853 SMARCD1 Zornitza Stark Phenotypes for gene: SMARCD1 were changed from Intellectual disability; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Mendeliome v1.2852 SMARCD1 Zornitza Stark edited their review of gene: SMARCD1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Mendeliome v1.2852 SMARCA5 Zornitza Stark Phenotypes for gene: SMARCA5 were changed from Neurodevelopmental disorder; microcephaly; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Mendeliome v1.2851 SMARCA5 Zornitza Stark edited their review of gene: SMARCA5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Mendeliome v1.2851 SMAD1 Zornitza Stark Phenotypes for gene: SMAD1 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension MONDO:0015924, SMAD1-related
Mendeliome v1.2850 SLIT3 Zornitza Stark Phenotypes for gene: SLIT3 were changed from Congenital diaphragmatic hernia to Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Mendeliome v1.2849 SLIT3 Zornitza Stark edited their review of gene: SLIT3: Changed phenotypes: Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Mendeliome v1.2849 SLIT2 Zornitza Stark Phenotypes for gene: SLIT2 were changed from CAKUT to CAKUT MONDO:0019719, SLIT2-related
Mendeliome v1.2848 SLIT2 Zornitza Stark edited their review of gene: SLIT2: Changed phenotypes: CAKUT MONDO:0019719, SLIT2-related
Mendeliome v1.2848 SLIRP Zornitza Stark Phenotypes for gene: SLIRP were changed from Mitochondrial encephalomyopathy with complex I and IV deficiency to Inborn mitochondrial metabolism disorder MONDO:0004069, SLIRP-related
Mendeliome v1.2847 SLIRP Zornitza Stark reviewed gene: SLIRP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn mitochondrial metabolism disorder MONDO:0004069, SLIRP-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2847 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from Mental retardation, autosomal recessive 48, MIM# 616269 to Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Mendeliome v1.2846 SLC6A17 Zornitza Stark edited their review of gene: SLC6A17: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
Mendeliome v1.2846 WNT1 Zornitza Stark Phenotypes for gene: WNT1 were changed from Osteogenesis imperfecta, type XV, MIM# 615220 to Osteogenesis imperfecta, type XV, MIM# 615220; Osteoporosis MONDO:0005298
Mendeliome v1.2845 WNT1 Zornitza Stark Publications for gene: WNT1 were set to 23499309; 23499310; 23656646; 26671912
Mendeliome v1.2844 WNT1 Zornitza Stark edited their review of gene: WNT1: Added comment: Multiple families with milder monoallelic disease reported.; Changed publications: 23499309, 23499310, 23656646, 26671912, 27005318, 25010833, 30246918, 30283887; Changed phenotypes: Osteogenesis imperfecta, type XV, MIM# 615220, Osteoporosis MONDO:0005298; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2844 MAP4K1 Zornitza Stark Marked gene: MAP4K1 as ready
Mendeliome v1.2844 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Mendeliome v1.2844 MAP4K1 Zornitza Stark Classified gene: MAP4K1 as Green List (high evidence)
Mendeliome v1.2844 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Mendeliome v1.2843 MAP4K1 Zornitza Stark gene: MAP4K1 was added
gene: MAP4K1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MAP4K1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K1 were set to 40716650
Phenotypes for gene: MAP4K1 were set to Inborn error of immunity, MONDO:0003778, MAP4K1-related
Review for gene: MAP4K1 was set to GREEN
Added comment: Heterozygous MAP4K1 loss-of-function variants were identified in two kindreds presenting with diverse immune dysregulatory symptoms, including recurrent fevers, inflammatory arthritis, EBV-related complications, and nephritis. Functional analysis of primary patient T cells, transcriptomics, and CRISPR-Cas9 editing demonstrated that HPK1 deficiency heightened T cell activation and inflammatory cytokine production. Penetrance was incomplete.

One of the families was multiplex (8 affected individuals) and the other had single individual affected, extensive functional data. Borderline Amber/Green.
Sources: Expert Review
Mendeliome v1.2842 MN1 Zornitza Stark commented on gene: MN1: Recently discussed at Clingen syndromic GCEP. Noted well described C terminal truncating variants to result in GOF and CEBALID syndrome. Defined a milder phenotype with LOF mechanism for NMD predicted variants and whole gene deletions to result in a non specific craniofacial phenotype involving cleft palate.
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Marked gene: ARHGAP36 as ready
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Classified gene: ARHGAP36 as Amber List (moderate evidence)
Mendeliome v1.2842 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2841 ARHGAP36 Zornitza Stark gene: ARHGAP36 was added
gene: ARHGAP36 was added to Mendeliome. Sources: Expert Review
SV/CNV, regulatory region tags were added to gene: ARHGAP36.
Mode of inheritance for gene: ARHGAP36 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: ARHGAP36 were set to 35986704; 40015599
Phenotypes for gene: ARHGAP36 were set to Bazex-Dupre-Christol syndrome, MIM# 301845
Mode of pathogenicity for gene: ARHGAP36 was set to Other
Review for gene: ARHGAP36 was set to AMBER
Added comment: Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward.

It is caused by small duplications in an intergenic region on chromosome Xq26 harbouring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene.

Genomic coordinates (GRCh38) : X:129,500,001-138,900,000.

At least 9 families reported but AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.
Sources: Expert Review
Mendeliome v1.2840 YWHAZ Zornitza Stark Phenotypes for gene: YWHAZ were changed from Intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Mendeliome v1.2839 YWHAZ Zornitza Stark Publications for gene: YWHAZ were set to 36001342
Mendeliome v1.2838 YWHAZ Zornitza Stark Classified gene: YWHAZ as Amber List (moderate evidence)
Mendeliome v1.2838 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2837 YWHAZ Zornitza Stark edited their review of gene: YWHAZ: Added comment: PMID 31024343: 5 individuals with de novo variants in this gene, two had a clinical diagnosis of Rasopathy. 3 missense variants and 2 high impact variants (one is NMD escape). Parentage not confirmed in 3. Two had other possible variants of interest.

Used Xenopus to investigate the effect of one of the missense variants, S230W, and demonstrated activation of the Raf-MEK-Erk pathway and embryonic defects when expressed at high levels. Suggests GoF as mechanism.

Further de novo missense identified in a large cohort of NDDs, PMID 35143101.

PMID 35501409: knockout Zebrafish, altered brain activity and behaviour.

PMID 22124272, 26207352: two mouse models also support role in brain development.

MODERATE by ClinGen, but note this is mostly driven by experimental data points. Also note there is evidence for both GoF and LoF mechanism, potentially two distinct disorders?; Changed rating: AMBER; Changed publications: 36001342, 31024343, 35143101, 35501409, 22124272, 26207352; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Mendeliome v1.2837 RUSC2 Zornitza Stark commented on gene: RUSC2: LIMITED by ClinGen but note multiple P/LP ClinVar submissions
Mendeliome v1.2837 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 37768732; 39930170; 36826837; 40319332
Mendeliome v1.2836 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX, MIM#258865; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280 to Orofaciodigital syndrome type IX, MIM#258865; Alsahan-Harris syndrome, MIM#621307; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2835 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 31130284, 36826837 and 32573025: 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by brain abnormalities, including holoprosencephaly and anencephaly, and ocular defects including microphthalmia/anophthalmia and cyclopia. This has been given a separate MIM by OMIM but more likely represents the severe end of the spectrum of a broader ciliopathy phenotype.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170, 36826837, 40319332, 31130284, 36826837; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, Retinitis pigmentosa 100, MIM# 621280, Alsahan-Harris syndrome, MIM#621307
Mendeliome v1.2835 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280 to Orofaciodigital syndrome type IX, MIM#258865; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2834 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 37768732; 39930170
Mendeliome v1.2833 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 36826837 and 40319332: four more individuals reported with OFD phenotype.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170, 36826837, 40319332; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, syndromic hypopituitarism, Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2833 SLC9A1 Chirag Patel Classified gene: SLC9A1 as Green List (high evidence)
Mendeliome v1.2833 SLC9A1 Chirag Patel Gene: slc9a1 has been classified as Green List (High Evidence).
Mendeliome v1.2832 SLC9A1 Chirag Patel reviewed gene: SLC9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lichtenstein-Knorr syndrome MONDO:0014572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2832 PSMB10 Chirag Patel commented on gene: PSMB10
Mendeliome v1.2832 PSMB10 Chirag Patel Deleted their review
Mendeliome v1.2832 PSMB10 Chirag Patel reviewed gene: PSMB10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.2832 ESRP1 Chirag Patel Classified gene: ESRP1 as Red List (low evidence)
Mendeliome v1.2832 ESRP1 Chirag Patel Gene: esrp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2831 ESRP1 Chirag Patel reviewed gene: ESRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.2831 IGKC Bryony Thompson Classified gene: IGKC as Amber List (moderate evidence)
Mendeliome v1.2831 IGKC Bryony Thompson Added comment: Comment on list classification: Gene does not have a NCBI transcript, therefore variants in this gene may not be annotated by some curation tools
Mendeliome v1.2831 IGKC Bryony Thompson Gene: igkc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2830 IGKC Bryony Thompson Tag technically challenging tag was added to gene: IGKC.
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Added comment: Comment on list classification: Gene does not have an NCBI transcript, therefore some curation tools will not annotate variants in this gene.
Mendeliome v1.2830 TRU-TCA1-1 Bryony Thompson Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2829 TRU-TCA1-1 Bryony Thompson Tag technically challenging tag was added to gene: TRU-TCA1-1.
Mendeliome v1.2829 IGHM Bryony Thompson Classified gene: IGHM as Green List (high evidence)
Mendeliome v1.2829 IGHM Bryony Thompson Added comment: Comment on list classification: Gene does not have an NCBI transcript, so it may have annotation issues in some curation tools
Mendeliome v1.2829 IGHM Bryony Thompson Gene: ighm has been classified as Green List (High Evidence).
Mendeliome v1.2828 IGHM Bryony Thompson Tag technically challenging tag was added to gene: IGHM.
Mendeliome v1.2828 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998 to Haemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2827 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Relapsing HLH; Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998 to Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2826 RC3H1 Zornitza Stark Publications for gene: RC3H1 were set to 31636267
Mendeliome v1.2825 RC3H1 Zornitza Stark edited their review of gene: RC3H1: Added comment: PMID 40769319: 3 individuals (heterozygous c.T674C (p.F225S)) from an extended kindred presenting with a spectrum of infections, lymphoproliferation, and autoimmune manifestations (upper respiratory infections, otitis media, sinusitis, abscess formation, pneumonia, and bacteremia, psoriasis, cytopenias, and liver disease. hyper-inflammation and lymphoproliferation manifesting with exaggerated generalized lymphadenopathy and splenomegaly. Transfected cell model provided functional support.

RED for mono-allelic association, single family.; Changed publications: 31636267, 15917799, 40769319; Changed phenotypes: Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v1.2825 RNU5B-1 Zornitza Stark Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related to Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Mendeliome v1.2824 RNU5B-1 Zornitza Stark Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Mendeliome v1.2823 RNU5B-1 Zornitza Stark edited their review of gene: RNU5B-1: Changed publications: 40442284; Changed phenotypes: Neurodevelopmental disorder with seizures and joint laxity, MIM# 621302
Mendeliome v1.2823 RNU2-2P Zornitza Stark Phenotypes for gene: RNU2-2P were changed from Neurodevelopmental disorder, MONDO:0700092, RNU2-2-related to Developmental and epileptic encephalopathy 119, MIM# 621304
Mendeliome v1.2822 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679
Mendeliome v1.2821 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed publications: 40210679, 40442284
Mendeliome v1.2821 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed phenotypes: Developmental and epileptic encephalopathy 119, MIM# 621304
Mendeliome v1.2821 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Mendeliome v1.2820 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Mendeliome v1.2820 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Mendeliome v1.2820 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2820 ST5 Zornitza Stark Tag new gene name tag was added to gene: ST5.
Mendeliome v1.2820 ST5 Zornitza Stark Marked gene: ST5 as ready
Mendeliome v1.2820 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Mendeliome v1.2820 ST5 Zornitza Stark Classified gene: ST5 as Green List (high evidence)
Mendeliome v1.2820 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Mendeliome v1.2819 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Mendeliome v1.2819 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2818 OGFRL1 Zornitza Stark Marked gene: OGFRL1 as ready
Mendeliome v1.2818 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2818 OGFRL1 Zornitza Stark Classified gene: OGFRL1 as Red List (low evidence)
Mendeliome v1.2818 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Mendeliome v1.2817 OGFRL1 Rylee Peters gene: OGFRL1 was added
gene: OGFRL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OGFRL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGFRL1 were set to PMID: 38699440
Phenotypes for gene: OGFRL1 were set to Cherubism (MONDO:0007315), OGFRL1-related
Review for gene: OGFRL1 was set to RED
Added comment: 3x individuals from 2 unrelated families with cherubism and homozygous NMD-predicted variants in OGFRL1.

In one family, the NMD-predicted OGFRL1 variant was identified in 2x affected individuals and was either heterozygous or absent in 7x unaffected family members tested.

OGFRL1 knockout mice and mice carrying a patient frameshift mutation were generated, however, neither mouse model recapitulated human cherubism.

Absence of homozygous LoF variants in gnomAD v4.
Sources: Literature
Mendeliome v1.2817 FRYL Sarah Milton reviewed gene: FRYL: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38479391; Phenotypes: Pan-Chung-Bellen syndrome, MIM# 621049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2817 ST5 Rylee Peters gene: ST5 was added
gene: ST5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ST5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ST5 were set to PMID: 40717498
Phenotypes for gene: ST5 were set to Neurodevelopmental disorder (MONDO:0700092), DENND2B-related
Review for gene: ST5 was set to GREEN
Added comment: HGNC: DENND2B
Cohort of 11 individuals all with a history of motor and/or language developmental delay, intellectual disability in 6/11 (mild to severe), brain structure/function abnormalities were reported in 9/11 patients (7/11 seizures; 5/9 abnormal findings on brain MRI), muscle weakness/hypotonia in 8/9, psychosis in 4/10 patients, symptoms of catatonia in 4/10, other psychiatric/behavioural concerns (anxiety, attention deficit, autism or autistic features) in 10/10.

Total of 10 variants including 2x frameshift/nonsense, 6x missense, 1x splice, 1x single amino acid deletion – all absent from v4 and de novo except 1 inherited from a father with cognitive and psychiatric symptoms and the inframe del which has 2 hets in gnomAD and is inherited an unaffected father (no formal assessment).

In vivo zebrafish modelling measuring cilia length suggests that patient variants tested (9/10 excluding the splice variant) did not induce cilia length shortening, which is consistent with KO models and therefore a loss of function effect.
Sources: Literature
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2817 BLOC1S1 Rylee Peters reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2817 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Mendeliome v1.2817 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2816 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to Pre-print: Clinical Genetics, 2025; 0:1–7
Phenotypes for gene: TMEM17 were set to Meckel syndrome MONDO:0018921; TMEM17-related
Review for gene: TMEM17 was set to AMBER
Added comment: 4 fetuses (TOP/deceased) from 4 consanguineous unrelated families with a clinical diagnosis of Meckel-Gruber syndrome. Clinical features includes: encephalocele (4/4), enlarged/cystic kidneys (4/4), and postaxial polydactyly (1/4). WES identified 3 homozygous variants (p.(Glu2Serfs*58); p.(Pro123Thrfs*9); and p.(Pro123Arg)).

They also reported a 5th consanguineous family with 3 affected fetuses with clinical diagnosis of Meckel-Gruber syndrome. Both parents were heterozygote carriers of a TMEM17 variant (p.(Glu2Serfs*58)) but biological material from the fetuses was not available.

No functional studies performed. However, TMEM17 is a critical component of a protein complex in the basal body at the base of cilia. Knockdown of Tmem17 via small interfering RNA has been shown to have a modest effect on cilia formation, but significantly reduces the amount of the somatostatin receptor Sstr3 (182453) that localizes to cilia.
Sources: Literature
Mendeliome v1.2815 CHTF18 Zornitza Stark Marked gene: CHTF18 as ready
Mendeliome v1.2815 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Mendeliome v1.2815 CHTF18 Zornitza Stark Phenotypes for gene: CHTF18 were changed from complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465 to Neurodevelopmental disorder MONDO#0700092, CHTF18-related
Mendeliome v1.2814 CHTF18 Zornitza Stark Classified gene: CHTF18 as Green List (high evidence)
Mendeliome v1.2814 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Mendeliome v1.2813 CHTF18 Zornitza Stark reviewed gene: CHTF18: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO#0700092, CHTF18-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2813 KDM2B Zornitza Stark Publications for gene: KDM2B were set to 36322151
Mendeliome v1.2812 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Mendeliome v1.2812 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Mendeliome v1.2812 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Mendeliome v1.2812 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Mendeliome v1.2811 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to Neurodevelopmental disorder (MONDO:0700092), SNW1-related
Review for gene: SNW1 was set to GREEN
Added comment: cohort of 9 patients with moderate to profound ID, microcephaly, seizures (7/9), facial dysmorphism, and brain malformations (6/9 - corpus callosum hypoplasia, Dandy-Walker malformation).

3 splice, 1 frameshift, 2 missense, 3 in frame deletions, 1 start loss. all but 1 de novo (the last parents not available).

SNW1 is a core component of the spliceosome and facilitates the conformational changes of the spliceosome. Expression of variants in HEK293 cells showed some decreased SNW1 expression while others increased it (including the frameshift), and only the frameshift variant was mislocalised/in the cytoplasm instead of the nucleus. Several of the variants caused loss of binding to PPIL1 or other proteins which SNW1 usually recruits to the spliceosome. All variants in this study were found to either affect protein expression or localization or influence interactions with other proteins in the spliceosome complex suggesting loss of function.
Sources: Literature
Mendeliome v1.2811 KDM2B Lucy Spencer reviewed gene: KDM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 40420380; Phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2811 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Mendeliome v1.2811 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Mendeliome v1.2810 CHTF18 Sangavi Sivagnanasundram gene: CHTF18 was added
gene: CHTF18 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHTF18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHTF18 were set to 40717333
Phenotypes for gene: CHTF18 were set to complex neurodevelopmental disorder with or without congenital anomalies (Cohesinopathies) MONDO:0100465
Review for gene: CHTF18 was set to GREEN
Added comment: >5 unrelated individuals with a rare missense variant in the gene have been identified by the authors however the clinical details were presented on three.
3 different de novo missense variants were identified

3 individuals - neurodevelopment delay, epilepsy, de novo:
1 - 9M with DD, autism and seizures. De novo variant identified - p.Leu355Val
2 - 23month F with congenital bilateral ventriculomegaly status post ventriculoperitoneal shunt placement, epilepsy, right eye optic nerve hypoplasia, hypotonic cerebral palsy complicated by left hip subluxation, and G-tube dependence. De novo variant identified - p.His645Pro
3 - 3F presenting with global DD, hypotonia, seizure and abnormal brain MRI. De novo variant identified - p.Leu676Arg
Sources: Literature
Mendeliome v1.2810 PDCD6IP Sangavi Sivagnanasundram reviewed gene: PDCD6IP: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1111/cge.70025; Phenotypes: Neurodevelopmental disorder with microcephaly MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2810 SLC44A1 Zornitza Stark Phenotypes for gene: SLC44A1 were changed from progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria to Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, MIM# 618868
Mendeliome v1.2809 SLC44A1 Zornitza Stark edited their review of gene: SLC44A1: Changed rating: GREEN; Changed phenotypes: Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, MIM# 618868; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2809 ERCC1 Zornitza Stark Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, MIM# 610758; MONDO:0012554 to Cerebrooculofacioskeletal syndrome 4, MIM# 610758; MONDO:0012554; Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Mendeliome v1.2808 ERCC1 Zornitza Stark Publications for gene: ERCC1 were set to 17273966; 23623389; 33315086
Mendeliome v1.2807 SMAD5 Zornitza Stark Marked gene: SMAD5 as ready
Mendeliome v1.2807 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Mendeliome v1.2807 SMAD5 Zornitza Stark Classified gene: SMAD5 as Green List (high evidence)
Mendeliome v1.2807 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Mendeliome v1.2806 SMAD5 Sarah Milton changed review comment from: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature; to: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection of variants into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 SMAD5 Sarah Milton changed review comment from: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenitcal/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature; to: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 SMAD5 Sarah Milton gene: SMAD5 was added
gene: SMAD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD5 were set to PMID: 40619738
Phenotypes for gene: SMAD5 were set to Congenital heart disease, MONDO:0005453, SMAD5-related
Penetrance for gene: SMAD5 were set to Incomplete
Review for gene: SMAD5 was set to GREEN
Added comment: SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenitcal/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism.
Sources: Literature
Mendeliome v1.2806 TNFRSF11B Bryony Thompson Publications for gene: TNFRSF11B were set to 14672344
Mendeliome v1.2805 TNFRSF11B Bryony Thompson Phenotypes for gene: TNFRSF11B were changed from Paget disease of bone 5, juvenile-onset, MIM# 239000 to juvenile Paget disease MONDO:0009394; chondrocalcinosis 1 MONDO:0010917
Mendeliome v1.2804 TNFRSF11B Bryony Thompson Mode of inheritance for gene: TNFRSF11B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2803 TNFRSF11B Bryony Thompson reviewed gene: TNFRSF11B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24743232, 40735895, 29578045, 33559312, 33989379, 35412619; Phenotypes: chondrocalcinosis 1 MONDO:0010917; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2803 ATP6V0A4 Krithika Murali reviewed gene: ATP6V0A4: Rating: RED; Mode of pathogenicity: None; Publications: PMID:40299568; Phenotypes: Renal tubular acidosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2803 ATG2A Krithika Murali Marked gene: ATG2A as ready
Mendeliome v1.2803 ATG2A Krithika Murali Gene: atg2a has been classified as Red List (Low Evidence).
Mendeliome v1.2803 ATG2A Krithika Murali gene: ATG2A was added
gene: ATG2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG2A were set to PMID:40631414
Phenotypes for gene: ATG2A were set to complex neurodevelopmental disorder, ATG2A-related - MONDO:0100038
Review for gene: ATG2A was set to RED
Added comment: PMID:40631414 report a 3 yo F with homozygous ATG2A missense variant (c.1372G>C (p.Gly433Ala) with developmental regression, seizures, cerebellar ataxia, and MRI-brain abnormalities (diffuse cerebral and cerebellar atrophy). Provide supportive functional evidence.
Sources: Literature
Mendeliome v1.2802 CFAP43 Zornitza Stark Classified gene: CFAP43 as Amber List (moderate evidence)
Mendeliome v1.2802 CFAP43 Zornitza Stark Gene: cfap43 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2801 CFAP43 Zornitza Stark edited their review of gene: CFAP43: Added comment: DISPUTED by ClinGen for biallelic association with PCD.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Marked gene: RNU5A-1 as ready
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Classified gene: RNU5A-1 as Amber List (moderate evidence)
Mendeliome v1.2801 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2800 RNU5A-1 Zornitza Stark gene: RNU5A-1 was added
gene: RNU5A-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder (MONDO:0700092), RNU5A-1 related
Review for gene: RNU5A-1 was set to AMBER
Added comment: PMID: 40379786 (2025) - three unrelated individuals with de novo variants in the RNU5A-1 gene (classified as VUS) and a neurodevelopmental disorder. Six individuals with rare de novo variants were identified in total but clinical details were only available for 3/6. Of these three individuals, two harboured the same variant (n.40_41insA) on the maternal allele, while the third individual harboured a different variant (n.39del) but also on the 5′ loop I domain of RNU5A-1. Clinical data showed neurodevelopmental abnormalities (mild ID (2), severe ID (1), epilepsy (2), brain MRI abnormalities (1)) with variable congenital malformations.
Sources: Literature
Mendeliome v1.2799 AMFR Zornitza Stark Phenotypes for gene: AMFR were changed from Spastic paraplegia 89, autosomal recessive, MIM# 620379 to Spastic paraplegia 89, autosomal recessive, MIM# 620379; Inborn error of immunity, MONDO:0003778, AMFR-related
Mendeliome v1.2798 AMFR Zornitza Stark Publications for gene: AMFR were set to 37119330
Mendeliome v1.2797 AMFR Zornitza Stark edited their review of gene: AMFR: Added comment: PMID 38277122:

Single case report of 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, haemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. HLH was the working diagnosis. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy.

Rare monoallelic variant in autocrine motility factor receptor (AMFR) identified. AMFR encodes a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway.

Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans.

RED for this association.; Changed publications: 38277122; Changed phenotypes: Spastic paraplegia 89, autosomal recessive, MIM# 620379, Inborn error of immunity, MONDO:0003778, AMFR-related
Mendeliome v1.2797 ASXL1 Zornitza Stark Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome , MIM#605039 to Bohring-Opitz syndrome , MIM#605039; Combined immunodeficiency, MONDO:0015131, ASXL1-related
Mendeliome v1.2796 ASXL1 Zornitza Stark Publications for gene: ASXL1 were set to 29446906; 21706002
Mendeliome v1.2795 ASXL1 Zornitza Stark edited their review of gene: ASXL1: Added comment: PMID 40742536. Single individual with biallelic variants reported. The patient had a history of haematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction.

Note mono allelic variants are associated with Bohring Opitz syndrome and somatic variants are associated with clonal haematopoiesis.

RED for biallelic association.; Changed publications: 29446906, 21706002, 40742536; Changed phenotypes: Bohring-Opitz syndrome , MIM#605039, Combined immunodeficiency, MONDO:0015131, ASXL1-related
Mendeliome v1.2795 RCC1 Zornitza Stark Marked gene: RCC1 as ready
Mendeliome v1.2795 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Mendeliome v1.2795 RCC1 Zornitza Stark Classified gene: RCC1 as Green List (high evidence)
Mendeliome v1.2795 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Mendeliome v1.2794 RCC1 Zornitza Stark gene: RCC1 was added
gene: RCC1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RCC1 were set to 40683276
Phenotypes for gene: RCC1 were set to Hereditary peripheral neuropathy, MONDO:0020127, RCC1-related
Review for gene: RCC1 was set to GREEN
Added comment: 24 individuals from 12 families reported with severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]).

Eight biallelic missense variants in RCC1 identified.

Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients.

The RCC1 variants coded for proteins that alter GDP-to-GTP exchange activity and had reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress.
Sources: Expert Review
Mendeliome v1.2793 ERCC1 Sarah Milton reviewed gene: ERCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40684071; Phenotypes: Hepatorenal syndrome, MONDO:0001382, ERCC1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2793 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX; syndromic hypopituitarism to Orofaciodigital syndrome type IX; syndromic hypopituitarism; Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2792 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284
Mendeliome v1.2791 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: Association with RP:
PMID 37768732: 4 individuals from three unrelated families with bi-allelic variants as per review by Achchuthan Shamugasundram. Some supportive functional data. PMID 39930170: fourth family reported.; Changed publications: 24285566, 32573025, 32060556, 31130284, 39930170; Changed phenotypes: Orofaciodigital syndrome type IX, syndromic hypopituitarism, Retinitis pigmentosa 100, MIM# 621280
Mendeliome v1.2791 BSN Zornitza Stark Phenotypes for gene: BSN were changed from Epilepsy MONDO:0005027 to Neurodevelopmental disorder (MONDO:0700092), BSN-related
Mendeliome v1.2790 BSN Zornitza Stark edited their review of gene: BSN: Changed rating: GREEN; Changed phenotypes: Neurodevelopmental disorder (MONDO:0700092), BSN-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2790 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Craniofacial microsomia MONDO:0015397 to Syndromic disease, MONDO:0002254, NR6A1-related
Mendeliome v1.2789 NR6A1 Zornitza Stark reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic disease, MONDO:0002254, NR6A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2789 BSN Lauren Rogers reviewed gene: BSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 40393460; Phenotypes: Epilepsy (MONDO:0005027), BSN-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2789 ZNF597 Zornitza Stark Marked gene: ZNF597 as ready
Mendeliome v1.2789 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Mendeliome v1.2789 ZNF597 Zornitza Stark gene: ZNF597 was added
gene: ZNF597 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZNF597 was set to Other
Publications for gene: ZNF597 were set to 19968752; 28157578; 32576657
Phenotypes for gene: ZNF597 were set to Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: ZNF597 was set to RED
Added comment: ZNF597 is an imprinted gene- maternally expressed and paternally imprinted.
- ZNF597 is highly expressed in the placenta and proposed to have an important role in placental development.
- Knockout ZNF597 mice (homozygous -/-) is embryonic lethal due to failed embryonic organization before cardiogenesis at embryonic day 7.5. This period is equivalent to human Carnegie Stage 9 that occurs during week 3 between 19 to 21 days (5 weeks' gestation).
- Literature associated with ZNF597 including maternal uniparental disomy of chromosome 16 (UPD(16)mat) or loss of paternal imprinting of ZNF59, resulting in an overexpression of ZNF597.
- Unpublished in-house data/observation: A heterozygous deletion with a breakpoint in ZNF597 was observed in the female partner of a couple experiencing x4 early pregnancy loss at 5-8 weeks' gestation.
Sources: Expert list
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Marked gene: ZFP36L2 as ready
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Classified gene: ZFP36L2 as Green List (high evidence)
Mendeliome v1.2788 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Mendeliome v1.2787 ZFP36L2 Zornitza Stark gene: ZFP36L2 was added
gene: ZFP36L2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ZFP36L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFP36L2 were set to 34611029; 38829516; 37211617
Phenotypes for gene: ZFP36L2 were set to Oocyte/zygote/embryo maturation arrest 13, MIM# 620154
Review for gene: ZFP36L2 was set to GREEN
Added comment: i) Literature in OMIM- PMID:34611029- x2 unrelated infertile Chinese women with defective oocyte maturation carrying different biallelic variants and functional analysis suggested that the variants cause maternal mRNA decay defects that result in female infertility.

ii) New papers reporting biallelic variants in conjunction with female infertility due to oocyte maturation defect+/- embryonic development arrest
- PMID: 38829516: Novel compound heterozygous variant (p.His62Gln and p.Pro290Leu) in a patient with oocyte maturation defect. These variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes.
- PMID: 37211617: Novel homozygous variant c.853_861del (p.285_287del) in the affected individual with oocyte maturation defect from a consanguineous family. In vitro studies showed that the variant caused decreased protein levels of ZFP36L2 in oocytes due to mRNA instability and might lead to the loss of its function to degrade maternal mRNAs
Sources: Expert list
Mendeliome v1.2786 WNT6 Zornitza Stark Marked gene: WNT6 as ready
Mendeliome v1.2786 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2786 WNT6 Zornitza Stark Classified gene: WNT6 as Amber List (moderate evidence)
Mendeliome v1.2786 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2785 WNT6 Zornitza Stark gene: WNT6 was added
gene: WNT6 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: WNT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNT6 were set to 36385415; 25750203
Phenotypes for gene: WNT6 were set to recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: WNT6 was set to AMBER
Added comment: i) PMID: 36385415- heterozygous missense variant (p.Arg70Gly) in a female with recurrent pregnancy loss (C21)

ii) PMID: 25750203- four novel heterozygous (checked Sanger traces) variants (i.e, one missense P.Leu148Arg, one synonymous c. 522C>T, one variant in intron 1 c. 297+40G>A, and one variant in the 3′UTR c. 1127G>A ) in 4 women with unexplained recurrent miscarriages (RM), but only the missense variant was shown to affect the functional region of WNT6 that might explain the unexplained RM

In effect, only 2 cases with limited other supporting data, hence Amber.
Sources: Expert list
Mendeliome v1.2784 USP26 Zornitza Stark Marked gene: USP26 as ready
Mendeliome v1.2784 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2784 USP26 Zornitza Stark Classified gene: USP26 as Amber List (moderate evidence)
Mendeliome v1.2784 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2783 USP26 Zornitza Stark edited their review of gene: USP26: Changed rating: AMBER
Mendeliome v1.2783 USP26 Zornitza Stark gene: USP26 was added
gene: USP26 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: USP26 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: USP26 were set to 34202084; 27089915
Phenotypes for gene: USP26 were set to Spermatogenic failure, X-linked 6, MIM# 301101
Added comment: i) PMID: 34202084- hemizygous missense variants in 2 unrelated affected Chinese men with infertility due to asthenoteratozoospermia (R825G in proband H002, and N799S in proband H042) and functional analysis showed markedly reduced USP26 mRNA and protein levels in patient sperm.

ii) PMID: 27089915- a novel hemizygous missense variant R344W in two affected Chinese men with non-obstructive azoospermia, which has been shown functionally to have reduce binding affinity and deubiquitinating activity of USP26 to androgen receptors.

Rated Amber as missense variants with little other supporting data.
Sources: Expert list
Mendeliome v1.2782 UBE2B Zornitza Stark Marked gene: UBE2B as ready
Mendeliome v1.2782 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Mendeliome v1.2782 UBE2B Zornitza Stark Classified gene: UBE2B as Green List (high evidence)
Mendeliome v1.2782 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Mendeliome v1.2781 UBE2B Zornitza Stark gene: UBE2B was added
gene: UBE2B was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: UBE2B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UBE2B were set to 23378580; 26223869; 12784252
Phenotypes for gene: UBE2B were set to Male infertility, MONDO:0005372
Review for gene: UBE2B was set to GREEN
Added comment: i) PMID: 23378580 (2013)- Identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous. Their findings suggested that two distinct molecular mechanisms, mRNA editing and splicing processing, were disrupted in oligozoospermia.

ii) PMID: 26223869 (2015): Reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patients in the Chinese population, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Expert list
Mendeliome v1.2780 TIMP2 Zornitza Stark Marked gene: TIMP2 as ready
Mendeliome v1.2780 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2780 TIMP2 Zornitza Stark Classified gene: TIMP2 as Amber List (moderate evidence)
Mendeliome v1.2780 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2779 TIMP2 Zornitza Stark gene: TIMP2 was added
gene: TIMP2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TIMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TIMP2 were set to 20847186; 34756330
Phenotypes for gene: TIMP2 were set to Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: TIMP2 was set to AMBER
Added comment: i) PMID: 20847186- In family 6, TIMP2 partial duplication (involves Ex1-2) in mother and 4 out of 5 miscarriages. They have not yet been associated with RPL in humans, however, overexpression of TIMP2 was detected in a mouse model of RPL (Dixon et al., 2006). The TIMP2 disruption in miscarriages in Family 6 may have affected the placental development, but the possibility remains that maternal disruption of TIMP2 may contribute to RPL by impairing the remodeling of the endometrium in early pregnancy. Functional study was performed by PMID: 25674159, which showed reduced RNA and protein expression in chorionic villi cultures from miscarriages with the CNV.

ii) PMID: 34756330- de novo damaging heterozygous missense TIMP2 variant, c.[553G>A]; p.[Gly185Arg] in an eight-week euploid embryonic loss. The MMP2/TIMP2 complex is involved in several gestational processes including implantation and placentation.

iii) PMID: 11912288- The disruption of the TIMP2 gene was considered to be relevant for recurrent miscarriage due to its critical role in modulating invasion of the trophoblast into maternal endometrium and in vascular remodeling and angiogenesis of maternal and placenta tissues in the first trimester.
Sources: Expert list
Mendeliome v1.2778 TBPL2 Zornitza Stark Marked gene: TBPL2 as ready
Mendeliome v1.2778 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Mendeliome v1.2778 TBPL2 Zornitza Stark Classified gene: TBPL2 as Green List (high evidence)
Mendeliome v1.2778 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Mendeliome v1.2777 TBPL2 Zornitza Stark gene: TBPL2 was added
gene: TBPL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TBPL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBPL2 were set to 37804378; 33966269; 33893736; 33541821
Phenotypes for gene: TBPL2 were set to Inherited oocyte maturation defect, MONDO:0014769, TBPL2-related
Review for gene: TBPL2 was set to GREEN
Added comment: New papers reporting biallelic variants in infertile women:
i) PMID: 37804378- Compound heterozygous novel p.Arg268Ter and recurrent p.Arg233Ter in a female with impaired ovarian folliculogenesis. Structure prediction by molecular modeling demonstrated that three-dimensional structure of TBPL2 was destabilized in mutant proteins.

ii) PMID: 33966269- Homozygous missense mutation p.C299R in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family. Functional assays showed that the transcriptional level of ZP3 was not completely blocked but severely reduced by the regulation of the mutant TBPL2, while the transcriptional level of H2Bc was significantly reduced but to a less severe extent compared with that of ZP3, suggesting that the missense had a damage to the transcription initiation function of TBPL2 and its downstream targeted genes got involved in different degrees. The mutant protein also has less stability, which contributes to the lower activity of transcription initiation in the mutant form.

iii) PMID: 33893736- Homozygous splicing variant (c.788 + 3A>G) in two unrelated families characterized by oocyte maturation defects. Functional assays showed that the variant disrupted the integrity of TBPL2 mRNA and affected oocytes showed that vital genes for oocyte maturation and fertilization were widely and markedly downregulated, suggesting that a mutation in TBPL2, led to global gene alterations in oocytes; the same variant reported before in PMID: 33541821 in three affected females with diminished ovarian reserve from 3 independent families.
Sources: Expert list
Mendeliome v1.2776 TACC3 Zornitza Stark Marked gene: TACC3 as ready
Mendeliome v1.2776 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2776 TACC3 Zornitza Stark Classified gene: TACC3 as Amber List (moderate evidence)
Mendeliome v1.2776 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2775 TACC3 Zornitza Stark gene: TACC3 was added
gene: TACC3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TACC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TACC3 were set to 36395215
Phenotypes for gene: TACC3 were set to Female infertility due to oocyte meiotic arrest, MONDO:0044626
Review for gene: TACC3 was set to AMBER
Added comment: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.
Sources: Expert list
Mendeliome v1.2774 RXFP2 Zornitza Stark Phenotypes for gene: RXFP2 were changed from Cryptorchidism to Infertility; cryptorchidism; non-obstructive azoospermia
Mendeliome v1.2773 RXFP2 Zornitza Stark Publications for gene: RXFP2 were set to 31167797; 20963592
Mendeliome v1.2772 RXFP2 Zornitza Stark Classified gene: RXFP2 as Green List (high evidence)
Mendeliome v1.2772 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Green List (High Evidence).
Mendeliome v1.2771 RXFP2 Zornitza Stark edited their review of gene: RXFP2: Added comment: New literature PMID: 39222519- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism.; Changed rating: GREEN; Changed publications: 31167797, 20963592, 39222519
Mendeliome v1.2771 PABPC1L Zornitza Stark Marked gene: PABPC1L as ready
Mendeliome v1.2771 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Mendeliome v1.2771 PABPC1L Zornitza Stark Classified gene: PABPC1L as Green List (high evidence)
Mendeliome v1.2771 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Mendeliome v1.2770 PABPC1L Zornitza Stark gene: PABPC1L was added
gene: PABPC1L was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PABPC1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PABPC1L were set to 37052235; 37723834; 38177974; 32172300
Phenotypes for gene: PABPC1L were set to Oocyte/zygote/embryo maturation arrest 22, #MIM 621093
Review for gene: PABPC1L was set to GREEN
Added comment: i) Literature in OMIM (PMID: 37052235;37723834;38177974)- >3 unrelated infertile women (due to a mixed phenotype including oocyte maturation abnormalities, fertilization failure, and embryonic development arrest) with different biallelic variants

ii) Additional paper (PMID: 32172300)- Homozygous likely deleterious variant in PABPC1L p.(Met26Lys) in a woman whose infertility phenotype resembles that of Pabpc1l−/− mouse. During her IVF cycles, 18 oocytes were retrieved and subjected to IVF and ICSI. Nine oocytes were assigned to ICSI, but eight were at germinal vesicle stage and only one showed polar body and failed to fertilize following ICSI. Similarly, nine oocytes were assigned to IVF, and only two showed polar body on the next day without any sign of fertilization. The remaining oocytes were at germinal vesicle stage.
Sources: Expert list
Mendeliome v1.2769 NLRP14 Zornitza Stark Marked gene: NLRP14 as ready
Mendeliome v1.2769 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2769 NLRP14 Zornitza Stark Classified gene: NLRP14 as Amber List (moderate evidence)
Mendeliome v1.2769 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2768 NLRP14 Zornitza Stark gene: NLRP14 was added
gene: NLRP14 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NLRP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NLRP14 were set to 38060382
Phenotypes for gene: NLRP14 were set to Inherited oocyte maturation defect, MONDO:0014769, NLRP14-related and early embryo arrest
Review for gene: NLRP14 was set to AMBER
Added comment: PMID: 38060382- Compound heterozygous variants (p.Cys428Profs∗28/p.Leu887delinsArgTyr) reported in an infertile woman with oocyte maturation defects and early embryo arrest (EEA).
- Functional analysis showed comparable protein levels compared with the wild-type control, although a truncated band of the expected size (47 kDa) was observed for the p.Cys428Profs∗28 variant.
-The truncated variant, p.Cys428Profs∗28, is lacking the LRR domain and, hence, completely loses the ability to bind with UHRF1. The p.Leu887delinsArgTyr variant results in significant alteration in binding modes with decreased binding area and binding free energy, which introduced regional instability in the NLRP14-UHRF1 interaction. The interaction of both variants and UHRF1 was disrupted and might lead to increased UHRF1 protein degradation in oocytes.
Sources: Expert list
Mendeliome v1.2767 MEI1 Zornitza Stark Marked gene: MEI1 as ready
Mendeliome v1.2767 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Mendeliome v1.2767 MEI1 Zornitza Stark Classified gene: MEI1 as Green List (high evidence)
Mendeliome v1.2767 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Mendeliome v1.2766 MEI1 Zornitza Stark gene: MEI1 was added
gene: MEI1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MEI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MEI1 were set to 30388401; 38416203; 34037756; 36759719; 32741963; 36017582
Phenotypes for gene: MEI1 were set to Recurrent hydatidiform mole 3, MIM# 618431; Non-obstructive azoospermia
Review for gene: MEI1 was set to GREEN
Added comment: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA)

New papers (biallelic variants for OZEMA):
i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles.

ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1.

New papers (biallelic variants for NOA):
i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro.
- others: PMID: 32741963;36017582

Note: Moderate evidence for OZEMA and HM in FeRGI database
Sources: Expert list
Mendeliome v1.2765 MAJIN Zornitza Stark Marked gene: MAJIN as ready
Mendeliome v1.2765 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2765 MAJIN Zornitza Stark Classified gene: MAJIN as Amber List (moderate evidence)
Mendeliome v1.2765 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2764 MAJIN Zornitza Stark gene: MAJIN was added
gene: MAJIN was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MAJIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAJIN were set to 39545410; 33211200
Phenotypes for gene: MAJIN were set to Recurrent hydatidiform mole, non-obstructive azoospermia
Review for gene: MAJIN was set to AMBER
Added comment: New papers (biallelic variant for HM/male infertility):
i) PMID: 39545410- Novel homozygous splice donor site variant c.349+1G>T in patient 1824 (Italian) with 2 HMs followed by secondary infertility and substantially reduced bilateral ovarian volumes. MAJIN codes for a junction protein that forms a complex with TERB1 and TERB2, which together bind to telomeres and anchor them to the inner nuclear membrane components KASH5 and SUN1. This attachment of chromosomes to the nuclear envelope is essential for homologous chromosome movement and synapsis. In mice, both male and female null mutants Majin are infertile (PMID: 26548954). In humans, biallelic mutations in MAJIN have been reported in infertile males.

ii) PMID: 33211200- A homozygous p.Arg53His in NOA-affected male (Individual 4- M1646) with high CADD scores and low gnomad freq. Mice disrupted for either Majin or Terb2 display impaired synapsis, zygotene arrest, a lack of postmeiotic cells and infertility (Shibuya et al. 2015; Zhang et al. 2017).
Sources: Expert list
Mendeliome v1.2763 LHX8 Zornitza Stark Marked gene: LHX8 as ready
Mendeliome v1.2763 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Mendeliome v1.2763 LHX8 Zornitza Stark Classified gene: LHX8 as Green List (high evidence)
Mendeliome v1.2763 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Mendeliome v1.2762 KIAA1683 Zornitza Stark Marked gene: KIAA1683 as ready
Mendeliome v1.2762 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Mendeliome v1.2762 KIAA1683 Zornitza Stark Classified gene: KIAA1683 as Green List (high evidence)
Mendeliome v1.2762 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Mendeliome v1.2761 KIAA1683 Zornitza Stark gene: KIAA1683 was added
gene: KIAA1683 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KIAA1683 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1683 were set to 36321563; 39872118; 37140151; 37184908; 40437858
Phenotypes for gene: KIAA1683 were set to Spermatogenic failure 78, #MIM 620170
Review for gene: KIAA1683 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 36321563, 39872118, 37140151, 37184908 (>3 unrelated Chinese men with infertility due to spermatogenic failure with hom/com het variants).

New paper: i) PMID: 40437858 (2025)- novel hom p.Trp796Ter in infertile man with fertilization failure and history of two miscarriages with his partner. According to the prediction of protein conformations, it was found that the protein conformations were truncated in the mutated IQCN gene, which probably affected the function of the patient's sperm.
Sources: Expert list
Mendeliome v1.2760 KCNU1 Zornitza Stark Marked gene: KCNU1 as ready
Mendeliome v1.2760 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Mendeliome v1.2760 KCNU1 Zornitza Stark Classified gene: KCNU1 as Green List (high evidence)
Mendeliome v1.2760 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Mendeliome v1.2759 KCNU1 Zornitza Stark gene: KCNU1 was added
gene: KCNU1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNU1 were set to 34980136; 35551387; 20138882; 21427226; 25271166; 35551387
Phenotypes for gene: KCNU1 were set to Spermatogenic failure 79, #MIM 620196
Review for gene: KCNU1 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 34980136, 35551387- 3 unrelated male with spermatogenic failure with different homozygous variants, supported by functional evidence; PubMed: 20138882, 21427226, 25271166- Slo3 -/- KO mice were infertile, 35551387- mice with homozygous H720R variant, corresponding to the human H715R variant recapitulated human phenotype.
Sources: Expert list
Mendeliome v1.2758 GGN Zornitza Stark Classified gene: GGN as Green List (high evidence)
Mendeliome v1.2758 GGN Zornitza Stark Gene: ggn has been classified as Green List (High Evidence).
Mendeliome v1.2757 GGN Zornitza Stark edited their review of gene: GGN: Changed rating: GREEN
Mendeliome v1.2757 GGN Zornitza Stark edited their review of gene: GGN: Added comment: PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.; Changed publications: 31985809, 33108537, 23451117; Changed phenotypes: Spermatogenic failure 69, MIM# 619826
Mendeliome v1.2757 FOXD1 Zornitza Stark Marked gene: FOXD1 as ready
Mendeliome v1.2757 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Mendeliome v1.2757 FOXD1 Zornitza Stark Classified gene: FOXD1 as Green List (high evidence)
Mendeliome v1.2757 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Mendeliome v1.2756 FOXD1 Zornitza Stark gene: FOXD1 was added
gene: FOXD1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FOXD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXD1 were set to 27805902; 31395028
Phenotypes for gene: FOXD1 were set to Recurrent pregnancy loss and repeated implantation failure susceptibility, MONDO:0000144, FOXD1-related
Review for gene: FOXD1 was set to GREEN
Added comment: i) PMID: 27805902- 18 heterozygous (only 10 were nonsynonymous) variants were identified only in recurrent spontaneous abortion (RSA) patients (total of 33 patients) not seen in ctrl group, and only 3 variants had functional assays performed- p.Ala356Gly (x1 patient),p.Ile364Met (x2 patients), and p.Ins429AlaAla (x12 patients). In vitro assays revealed they had a functional effect as they led to perturbations in FOXD1 transactivation properties on promoters of the Placental Growth Factor (PGF) and the complement component gene (C3) having key roles during implantation/placentation.

ii) PMID: 31395028- 9 heterozygous non-synonymous variants in patients affected by PE, IUGR, RPL and repeated implantation failure (RIF) , two of which (p.His267Tyr found in one RIF patient and p.Arg57del in one IUGR woman) represented novel and coherent candidates for in vitro testing. Functional experiments revealed that both led to an increased C3 (complement C3) promoter transcriptional activity. Also found increased FOXD1-p.Arg57del variant transactivation capacity on the PlGF (placental growth factor) promoter.The FOXD1 p.Ala356Gly and p.Ile364Met variants (previously found in RPL patients in PMID: 27805902) have also been identified in the present work in women with PE and IUGR and with isolated IUGR, respectively.

Documented in FeRGI database- limited evidence for repeated implantation failure.
Sources: Expert list
Mendeliome v1.2755 FBXO43 Zornitza Stark Marked gene: FBXO43 as ready
Mendeliome v1.2755 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Mendeliome v1.2755 FBXO43 Zornitza Stark Classified gene: FBXO43 as Green List (high evidence)
Mendeliome v1.2755 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Mendeliome v1.2754 FBXO43 Zornitza Stark gene: FBXO43 was added
gene: FBXO43 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBXO43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO43 were set to 34052850; 30878252; 34595750
Phenotypes for gene: FBXO43 were set to Oocyte/zygote/embryo maturation arrest 12, MIM# 619697; Spermatogenic failure 64, MIM# 619696
Review for gene: FBXO43 was set to GREEN
Added comment: Literature in OMIM: PMID: 34052850 (three different homozygous variants in 3 unrelated women; 30878252, 34595750 (two different families with different homozygous variants)
Sources: Expert list
Mendeliome v1.2753 ELL3 Zornitza Stark Marked gene: ELL3 as ready
Mendeliome v1.2753 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Mendeliome v1.2753 ELL3 Zornitza Stark Classified gene: ELL3 as Green List (high evidence)
Mendeliome v1.2753 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Mendeliome v1.2752 ELL3 Zornitza Stark gene: ELL3 was added
gene: ELL3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ELL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELL3 were set to 39820605
Phenotypes for gene: ELL3 were set to Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related
Review for gene: ELL3 was set to GREEN
Added comment: PMID:39820605- 8 different heterozygous variants (5 missense, 3 splicing) in 8 unrelated couples who experienced consecutive early miscarriages due to embryonic aneuploidy. For the three splice variants, mini-gene splicing assays revealed that all led to abnormal splicing, and consequently premature termination of translation or exon skipping, consistent with LOF effect. Findings from functional analysis on human oocytes and knockout mouse oocytes overall supporting that ELL3 depletion increases the incidence of meiotic spindle abnormality and oocyte aneuploidy.
Sources: Expert list
Mendeliome v1.2751 CHEK1 Zornitza Stark Marked gene: CHEK1 as ready
Mendeliome v1.2751 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Mendeliome v1.2751 CHEK1 Zornitza Stark Classified gene: CHEK1 as Green List (high evidence)
Mendeliome v1.2751 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Mendeliome v1.2750 CHEK1 Zornitza Stark gene: CHEK1 was added
gene: CHEK1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CHEK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHEK1 were set to 33953335; 33948904
Phenotypes for gene: CHEK1 were set to Oocyte/zygote/embryo maturation arrest 21, MIM# 620610
Review for gene: CHEK1 was set to GREEN
Added comment: Literature in OMIM- PMID: 33953335; 33948904
- >3 unrelated with infertility due to zygote/embryo cleavage arrest with three different missense variants and 1 1bp deletion. Functional studies using transfection studies showed that all mutant increased cytoplasmic localization significantly greater kinase activity. Injection of all mutant cRNA into mouse zygotes with 2 distinct pronuclei also resulted in significantly decreased cleavage rates compared to wildtype.
Sources: Expert list
Mendeliome v1.2749 CDC25A Zornitza Stark Marked gene: CDC25A as ready
Mendeliome v1.2749 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Mendeliome v1.2749 CDC25A Zornitza Stark Classified gene: CDC25A as Green List (high evidence)
Mendeliome v1.2749 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Mendeliome v1.2748 CDC25A Zornitza Stark gene: CDC25A was added
gene: CDC25A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC25A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC25A were set to 40342881; 30009144; 16720623
Phenotypes for gene: CDC25A were set to Spermatogenic failure, MONDO:0004983, CDC25A-related
Review for gene: CDC25A was set to GREEN
Added comment: i) PMID: 40342881- Five novel heterozygous variants (Lys500Asn in 8 cases, His459Leu in 12 cases, Ser485Asp, Thr503Ser, c.1434 + 5G>C) and one previously identified SNP (in 7 cases) in azoospermic males from the Bengali-speaking Indian population. qPCR analysis indicated downregulation of CDC25A mRNA expression in azoospermic patients relative to fertile controls. Relative expression levels of CDC25A were about 2.5-fold lower in azoospermic testicular tissue and semen samples, reflecting diminished transcriptional activity in affected patients. This reduction in gene expression may reflect a potential functional deficiency of CDC25A, contributing to spermatogenic arrest. The decreased level of CDC25A mRNA levels corresponds with the findings of pathogenic variants identified in azoospermic patients, thus solidifying the evidence of CDC25A mutations contributing to male infertility.

ii) PMID: 30009144,16720623- decreased expression of CDC25A observed in testicular biopsies from azoospermic men, suggesting association with meiotic arrest as the etiology of spermatogenic failure.
Sources: Literature
Mendeliome v1.2747 CAPS Zornitza Stark Marked gene: CAPS as ready
Mendeliome v1.2747 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2747 CAPS Zornitza Stark Classified gene: CAPS as Amber List (moderate evidence)
Mendeliome v1.2747 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2746 CAPS Zornitza Stark gene: CAPS was added
gene: CAPS was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CAPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPS were set to 30339840
Phenotypes for gene: CAPS were set to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CAPS-related
Review for gene: CAPS was set to AMBER
Added comment: PMID: 30339840- Homozygous p.L127Wfs in a consanguineous family of 3 sisters with unexplained RPL. In vitro study also showed that mRNA expression of CAPS was downregulated in decidual and placental villous tissues of RPL patients, and CAPS expression in CAPS–homo-919–transfected cells showed a significant decrease compared with the other groups. Transwell assay with Matrigel also revealed that CAPS–homo-919 could affect JAR cell invasion compared with NC (P < 0.01), which might impair trophoblast infiltration ability. An enzyme-linked immunosorbent assay showed that CAPS–homo-919 could induce a dramatic increase in PGE2 release from the RL95-2 cells (P < 0.05), compared with NC.
Sources: Expert list
Mendeliome v1.2745 C4BPA Zornitza Stark Marked gene: C4BPA as ready
Mendeliome v1.2745 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2745 C4BPA Zornitza Stark Classified gene: C4BPA as Amber List (moderate evidence)
Mendeliome v1.2745 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2744 C4BPA Zornitza Stark gene: C4BPA was added
gene: C4BPA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C4BPA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C4BPA were set to 23508668
Phenotypes for gene: C4BPA were set to recurrent pregnancy loss susceptibility MONDO:0000144, C4BPA-related
Review for gene: C4BPA was set to AMBER
Added comment: PMID: 23508668- Five unrelated female with history of recurrent RPL (<10 weeks) carrying het missnese variants (See table 3- G423E, R120H, I126T, P4Q).
- The I126T mutation in CCP2 of C4BP α-chain is of particular interest as it was found only in one patient but not in healthy controls. This rare mutation affected both expression level of C4BP α-chain as well as its function, i.e., degradation of C4b and C3b in solution.
R120H, found in two patients and no controls, increased the ability of C4BP to act as cofactor in degradation of C4b but decreased its activity in degradation of C3b both in solution and deposited on the cell surface. The other 2 variants have been observed in controls.
- Homozygous C4BP knockout mice often die during second or third pregnancy (unpublished observation). This would imply a pivotal role of this protein in maintenance of successful pregnancy, although the mechanism is not known.
Sources: Expert list
Mendeliome v1.2743 C11orf80 Zornitza Stark Marked gene: C11orf80 as ready
Mendeliome v1.2743 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2743 C11orf80 Zornitza Stark Classified gene: C11orf80 as Amber List (moderate evidence)
Mendeliome v1.2743 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2742 C11orf80 Zornitza Stark Tag new gene name tag was added to gene: C11orf80.
Mendeliome v1.2742 C11orf80 Zornitza Stark gene: C11orf80 was added
gene: C11orf80 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: C11orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C11orf80 were set to 30388401; 36732965
Phenotypes for gene: C11orf80 were set to Recurrent hydatidiform mole 4, MIM # 618432
Review for gene: C11orf80 was set to AMBER
Added comment: Note: HGNC Approved Gene Symbol- TOP6BL

Literature in OMIM- PubMed: 30388401- Two unrelated females with RHMs carrying a homozygous p.Glu262∗ and p.Ser501Pro, respectively.

New paper (biallelic variants for OZEMA/NOA)
i) PMID: 36732965- A homozygous LOF p.E162* in four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility. Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient.
Sources: Expert list
Mendeliome v1.2741 BCORL1 Zornitza Stark Phenotypes for gene: BCORL1 were changed from Shukla-Vernon syndrome, MIM#301029 to Shukla-Vernon syndrome, MIM#301029; Spermatogenic failure, MONDO:0004983, BCORL1-related
Mendeliome v1.2740 BCORL1 Zornitza Stark Publications for gene: BCORL1 were set to 24123876; 30941876
Mendeliome v1.2739 BCORL1 Zornitza Stark Mode of inheritance for gene: BCORL1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2738 BCORL1 Zornitza Stark Classified gene: BCORL1 as Green List (high evidence)
Mendeliome v1.2738 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Mendeliome v1.2737 BCORL1 Zornitza Stark edited their review of gene: BCORL1: Added comment: Association with spermatogenic failure:

i) PMID: 38342987- novel hemizygous nonsense variant (c.1564G > T:p.Glu522*) in a male patient with oligoasthenoteratozoospermia (OAT) from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Also identified four hemizygous missense variants (c.2615T > G:p.Val872Gly, c.2669G > A:p.Arg890Gln, c.3164A > G:p.Asp1055Gly and c.3344C > T:p.Pro1115Leu) in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%). They hypothesized that the BCORL1 (c.2615 T > G, c.2669G > A, c.3164A > G, c.3344C > T) missense mutations may have led to an accumulation of dysfunctional toxic proteins that resulted in a more severe male infertility phenotype in the patient (NOA).

ii) PMID: 32376790- Hemizygous missense variant in a male patient with NOA without other diseases, which also found that the knockout of Bcorl1 in mice resulted in OAT with the abnormal brain development. It had not been previously linked to male infertility. This study demonstrates, for the first time, that loss of Bcorl1 causes spermatogenesis failure.

iii) PMID: 39267058- hemizygous missense variant (p.Arg19Gln) in a infertile male with oliogasthenozoospermia, no functional data

iv) PMID: 39189935- novel hemizygous missense variant (p.G1391R) and a recurrent variant (p.V872G) in BCORL1 from four OAT patients. Functional assays showed that the variants disturb the transcription of spermatogenetic genes such as SYCE1 and DAZL, impair the interaction with HDAC7, and cause epigenetic changes such as changes in level of histone modification with different extent, including the enhancement in acetylation of H3K14, and the reduction in acetylation of H4K5 and H4K8.; Changed rating: GREEN; Changed publications: 24123876, 30941876, 38342987, 32376790, 39267058, 39189935; Changed phenotypes: Shukla-Vernon syndrome, MIM#301029, Spermatogenic failure, MONDO:0004983, BCORL1-related
Mendeliome v1.2737 BCORL1 Zornitza Stark changed review comment from: Classified as LIMITED by ClinGen.; to: Classified as LIMITED by ClinGen, Shukla-Vernon syndrome, MIM#301029
Mendeliome v1.2737 ASTL Zornitza Stark Publications for gene: ASTL were set to 34704130
Mendeliome v1.2736 ASTL Zornitza Stark Classified gene: ASTL as Green List (high evidence)
Mendeliome v1.2736 ASTL Zornitza Stark Gene: astl has been classified as Green List (High Evidence).
Mendeliome v1.2735 ASTL Zornitza Stark edited their review of gene: ASTL: Changed rating: GREEN
Mendeliome v1.2735 ASTL Zornitza Stark edited their review of gene: ASTL: Added comment: New papers (biallelic variants)
i) PMID: 37640117 - Novel compound heterozygous missense variants (p.Arg117Cys and p.Arg274Trp) in a Chinese woman with primary infertility and polyspermy in IVF. Moreover, transfection studies using CHO-K1 cells indicated that mutant cells showed abnormal ovastacin zymogen activation or decreased enzyme stability.

ii) PMID: 37133443- Biallelic variants in four independent affected individuals with primary infertility. The frameshift variants significantly decreased the quantity of ASTL protein in vitro. And all missense variants affected the enzymatic activity that cleaves ZP2 in mouse egg in vitro. Three knock-in female mice (corresponding to three missense variants in patients) all show subfertility due to low embryo developmental potential.; Changed publications: 34704130, 37640117, 37133443; Changed phenotypes: Oocyte maturation defect 11, MIM# 619643
Mendeliome v1.2735 ACTL7A Zornitza Stark Marked gene: ACTL7A as ready
Mendeliome v1.2735 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Mendeliome v1.2735 ACTL7A Zornitza Stark Classified gene: ACTL7A as Green List (high evidence)
Mendeliome v1.2735 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Mendeliome v1.2734 ACTL7A Zornitza Stark gene: ACTL7A was added
gene: ACTL7A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ACTL7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL7A were set to 32923619; 34727571; 36593593; 37004249; 37991128; 36574082; 35921706
Phenotypes for gene: ACTL7A were set to Spermatogenic failure 86, #MIM 620499
Review for gene: ACTL7A was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 32923619, 34727571, 36593593, 37004249- different biallelic variants reported in >3 unrelated infertile men

Other papers:
i) PMID: 37991128 (2025)- two infertile males with com het p.R373H/p.G402S and hom p.R373C. All located within actin domain and predicted to be pathogenic.The protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting.

ii)PMID: 36574082 (2023)- Two infertile brothers with hom p.D75A with teratozoospermia and fertilization failure. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. The variant also caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients.

iii) PMID: 35921706 (2022)- Actl7a gene knockout (KO) mice led to malformed formation of sperm acrosomes, male infertility, fertilization failure during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and reduced sperm-zona pellucida (ZP) binding ability. Localization of the zona pellucida binding protein (ZPBP) was altered in the sperm of Actl7a homozygous KO male mice.
Sources: Expert list
Mendeliome v1.2733 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Mendeliome v1.2732 MARK2 Zornitza Stark reviewed gene: MARK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 76, MIM# 621285; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2732 TRIM63 Zornitza Stark Phenotypes for gene: TRIM63 were changed from Hypertrophic cardiomyopathy, MONDO:0005045 to Cardiomyopathy, familial hypertrophic, 31, MIM# 621270
Mendeliome v1.2731 TRIM63 Zornitza Stark edited their review of gene: TRIM63: Changed phenotypes: Cardiomyopathy, familial hypertrophic, 31, MIM# 621270
Mendeliome v1.2731 PDE1B Zornitza Stark Marked gene: PDE1B as ready
Mendeliome v1.2731 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Mendeliome v1.2731 PDE1B Zornitza Stark Phenotypes for gene: PDE1B were changed from movement disorder, MONDO:0005395 to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PDE1B-related
Mendeliome v1.2730 PDE1B Zornitza Stark Classified gene: PDE1B as Green List (high evidence)
Mendeliome v1.2730 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Mendeliome v1.2729 PDE1B Zornitza Stark reviewed gene: PDE1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Complex neurodevelopmental disorder with motor features, MONDO:0100516, PDE1B-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2729 PDE1B Achchuthan Shanmugasundram gene: PDE1B was added
gene: PDE1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE1B were set to 40492975
Phenotypes for gene: PDE1B were set to movement disorder, MONDO:0005395
Review for gene: PDE1B was set to GREEN
Added comment: PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total.

They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability. Functional evidence is also available for these variants.
Sources: Literature
Mendeliome v1.2729 ATG4D Zornitza Stark Phenotypes for gene: ATG4D were changed from Neurodevelopmental disorder, MONDO:0700092, ATG4D-related to Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Spermatogenic failure 101, MIM# 621269
Mendeliome v1.2728 ATG4D Zornitza Stark Publications for gene: ATG4D were set to PMID: 36765070
Mendeliome v1.2727 ATG4D Zornitza Stark edited their review of gene: ATG4D: Added comment: PMID 33988247: 4 individuals from 3 unrelated families, all variants are missense, limited functional data.; Changed publications: 33988247; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related, Spermatogenic failure 101, MIM# 621269
Mendeliome v1.2727 PMEPA1 Zornitza Stark Classified gene: PMEPA1 as Green List (high evidence)
Mendeliome v1.2727 PMEPA1 Zornitza Stark Gene: pmepa1 has been classified as Green List (High Evidence).
Mendeliome v1.2726 PMEPA1 Zornitza Stark edited their review of gene: PMEPA1: Changed rating: GREEN
Mendeliome v1.2726 LIFR Ava Stevenson reviewed gene: LIFR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, MIM# 601559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2726 ITPR3 Zornitza Stark Phenotypes for gene: ITPR3 were changed from Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111; Combined immunodeficiency, MONDO:0015131, ITPR3-related to Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111; Combined immunodeficiency, MONDO:0015131, ITPR3-related; Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254
Mendeliome v1.2725 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to 32949214; 24627108; 36302985
Mendeliome v1.2724 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Added comment: PMIDs 36302985, 39270020, 39560673: More than 10 individuals reported with heterozygous variant and combined immunodeficiency +/- ectodermal features and neuropathy.; Changed publications: 32949214, 24627108, 36302985, 36302985, 39270020, 39560673; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111, Combined immunodeficiency, MONDO:0015131, ITPR3-related, Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254
Mendeliome v1.2724 LRP6 Zornitza Stark Phenotypes for gene: LRP6 were changed from Tooth agenesis, selective, 7, MIM# 616724 to Tooth agenesis, selective, 7, MIM# 616724; Exudative vitreoretinopathy 8, MIM# 621268
Mendeliome v1.2723 LRP6 Zornitza Stark Publications for gene: LRP6 were set to
Mendeliome v1.2722 LRP6 Zornitza Stark reviewed gene: LRP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34896607; Phenotypes: Exudative vitreoretinopathy 8, MIM# 621268; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2722 FASTKD5 Zornitza Stark Marked gene: FASTKD5 as ready
Mendeliome v1.2722 FASTKD5 Zornitza Stark Gene: fastkd5 has been classified as Green List (High Evidence).
Mendeliome v1.2722 FASTKD5 Zornitza Stark Phenotypes for gene: FASTKD5 were changed from Leigh syndrome MONDO:0009723 to Leigh syndrome MONDO:0009723, FASTKD5-related
Mendeliome v1.2721 DST Zornitza Stark Phenotypes for gene: DST were changed from Neuropathy, hereditary sensory and autonomic, type VI, MIM#614653; Epidermolysis bullosa simplex, autosomal recessive 2, MIM#615425 to Neuropathy, hereditary sensory and autonomic, type VI, MIM#614653; Epidermolysis bullosa simplex, autosomal recessive 2, MIM#615425; congenital myopathy MONDO:0019952, DST-related
Mendeliome v1.2720 DST Zornitza Stark Publications for gene: DST were set to 22522446; 30371979; 28468842
Mendeliome v1.2719 DST Chirag Patel reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40497796; Phenotypes: congenital myopathy MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2719 FASTKD5 Chirag Patel Classified gene: FASTKD5 as Green List (high evidence)
Mendeliome v1.2719 FASTKD5 Chirag Patel Gene: fastkd5 has been classified as Green List (High Evidence).
Mendeliome v1.2718 FASTKD5 Chirag Patel gene: FASTKD5 was added
gene: FASTKD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FASTKD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FASTKD5 were set to PMID: 40499538
Phenotypes for gene: FASTKD5 were set to Leigh syndrome MONDO:0009723
Review for gene: FASTKD5 was set to GREEN
Added comment: 3 unrelated individuals with Leigh syndrome (1 x severe/early-onset/fatal, 1 x milder/childhood-onset, 1 x adult-onset). WES identified compound heterozygous variants in FASTKD5 gene (3 x missense variants, 2 x frameshift variants leading to a premature stop codon). The FASTKD5 gene codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript.

Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense variants, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. 2/3 missense variants resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability.
Sources: Literature
Mendeliome v1.2717 GLIS1 Bryony Thompson Phenotypes for gene: GLIS1 were changed from Increased ocular pressure; Glaucoma to Increased ocular pressure; Glaucoma MONDO:0005041
Mendeliome v1.2716 GINS2 Bryony Thompson Phenotypes for gene: GINS2 were changed from Meier-Gorlin syndrome with craniosynostosis to Meier-Gorlin syndrome with craniosynostosis MONDO:0016817
Mendeliome v1.2715 GATC Bryony Thompson Phenotypes for gene: GATC were changed from Mitochondrial cardiomyopathy to Mitochondrial cardiomyopathy; inborn mitochondrial metabolism disorder MONDO:0004069
Mendeliome v1.2714 FEM1B Zornitza Stark Phenotypes for gene: FEM1B were changed from Syndromic disease MONDO:0002254, FEM1B-related to Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, MIM# 621263
Mendeliome v1.2713 FEM1B Zornitza Stark edited their review of gene: FEM1B: Changed phenotypes: Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, MIM# 621263
Mendeliome v1.2713 DOT1L Zornitza Stark Phenotypes for gene: DOT1L were changed from Neurodevelopmental disorder, MONDO:0700092, DOT1L-related to Nil-Deshwan neurodevelopmental syndrome, MIM# 621265
Mendeliome v1.2712 DOT1L Zornitza Stark edited their review of gene: DOT1L: Changed phenotypes: Nil-Deshwan neurodevelopmental syndrome, MIM# 621265
Mendeliome v1.2712 RPL17 Zornitza Stark Marked gene: RPL17 as ready
Mendeliome v1.2712 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Mendeliome v1.2712 RPL17 Zornitza Stark Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia, MONDO:0015253 to Diamond-Blackfan anaemia 22, MIM# 621262
Mendeliome v1.2711 RPL17 Zornitza Stark Classified gene: RPL17 as Green List (high evidence)
Mendeliome v1.2711 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Mendeliome v1.2710 RPL17 Zornitza Stark reviewed gene: RPL17: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anemia 22, MIM# 621262; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2710 GATB Bryony Thompson Phenotypes for gene: GATB were changed from Mitochondrial cardiomyopathy to inborn mitochondrial metabolism disorder MONDO:0004069
Mendeliome v1.2709 GATB Bryony Thompson Publications for gene: GATB were set to 30283131
Mendeliome v1.2708 GATB Bryony Thompson Classified gene: GATB as Amber List (moderate evidence)
Mendeliome v1.2708 GATB Bryony Thompson Gene: gatb has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2707 GATB Bryony Thompson reviewed gene: GATB: Rating: AMBER; Mode of pathogenicity: None; Publications: 30283131, 38703036; Phenotypes: inborn mitochondrial metabolism disorder MONDO:0004069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2707 GAS1 Bryony Thompson Phenotypes for gene: GAS1 were changed from Holoprosencephaly to Holoprosencephaly MONDO:0016296
Mendeliome v1.2706 GALM Bryony Thompson Phenotypes for gene: GALM were changed from galactosaemia; type IV galactosaemia to galactosaemia; type IV galactosaemia MONDO:0030105
Mendeliome v1.2705 FST Bryony Thompson Phenotypes for gene: FST were changed from Cleft lip and palate to Cleft lip and palate MONDO:0016044
Mendeliome v1.2704 FRY Bryony Thompson Phenotypes for gene: FRY were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2703 FOXR1 Bryony Thompson Phenotypes for gene: FOXR1 were changed from Postnatal microcephaly, progressive brain atrophy and global developmental delay to Postnatal microcephaly, progressive brain atrophy and global developmental delay; Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2702 FOXP4 Bryony Thompson Phenotypes for gene: FOXP4 were changed from Neurodevelopmental disorder; multiple congenital abnormalities to Complex neurodevelopmental disorder MONDO:0100038
Mendeliome v1.2701 LONP1 Zornitza Stark Phenotypes for gene: LONP1 were changed from CODAS syndrome, MIM#600373; Mitochondrial cytopathy to CODAS syndrome, MIM#600373; mitochondrial disease (MONDO:0044970), LONP1-related
Mendeliome v1.2700 LONP1 Zornitza Stark Publications for gene: LONP1 were set to 31636596
Mendeliome v1.2699 LONP1 Zornitza Stark Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2698 LONP1 Lauren Rogers Deleted their comment
Mendeliome v1.2698 LONP1 Lauren Rogers changed review comment from: ew reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301.

- PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures.
p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case)

- PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly.
- p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication).
- p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case)

- p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication)

LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded.; to: New reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301.

- PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures.
p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case)

- PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly.
- p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication).
- p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case)

- p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication)

LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded.
Mendeliome v1.2698 LONP1 Lauren Rogers commented on gene: LONP1: ew reports of autosomal dominant mitochondrial disease due to missense variants at p.Arg301.

- PMID: 36353900; Hartley 2023: 1x heterozygous de novo individual with p.(Arg301Gln), with dystonia, hearing loss, seizures.
p.(Arg301Gln) has been reported as de novo in a heterozygous individual with dystonia, delayed speech and language development (VCGS/MCRI internal case)

- PMID: 31923470; Besse 2020: 1x heterozygous de novo individual with p.(Arg301Trp) with seizures, encephalopathy, pachygyria and microcephaly.
- p.(Arg301Trp) has also been reported in a heterozygous individual with recurrent neonatal seizures, suspected mitochondrial disorder, elevated lactate, microcephaly, EEG showing significantly increased seizure susceptibility which was de novo but parentage not tested (ClinVar, personal communication).
- p.(Arg301Trp) has also been identified in a heterozygous individual with neonatal intractable epileptic encephalopathy and lactic acidosis. MRI changes in keeping with mitochondrial disorder, a combined Complex I and complex IV defect identified in muscle (but not liver) by RCE (VCGS/MCRI internal case)

- p.(Arg301Gly) has been reported de novo in a heterozygous individual with epileptic encephalopathy, microcephaly and dyskinesia (ClinVar, personal communication)

LONP1 functions as both a chaperone and an ATP-dependent protease. Functional evidence in Besse shows p.(Arg301Trp) results in loss of chaperone activity but retains proteolytic activity. Expression of WT LONP1 in patient fibroblast cells did not rescue dysfunction (measured via levels of MRPL44, RPL11, PDHE1a, TFAM, PINK1, complex 1 and complex IV) - indicating NOT LoF effect. Overexpression of LONP1 in control fibroblast cells leads to dysfunction (decrease in NDUFB8, COXIV, MRPL44 and TFAM), however, MRPL11, PDHE1a and PINK1 proteins were unchanged compared to controls. Variant p.R721G associated with AR disease showed decreased homo-oligomerisation whilst p.R301W showed increased WT-Mut and WT-WT oligomers. GoF was suggested but no dose-dependent studies so DN cannot be excluded.
Mendeliome v1.2698 LONP1 Lauren Rogers reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36353900, 31923470; Phenotypes: mitochondrial disease (MONDO:0044970), LONP1-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2698 BHLHA9 Zornitza Stark Tag SV/CNV tag was added to gene: BHLHA9.
Mendeliome v1.2698 NEXN Zornitza Stark Phenotypes for gene: NEXN were changed from Lethal fetal cardiomyopathy; Hydrops fetalis; Cardiomyopathy, dilated 1CC - MIM#613122 to Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261; Cardiomyopathy, dilated 1CC - MIM#613122
Mendeliome v1.2697 NEXN Zornitza Stark reviewed gene: NEXN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2697 BHLHA9 Sarah Milton changed review comment from: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated within families of affected individuals on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptosis activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.; to: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated within families of affected individuals on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptotic activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.
Mendeliome v1.2697 BHLHA9 Sarah Milton changed review comment from: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated in affected families on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptosis activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.; to: BHLHA9 encodes a transcription factor involved in embryonic limb development, essential for interdigital apoptosis in central limb mesenchyme cells.

Duplications encompassing a 11.8kb critical region involving BHLHA9 have been reported in a number of publications to result in split hand foot malformation with long bone deficiency in at least 50 affected individuals. This has segregated within families of affected individuals on a number of occasions.

However, penetrance of approximately 50% has been noted with significant intrafamilial variability. It should also be noted that in gnomad v4 structural variants there are 15 dups encompassing this same region in het individuals with a DGV gold track demonstrating dups in 3 individuals.

Duan et al 2022 (PMID: 36035248) proposed copy number gains might enhance the regulatory potential as a transcription factor; thus, the apoptosis activity may be overly or ectopically increased in central limb mesenchymal cells during limb development. Authors proposed a gene dosage change with increasing copies of BHLHA9 showing increasing penetrance using examples of individuals with homozygous duplications or heterozygous triplications.
Mendeliome v1.2697 BHLHA9 Sarah Milton reviewed gene: BHLHA9: 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: 22147889, 23790188, 29970136, 31200655, 36035248, 36028842, 36551834; Phenotypes: Split-hand/foot malformation with long bone deficiency 3 MIM#612576; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2697 PIGU Zornitza Stark Classified gene: PIGU as Amber List (moderate evidence)
Mendeliome v1.2697 PIGU Zornitza Stark Gene: pigu has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2696 PIGU Zornitza Stark edited their review of gene: PIGU: Added comment: Downgrade to Amber in light of ClinGen assessment. Only 2 variants reported.; Changed rating: AMBER
Mendeliome v1.2696 POLD3 Zornitza Stark Classified gene: POLD3 as Amber List (moderate evidence)
Mendeliome v1.2696 POLD3 Zornitza Stark Gene: pold3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2695 NFE2 Zornitza Stark Marked gene: NFE2 as ready
Mendeliome v1.2695 NFE2 Zornitza Stark Gene: nfe2 has been classified as Red List (Low Evidence).
Mendeliome v1.2695 NFE2 Zornitza Stark Phenotypes for gene: NFE2 were changed from thrombocytopenia MONDO:0002049 to thrombocytopenia MONDO:0002049, NFE2-related
Mendeliome v1.2694 NFE2 Zornitza Stark Classified gene: NFE2 as Red List (low evidence)
Mendeliome v1.2694 NFE2 Zornitza Stark Gene: nfe2 has been classified as Red List (Low Evidence).
Mendeliome v1.2693 FAAH2 Zornitza Stark Tag disputed tag was added to gene: FAAH2.
Mendeliome v1.2693 FAAH2 Sangavi Sivagnanasundram reviewed gene: FAAH2: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008804; Phenotypes: X-linked complex neurodevelopmental disorder MONDO:0100148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2693 NFE2 Sangavi Sivagnanasundram gene: NFE2 was added
gene: NFE2 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: NFE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFE2 were set to 31951293
Phenotypes for gene: NFE2 were set to thrombocytopenia MONDO:0002049
Review for gene: NFE2 was set to RED
Added comment: Classified as Limited by Hemostasis Thrombosis GCEP on 16/06/2025

Homozygous frameshift variant reported in a single proband (c.952delA, p.T318fsX326 - absent in gnomAD v4.1).
Sources: ClinGen
Mendeliome v1.2693 SLFN14 Sangavi Sivagnanasundram reviewed gene: SLFN14: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006205; Phenotypes: platelet-type bleeding disorder 20 MONDO:0014830; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2693 ERLIN2 Sangavi Sivagnanasundram reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary spastic paraplegia 18 MONDO:0012639; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2693 POLD3 Sangavi Sivagnanasundram reviewed gene: POLD3: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008872; Phenotypes: immunodeficiency 122 MONDO:0971151; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2693 PIGU Sangavi Sivagnanasundram reviewed gene: PIGU: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005799; Phenotypes: glycosylphosphatidylinositol biosynthesis defect 21 MONDO:0032824; Mode of inheritance: None
Mendeliome v1.2693 FAAP100 Zornitza Stark Phenotypes for gene: FAAP100 were changed from Fanconi anaemia, MONDO:0019391, FAAP100-related to Fanconi anaemia, complementation group X, MIM# 621258
Mendeliome v1.2692 FAAP100 Zornitza Stark edited their review of gene: FAAP100: Changed phenotypes: Fanconi anaemia, complementation group X, MIM# 621258
Mendeliome v1.2692 TMEM63B Zornitza Stark Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062, TMEM63B-related to Developmental and epileptic encephalopathy 118, MIM#621250
Mendeliome v1.2691 LGI1 Krithika Murali Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1, MIM# 6000512; Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related to Epilepsy, familial temporal lobe, 1, MIM# 6000512; Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related
Mendeliome v1.2690 LGI1 Krithika Murali Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1, MIM# 6000512 to Epilepsy, familial temporal lobe, 1, MIM# 6000512; Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related
Mendeliome v1.2689 LGI1 Krithika Murali Mode of inheritance for gene: LGI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2688 LGI1 Krithika Murali reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40455867; Phenotypes: Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2688 ELFN1 Krithika Murali Classified gene: ELFN1 as Green List (high evidence)
Mendeliome v1.2688 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Mendeliome v1.2687 ELFN1 Krithika Murali Marked gene: ELFN1 as ready
Mendeliome v1.2687 ELFN1 Krithika Murali Gene: elfn1 has been classified as Red List (Low Evidence).
Mendeliome v1.2687 ELFN1 Krithika Murali gene: ELFN1 was added
gene: ELFN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELFN1 were set to PMID: 40576023
Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092, ELFN1-related
Review for gene: ELFN1 was set to GREEN
Added comment: PMID: 40576023 report 8 individuals from 5 unrelated families and 6 previously reported patients from 2 families. Most patients had homozygous biallelic deletions / PTCs in ELFN1 (including one involving 5'UTR). One family had biallelic missense variants,

All patients had dev delay/ID. Other features included autism/ADHD/behavioural issues, hypotonia/muscle weakness, paediatric-onset ataxia/movement disorder and epilepsy.

Supportive functional modelling in mice and zebrafish. Some emerging evidence for haploinsufficiency.
Sources: Literature
Mendeliome v1.2686 TEX14 Bryony Thompson Marked gene: TEX14 as ready
Mendeliome v1.2686 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Mendeliome v1.2686 TEX14 Bryony Thompson Classified gene: TEX14 as Green List (high evidence)
Mendeliome v1.2686 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Mendeliome v1.2685 TEX14 Bryony Thompson gene: TEX14 was added
gene: TEX14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEX14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEX14 were set to 16549803; 40492599; 28206990; 29790874; 36017582
Phenotypes for gene: TEX14 were set to Spermatogenic failure MONDO:0004983, TEX14-related
Review for gene: TEX14 was set to GREEN
Added comment: Multiple probands reported with biallelic LoF variants and a supporting mouse model.
Sources: Literature
Mendeliome v1.2684 WDR91 Bryony Thompson Phenotypes for gene: WDR91 were changed from Hydrocephalus; cerebellar hypoplasia; hygroma to Complex neurodevelopmental disorder MONDO:0100038
Mendeliome v1.2683 WDR91 Bryony Thompson Publications for gene: WDR91 were set to 34028500; 28860274; 32732226; 28969387
Mendeliome v1.2682 WDR91 Bryony Thompson Classified gene: WDR91 as Green List (high evidence)
Mendeliome v1.2682 WDR91 Bryony Thompson Gene: wdr91 has been classified as Green List (High Evidence).
Mendeliome v1.2681 WDR91 Bryony Thompson reviewed gene: WDR91: Rating: GREEN; Mode of pathogenicity: None; Publications: 32732226, 38041506, 34791078, 40550703, 28860274, 34028500, ClinVar: SCV000965687.1; Phenotypes: Complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2681 MIB1 Zornitza Stark Classified gene: MIB1 as Red List (low evidence)
Mendeliome v1.2681 MIB1 Zornitza Stark Gene: mib1 has been classified as Red List (Low Evidence).
Mendeliome v1.2680 ADD1 Zornitza Stark Classified gene: ADD1 as Amber List (moderate evidence)
Mendeliome v1.2680 ADD1 Zornitza Stark Gene: add1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2679 ADAM23 Zornitza Stark Marked gene: ADAM23 as ready
Mendeliome v1.2679 ADAM23 Zornitza Stark Gene: adam23 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2679 ADAM23 Zornitza Stark Classified gene: ADAM23 as Amber List (moderate evidence)
Mendeliome v1.2679 ADAM23 Zornitza Stark Gene: adam23 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2678 SIDT2 Zornitza Stark Marked gene: SIDT2 as ready
Mendeliome v1.2678 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2678 SIDT2 Zornitza Stark Classified gene: SIDT2 as Amber List (moderate evidence)
Mendeliome v1.2678 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2677 SREK1 Zornitza Stark Marked gene: SREK1 as ready
Mendeliome v1.2677 SREK1 Zornitza Stark Gene: srek1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2677 SREK1 Zornitza Stark Classified gene: SREK1 as Amber List (moderate evidence)
Mendeliome v1.2677 SREK1 Zornitza Stark Gene: srek1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2676 NSUN3 Zornitza Stark Publications for gene: NSUN3 were set to 27356879; 32488845
Mendeliome v1.2675 NSUN3 Zornitza Stark Classified gene: NSUN3 as Green List (high evidence)
Mendeliome v1.2675 NSUN3 Zornitza Stark Gene: nsun3 has been classified as Green List (High Evidence).
Mendeliome v1.2674 POC5 Zornitza Stark Phenotypes for gene: POC5 were changed from Idiopathic scoliosis; retinitis pigmentosa; short stature; microcephaly; recurrent glomerulonephritis to Ciliopathy, MONDO:0005308, POC5-related; Scoliosis, MONDO:0005392, POC5-related
Mendeliome v1.2673 POC5 Zornitza Stark Publications for gene: POC5 were set to 25642776; 29272404
Mendeliome v1.2672 POC5 Zornitza Stark reviewed gene: POC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40590205, 29272404; Phenotypes: Ciliopathy, MONDO:0005308, POC5-related, Scoliosis, MONDO:0005392, POC5-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2672 FGF4 Zornitza Stark Phenotypes for gene: FGF4 were changed from Jeune Syndrome, FGF4-related, MONDO:0018770 to Short-rib thoracic dysplasia 22 without polydactyly, MIM# 621260
Mendeliome v1.2671 FGF4 Zornitza Stark reviewed gene: FGF4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 22 without polydactyly, MIM# 621260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2671 RDH8 Zornitza Stark Marked gene: RDH8 as ready
Mendeliome v1.2671 RDH8 Zornitza Stark Gene: rdh8 has been classified as Red List (Low Evidence).
Mendeliome v1.2671 RDH8 Zornitza Stark gene: RDH8 was added
gene: RDH8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RDH8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH8 were set to 37628710; 18048336; 22621924
Phenotypes for gene: RDH8 were set to Stargardt disease 5, MIM# 621259
Review for gene: RDH8 was set to RED
Added comment: Two siblings reported with homozygous splicing variant and Stargardt disease, some supportive functional data.
Sources: Literature
Mendeliome v1.2670 CFAP221 Zornitza Stark Phenotypes for gene: CFAP221 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 55, MIM# 279000
Mendeliome v1.2669 CFAP221 Zornitza Stark Publications for gene: CFAP221 were set to 31636325
Mendeliome v1.2668 CFAP221 Zornitza Stark Classified gene: CFAP221 as Green List (high evidence)
Mendeliome v1.2668 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Green List (High Evidence).
Mendeliome v1.2667 CFAP221 Zornitza Stark edited their review of gene: CFAP221: Added comment: Five additional individuals reported, although two of them are homozygous for the same variant.; Changed rating: GREEN; Changed publications: 31636325, 39362668, 40250778, 38960684, 40272718; Changed phenotypes: Ciliary dyskinesia, primary, 55, MIM# 279000
Mendeliome v1.2667 NSUN3 Sangavi Sivagnanasundram changed review comment from: Four other unrelated families reported with biallelic variants and presented with optic neuropathy of varying severities and oxidative phosphorylation deficiency. All affected individuals presented with a range of other phenotypes including but not limited to ID/DD, cardiac abnormalities, skeletal abnormalities and hearing impairment. Two families (Family 1 and Family 3) show segregation evidence across affected individuals however consanguinity was noted.; to: Four other unrelated families reported with biallelic variants and presented with optic neuropathy of varying severities and oxidative phosphorylation deficiency. All affected individuals presented with a range of other phenotypes including but not limited to ID/DD, cardiac abnormalities, skeletal abnormalities and hearing impairment. Two families (Family 1 and Family 3) show segregation evidence across affected individuals - consanguinity was noted in both families.
Mendeliome v1.2667 NSUN3 Sangavi Sivagnanasundram reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 40465263; Phenotypes: combined oxidative phosphorylation deficiency 48 MONDO:0033566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2667 SREK1 Sangavi Sivagnanasundram gene: SREK1 was added
gene: SREK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SREK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SREK1 were set to 40549565
Phenotypes for gene: SREK1 were set to Prader-Willi-like syndrome, SREK1-related MONDO:0008300
Review for gene: SREK1 was set to AMBER
Added comment: Three Pakistani probands from three consanguineous families identified with biallelic variants in SREK1. Affected individuals presented with hyperphagic obesity and neurodevelopmental delay. They also presented with psychological and behavioural issues and were phenotypically similar to Prader-Willi affected individuals.

Further testing was conducted using human induced pluripotent stem cell (iPSC) -derived neurons followed by RNA sequencing conducted on the neurons.
The results of the assay was suggestive that variants located in the RNA recognition domain (residues 19–96 and 173–256) of SREK1 downregulation of SNORD115 and SNORD116 leading to Prader-Willi-like phenotype however proper validation and controls weren't used.

No relevant mouse models were identified on IMPC (international mouse phenotype consortium) to further support gene-disease association there gene reviewed as Amber.

Variants identified in SREK1 - AF's from gnomADv4.1
P95L - absent in gnomAD v4.1
T194M - EAS PopMax AF - 0.03787% (47 hets)
E601K - SAS PopMax AF - 0.01319% (12 hets)
Sources: Literature
Mendeliome v1.2667 SIDT2 Sarah Milton gene: SIDT2 was added
gene: SIDT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIDT2 were set to PMID: 40541391
Phenotypes for gene: SIDT2 were set to Lysosomal storage disease, MONDO:0002561, SIDT2-related
Review for gene: SIDT2 was set to AMBER
Added comment: Encodes a lysosomal membrane protein involved in trafficking of RNA into the lysosome for degradation via RNAutophagy.

1 affected individual described in PMID: 40541391 with two variants in SIDT2 presenting with progressive neurological decline in childhood with poor coordination, dysarthria, ataxia, cerebellar atrophy and cognitive decline. One variant confirmed to be maternally inherited, the other inheritance was unknown due to lack of availability of family members (as such phase not confirmed). Variants were c.1586G>A (?listed as p.Arg529Trp however protein consequence should be p.Arg529Gln) and c.2032C>T|p.Arg678Trp.

Functional studies of patient fibroblasts showed markers of autophagy impairment and mouse models with reduced expression of SIDT2 had signs of progressive incoordination.
LOF proposed mechanism.
Sources: Literature
Mendeliome v1.2667 ADAM23 Sarah Milton changed review comment from: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature; to: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 form a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature
Mendeliome v1.2667 ADAM23 Sarah Milton changed review comment from: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature; to: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature
Mendeliome v1.2667 ADAM23 Sarah Milton gene: ADAM23 was added
gene: ADAM23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAM23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM23 were set to (PMID: 40455867)
Phenotypes for gene: ADAM23 were set to Neonatal-onset developmental and epileptic encephalopathy, MONDO:0100455, ADAM23-related
Review for gene: ADAM23 was set to AMBER
Added comment: ADAM23 encodes a transmembrane protein receptor which is a receptor for LGI1. LGI1/ADAM22/ADAM23 part of a complex that regulates excitatory synaptic transmission and neuronal excitability in the brain.

1 affected individual described in PMID: 40455867 with severe neonatal seizures, joint contractures, absent reflexes. Noted to have a homozygous NMD predicted variant in ADAM23.
Also had a de novo missense variant in PRKD1.

Knockout ADAM23 mice show early lethal epilepsy.
Sources: Literature
Mendeliome v1.2667 ADD1 Ava Stevenson reviewed gene: ADD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34906466; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2667 MIB1 Ava Stevenson reviewed gene: MIB1: Rating: RED; 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: 23033978, 23314057, 33057194, 30322850, 37405741, 39057643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2667 C10orf71 Zornitza Stark reviewed gene: C10orf71: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1QQ, MIM# 621251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2667 CD274 Zornitza Stark Phenotypes for gene: CD274 were changed from Immune dysregulation, autoimmunity and auto inflammation, MONDO:0957790 to Autoimmune disease, multisystem, infantile-onset, 5, MIM# 621235
Mendeliome v1.2666 CD274 Zornitza Stark edited their review of gene: CD274: Changed phenotypes: Autoimmune disease, multisystem, infantile-onset, 5, MIM# 621235
Mendeliome v1.2666 PDCD2 Zornitza Stark Marked gene: PDCD2 as ready
Mendeliome v1.2666 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2666 PDCD2 Zornitza Stark Classified gene: PDCD2 as Amber List (moderate evidence)
Mendeliome v1.2666 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2665 PDCD2 Zornitza Stark gene: PDCD2 was added
gene: PDCD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD2 were set to 40208938
Phenotypes for gene: PDCD2 were set to Non-immune hydrops fetalis, MONDO:0009369, PDCD2-related
Review for gene: PDCD2 was set to AMBER
Added comment: PMID: 40208938- Novel biallelic PDCD2 variants associated with hydrops fetalis and early pregnancy loss in two affected families. Family 1 with RPL had three fetuses with NIHF who were all homozygous for p.(Pro28Ser) in PDCD2, while Family 2 had p.(Pro28Ser) in trans with p.(Arg34Pro) in two fetuses with NIHF. Family 2 was additionally notable for having a healthy child who was homozygous for the reference allele, consistent with appropriate disease segregation with the PDCD2 variants. Functional studies using primary fetal fibroblasts and human cell lines for both variants showed reduced PDCD2 mRNA level in affected patients' fibroblasts, reduced cellular accumulation of mutant proteins with impaired ability to associate with the 40S subunit ribosomal protein uS5, and further depletion of PDCD2 in fibroblast cells severely impacted ribosome biogenesis. It is notable that formation of the PDCD2-uS5 complex was not completely abolished by the patient variants and that rRNA processing was only partially impaired, as indicated by levels of 40S pre-rRNAs. We thus suspect that the PDCD2 pathogenic variants p.(Pro28Ser) and p.(Arg34Pro) are hypomorphic alleles, with a low level of residual function allowing for cellular differentiation and growth to a certain extent.
Sources: Literature
Mendeliome v1.2664 SOX17 Zornitza Stark Phenotypes for gene: SOX17 were changed from Vesicoureteral reflux 3 MIM#613674; Pulmonary arterial hypertension, MONDO:0015924 to Vesicoureteral reflux 3 MIM#613674; Pulmonary hypertension, primary, 7, MIM# 621248
Mendeliome v1.2663 SOX17 Zornitza Stark edited their review of gene: SOX17: Changed phenotypes: Vesicoureteral reflux 3 MIM#613674, Pulmonary hypertension, primary, 7, MIM# 621248
Mendeliome v1.2663 TBC1D32 Achchuthan Shanmugasundram reviewed gene: TBC1D32: Rating: GREEN; Mode of pathogenicity: None; Publications: 37768732; Phenotypes: retinitis pigmentosa, MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2663 RPL17 Achchuthan Shanmugasundram gene: RPL17 was added
gene: RPL17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPL17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL17 were set to 39088281
Phenotypes for gene: RPL17 were set to Diamond-Blackfan anemia, MONDO:0015253
Review for gene: RPL17 was set to GREEN
Added comment: PMID:39088281 reported two different pedigrees identified with monoallelic variants in RPL17 gene (3C>G & c.452delC/ p.(Thr151Argfs*25). Affected individuals from both pedigrees exhibited clinical features and erythroid proliferation defects consistent with Diamond-Blackfan anaemia. Individuals from first family also presented with skeletal abnormalities, which were not reported in family 2. Modelling of rpl17 deficiency in zebrafish recapitulated the major clinical features of the disorder including anaemia and micrognathia. There is also functional evidence available from lymphoblastoid cell lines (LCLs) derived from patients, which displayed a ribosomal RNA maturation defect reflecting haploinsufficiency of RPL17.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.2663 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related to Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233; Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, MIM# 621234; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related
Mendeliome v1.2662 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454; 34826259; 39406892
Mendeliome v1.2661 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Added comment: PMID 37316189: two individuals with de novo variants and syndromic immunodysregulation, including craniofacial anomalies, hearing impairment, athelia, and developmental delay.; Changed publications: 34920454, 34826259, 37316189; Changed phenotypes: Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233, Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, MIM# 621234
Mendeliome v1.2661 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related to Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related
Mendeliome v1.2660 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Changed phenotypes: Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233
Mendeliome v1.2660 BMP6 Bryony Thompson Classified gene: BMP6 as Amber List (moderate evidence)
Mendeliome v1.2660 BMP6 Bryony Thompson Gene: bmp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2659 LDB3 Zornitza Stark Phenotypes for gene: LDB3 were changed from Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493; Cardiomyopathy, hypertrophic, 24 MIM#601493; Left ventricular noncompaction 3 MIM#601493; Myopathy, myofibrillar, 4 MIM#609452 to Cardiomyopathy, dilated, 2L, MIM# 621237; Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493; Cardiomyopathy, hypertrophic, 24 MIM#601493; Left ventricular noncompaction 3 MIM#601493; Myopathy, myofibrillar, 4 MIM#609452
Mendeliome v1.2658 LDB3 Zornitza Stark Publications for gene: LDB3 were set to 26419279; 16427346; 14660611; 14662268; 27546599; 25911362
Mendeliome v1.2657 LDB3 Zornitza Stark reviewed gene: LDB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36253531; Phenotypes: Cardiomyopathy, dilated, 2L, MIM# 621237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2657 THPO Elena Savva Mode of inheritance for gene: THPO was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2656 ATP2A2 Zornitza Stark Phenotypes for gene: ATP2A2 were changed from Acrokeratosis verruciformis MIM#101900; Darier disease MIM#124200; Congenital myopathy, MONDO:0019952, ATP2A2-related; rhabdomyolysis to Acrokeratosis verruciformis MIM#101900; Darier disease MIM#124200; Congenital myopathy, MONDO:0019952, ATP2A2-related; {Rhabdomyolysis, susceptibility to, 2}, MIM# 621236
Mendeliome v1.2655 ATP2A2 Zornitza Stark edited their review of gene: ATP2A2: Changed phenotypes: Congenital myopathy, MONDO:0019952, ATP2A2-related, {Rhabdomyolysis, susceptibility to, 2}, MIM# 621236
Mendeliome v1.2655 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited (fathers listed as affected). Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2655 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from fathers listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2655 CCM2 Sangavi Sivagnanasundram reviewed gene: CCM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19088123, 31446422; Phenotypes: cerebral cavernous malformation 2 MONDO:0011304; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2655 ANKS1B Zornitza Stark Phenotypes for gene: ANKS1B were changed from Neurodevelopmental syndrome; developmental delay; speech delay; motor delay; autism; intellectual disability to Neurodevelopmental disorder (MONDO:0700092), ANKS1B-related
Mendeliome v1.2654 ANKS1B Zornitza Stark Classified gene: ANKS1B as Green List (high evidence)
Mendeliome v1.2654 ANKS1B Zornitza Stark Gene: anks1b has been classified as Green List (High Evidence).
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from parents said to be affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from fathers listed as affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families, two paternally inherited from parents said to be affected. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2653 ANKS1B Lilian Downie Marked gene: ANKS1B as ready
Mendeliome v1.2653 ANKS1B Lilian Downie Added comment: Comment when marking as ready: Intragenic deletions >3indepedant families with developmental delay (speech and motor apraxia and dysmorphism) borderline IQ's, behavioural/ASD, reduced penetrance, most inherited from mildly or not affected parents. Mouse model.
Mendeliome v1.2653 ANKS1B Lilian Downie Gene: anks1b has been removed from the panel.
Mendeliome v1.2653 ANKS1B Lilian Downie Tag SV/CNV tag was added to gene: ANKS1B.
Mendeliome v1.2653 PMP2 Sangavi Sivagnanasundram reviewed gene: PMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37238449; Phenotypes: Charcot-Marie-Tooth disease MONDO:0015626; Mode of inheritance: None
Mendeliome v1.2653 BMP6 Sangavi Sivagnanasundram reviewed gene: BMP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 28335084, 29695288, 27590690, 34037557, 38719717; Phenotypes: iron overload, susceptibility to MONDO:0859316; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2653 NADK2 Sangavi Sivagnanasundram reviewed gene: NADK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: progressive encephalopathy with leukodystrophy due to DECR deficiency MONDO:0014464; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2653 A4GALT Sangavi Sivagnanasundram reviewed gene: A4GALT: Rating: GREEN; Mode of pathogenicity: None; Publications: 12823750, 15142124, 10747952, 10993874, 11896312, 27612185; Phenotypes: A4GALT-congenital disorder of glycosylation MONDO:0100587; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency is insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE (long isoform) and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE long isoform and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE (long isoform) and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2653 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions. Studies showed reduced transcript levels of both the MANE long isoform and the two short isoforms.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2653 Bryony Thompson removed gene:NOTCH2NL from the panel
Mendeliome v1.2652 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Mendeliome v1.2651 TUBA1C Zornitza Stark Marked gene: TUBA1C as ready
Mendeliome v1.2651 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Mendeliome v1.2651 TUBA1C Zornitza Stark Classified gene: TUBA1C as Green List (high evidence)
Mendeliome v1.2651 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Mendeliome v1.2650 TUBA1C Zornitza Stark gene: TUBA1C was added
gene: TUBA1C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUBA1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBA1C were set to 39209701
Phenotypes for gene: TUBA1C were set to Oocyte/zygote/embryo maturation arrest 24, MIM# 621232
Review for gene: TUBA1C was set to GREEN
Added comment: New paper (biallelic variants for OZEMA)- i) PMID: 39209701- patients 1 and 2 from unrelated families with primary infertility experiencing recurrent preimplantation embryo development arrest (RPEA) carrying homozygous nonsense variant (p.Gln358Ter) and frameshift deletion variant (p.Tyr444Metfs*42), respectively. Transfection studies showed that both variants caused a significant decrease in the abundance of encoded proteins and abnormal cytoplasmic localisation manifested as localised protein aggregation.
Sources: Literature
Mendeliome v1.2649 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Congenital myopathy 26, MIM# 621225; Hereditary ataxia MONDO:0100309, TUBA4A-related to Congenital myopathy 26, MIM# 621225; Hereditary ataxia MONDO:0100309, TUBA4A-related; Oocyte/zygote/embryo maturation arrest 23, MIM# 621231
Mendeliome v1.2648 TUBA4A Zornitza Stark reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 23, MIM# 621231; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2648 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Congenital myopathy MONDO:0019952 to Congenital myopathy 26, MIM# 621225; Hereditary ataxia MONDO:0100309, TUBA4A-related
Mendeliome v1.2647 NAA60 Sangavi Sivagnanasundram reviewed gene: NAA60: Rating: ; Mode of pathogenicity: None; Publications: 38480682; Phenotypes: basal ganglia calcification, idiopathic, 9, autosomal recessive MONDO:0968977; Mode of inheritance: None
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram edited their review of gene: MYPN: Changed publications: 28017374, 28220527, 31133047, 18006477
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram changed review comment from: Comment for gene-disease association
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554; to: Comment for gene-disease association (addition of publications)
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
(PMID for myopathy: 28017374, 28220527, 31133047)

AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554
(PMID for DCM: 18006477)

AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram changed review comment from: Comment for gene-disease association
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554; to: Comment for gene-disease association
AR myopathy - Definitive classification by ClinGen: https://search.clinicalgenome.org/CCID:005552
AD HCM - DISPUTED classification by ClinGen: https://search.clinicalgenome.org/CCID:005553
AD DCM - Limited classification by ClinGen: https://search.clinicalgenome.org/CCID:005554
Mendeliome v1.2647 MYPN Sangavi Sivagnanasundram reviewed gene: MYPN: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: MYPN-related myopathy MONDO:0015023, dilated cardiomyopathy MONDO:0005021, hypertrophic cardiomyopathy MONDO:0005045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2647 HRURF Zornitza Stark Marked gene: HRURF as ready
Mendeliome v1.2647 HRURF Zornitza Stark Gene: hrurf has been classified as Green List (High Evidence).
Mendeliome v1.2647 HRURF Zornitza Stark Classified gene: HRURF as Green List (high evidence)
Mendeliome v1.2647 HRURF Zornitza Stark Gene: hrurf has been classified as Green List (High Evidence).
Mendeliome v1.2646 HRURF Zornitza Stark gene: HRURF was added
gene: HRURF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HRURF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HRURF were set to 39872230; 40433810; 37012647; 28406533; 26269244; 24961381
Phenotypes for gene: HRURF were set to Hypotrichosis 4, MIM# 146550
Review for gene: HRURF was set to GREEN
Added comment: More than 10 unrelated individuals reported.
Sources: Literature
Mendeliome v1.2645 KCNA6 Zornitza Stark Marked gene: KCNA6 as ready
Mendeliome v1.2645 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Mendeliome v1.2645 KCNA6 Zornitza Stark Classified gene: KCNA6 as Green List (high evidence)
Mendeliome v1.2645 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Mendeliome v1.2644 KCNA6 Zornitza Stark gene: KCNA6 was added
gene: KCNA6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNA6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA6 were set to 36318112; 40472070
Phenotypes for gene: KCNA6 were set to Developmental and epileptic encephalopathy, MONDO:0100620, KCNA6-related
Review for gene: KCNA6 was set to GREEN
Added comment: PMID 36318112: four individuals with de novo variants in this gene and NDD/epilepsy phenotype. Supportive functional data. Additional individual in PMID 40472070 with de novo variant and epilepsy.
Sources: Literature
Mendeliome v1.2643 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature

gnomAD and dgv gold frequency in insufficient.
Mendeliome v1.2643 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature
Mendeliome v1.2643 ANKS1B Monica Petica changed review comment from: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature; to: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) - reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature
Mendeliome v1.2643 ANKS1B Monica Petica gene: ANKS1B was added
gene: ANKS1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANKS1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKS1B were set to PMID: 31388001; 38129387
Phenotypes for gene: ANKS1B were set to Neurodevelopmental syndrome; developmental delay; speech delay; motor delay; autism; intellectual disability
Penetrance for gene: ANKS1B were set to unknown
Review for gene: ANKS1B was set to GREEN
Added comment: Complex neurodevelopmental features (especially developmental delay, speech delay and motor delay) appear to be associated with haploinsufficiency of this gene.

Carbonell (PMID: 31388001) reports deletions in seven families. Five of these families carry frameshift deletions predicted to undergo NMD. While there are two shorter transcripts for the gene (AIDA-1C and AIDA 1D), the short isoforms showed reduced transcription similarly to the long isoform (AIDA-1B, MANE NM_001352186.2) - as tested in probands compared to their mothers who were unaffected and not carriers of the deletions.

Hoon Cho (PMID: 38129387) - presents five additional ANKS1B deletion patients. They list the variants as multigenic although they appear to only affect ANKS1B. The patients are listed to have neurodevelopmental syndrome and white matter/corpus callosum abnormalities on MRI. One of the five carries a frameshift deletion (35 year old male). Note: the nine patients listed at the top of Figure 1 are from Carbonell. Paper includes supportive mouse studies.
Sources: Literature
Mendeliome v1.2643 ZBTB7B Zornitza Stark Marked gene: ZBTB7B as ready
Mendeliome v1.2643 ZBTB7B Zornitza Stark Gene: zbtb7b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2643 ZBTB7B Zornitza Stark Classified gene: ZBTB7B as Amber List (moderate evidence)
Mendeliome v1.2643 ZBTB7B Zornitza Stark Gene: zbtb7b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2642 ZBTB7B Zornitza Stark gene: ZBTB7B was added
gene: ZBTB7B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB7B were set to 40392549
Phenotypes for gene: ZBTB7B were set to Inborn error of immunity, MONDO:0003778, ZBTB7B-related
Review for gene: ZBTB7B was set to AMBER
Added comment: Single patient presented with a complex syndromic phenotype including CID, severe atopy, severe fibroinflammatory interstitial lung disease, corneal vascularization and scarring, sensorineural hearing loss, global developmental delay, and growth failure.

K360N variant is not found in unaffected individuals; functional investigations indicate that K360N exhibits damaging multimorphic effects; and the causal relationship between K360N and the clinical phenotype was confirmed through gene transfer experiments in both T cells and pulmonary fibroblasts.
Sources: Literature
Mendeliome v1.2641 TOP2B Zornitza Stark Publications for gene: TOP2B were set to 28343847; 31198993; 31409799; 12773624
Mendeliome v1.2640 TOP2B Zornitza Stark edited their review of gene: TOP2B: Added comment: PMID 33459963: patient with intermediate phenotype and a de novo inframe deletion at p.Glu587. This variant is absent in gnomad and located in the Toprim domain (DECIPHER, PMID: 33459963). Clinical presentation included moderate intellectual disability, focal epilepsy and failure to thrive. This individual also presented with dysmorphic features, distal limb abnormalities and B-cell immunodeficiency characteristic of the current OMIM associated phenotype (MIM#609296) which ClinGen has assessed as moderate.
Phenotype may be related to variant location but more cases needed to see whether phenotypes are distinct, representing multiple disease entities or a continuum.; Changed publications: 28343847, 31198993, 31409799, 12773624, 33459963
Mendeliome v1.2640 PTPN2 Zornitza Stark Phenotypes for gene: PTPN2 were changed from Lupus; arthritis; common variable immunodeficiency to Autoinflammatory syndrome of childhood, MONDO:0957018, PTPN2-related
Mendeliome v1.2639 PTPN2 Zornitza Stark Publications for gene: PTPN2 were set to 32499645; 27658548
Mendeliome v1.2638 PTPN2 Zornitza Stark Classified gene: PTPN2 as Green List (high evidence)
Mendeliome v1.2638 PTPN2 Zornitza Stark Gene: ptpn2 has been classified as Green List (High Evidence).
Mendeliome v1.2637 PTPN2 Zornitza Stark reviewed gene: PTPN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39028869; Phenotypes: Autoinflammatory syndrome of childhood, MONDO:0957018, PTPN2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2637 ARF1 Zornitza Stark Phenotypes for gene: ARF1 were changed from Periventricular nodular heterotopia 8, MIM# 618185 to Periventricular nodular heterotopia 8, MIM# 618185; Type 1 interferrinopathy of childhood, MONDO:0957408, ARF1 related
Mendeliome v1.2636 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862; 36345169
Mendeliome v1.2635 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862; 36345169
Mendeliome v1.2634 ARF1 Zornitza Stark changed review comment from: Three unrelated individuals reported with de novo missense in this gene.
Sources: Expert list; to: Three unrelated individuals reported with de novo missense in this gene and PVNH.
Sources: Expert list
Mendeliome v1.2634 ARF1 Zornitza Stark edited their review of gene: ARF1: Added comment: PMID 37914730: Three individuals presenting with skin lesions resembling chilblains reported with missense changes at the same amino acid position, R99. Two demonstrated to be de novo. Extensive functional data.; Changed publications: 28868155, 37914730; Changed phenotypes: Periventricular nodular heterotopia 8, MIM# 618185, Type 1 interferrinopathy of childhood, MONDO:0957408, ARF1 related
Mendeliome v1.2634 PTPN1 Zornitza Stark Marked gene: PTPN1 as ready
Mendeliome v1.2634 PTPN1 Zornitza Stark Gene: ptpn1 has been classified as Green List (High Evidence).
Mendeliome v1.2634 PTPN1 Zornitza Stark Classified gene: PTPN1 as Green List (high evidence)
Mendeliome v1.2634 PTPN1 Zornitza Stark Gene: ptpn1 has been classified as Green List (High Evidence).
Mendeliome v1.2633 PTPN1 Zornitza Stark gene: PTPN1 was added
gene: PTPN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 39986310
Phenotypes for gene: PTPN1 were set to Type 1 interferonopathy of childhood, MONDO:0957408, PTPN1-related
Review for gene: PTPN1 was set to GREEN
Added comment: 12 patients from 11 families with phenotype characterised by subacute loss of skills following initially normal development, spastic dystonia, bulbar involvement, preserved head circumference, and an absence of seizures. The observation of enhanced type 1 IFN signalling in patient blood and CSF, and of increased levels of CSF neopterin suggests that PTPN1 haploinsufficiency can be classified as a novel type 1 interferonopathy. Features apparently distinguishing PTP1B-related encephalopathy from Aicardi-Goutières syndrome are a later age at onset (nine of 12 cases in cohort presenting beyond 18 months of age), notable bulbar involvement manifesting as difficulties with swallowing and expressive speech, and cerebral atrophy as the predominant neuroradiological sign.
Sources: Literature
Mendeliome v1.2632 WSB2 Krithika Murali Marked gene: WSB2 as ready
Mendeliome v1.2632 WSB2 Krithika Murali Gene: wsb2 has been classified as Green List (High Evidence).
Mendeliome v1.2632 WSB2 Krithika Murali Classified gene: WSB2 as Green List (high evidence)
Mendeliome v1.2632 WSB2 Krithika Murali Gene: wsb2 has been classified as Green List (High Evidence).
Mendeliome v1.2631 WSB2 Krithika Murali gene: WSB2 was added
gene: WSB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to PMID:40374945
Phenotypes for gene: WSB2 were set to Complex neurodevelopmental disorder, MONDO:0100038, WSB2-related
Review for gene: WSB2 was set to GREEN
Added comment: PMID: 40374945 describe 5 individuals from 4 unrelated families with biallelic WSB2 variants and a complex neurodevelopmental disorder. Phenotypic features include:
- Dev delay (all)
- Brain anomalies (4/5 including callosal anomalies and cerebellar hypoplasia)
- Dysmorphic feature
- IUGR/oligohydramnios (3/5)
- Hypotonia (all)
- Microcephaly (3/5)
- Seizures (3/5)

Includes two siblings with biallelic missense variants and shared phenotype. 3 unaffected siblings were heterozygous for the variant or hmz wt. Phenotypic features associated with hmz nonsense/fs variants were more severe than missense.

Supportive mouse model.
Sources: Literature
Mendeliome v1.2630 NKAP Zornitza Stark Mode of inheritance for gene: NKAP was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2629 PTPRB Bryony Thompson Marked gene: PTPRB as ready
Mendeliome v1.2629 PTPRB Bryony Thompson Gene: ptprb has been classified as Red List (Low Evidence).
Mendeliome v1.2629 PTPRB Bryony Thompson gene: PTPRB was added
gene: PTPRB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPRB was set to Unknown
Publications for gene: PTPRB were set to 40319023
Phenotypes for gene: PTPRB were set to central serous chorioretinopathy; varicose veins; glaucoma
Review for gene: PTPRB was set to RED
Added comment: A single risk allele (rs113791087 - missense) associated with the risk of central serous chorioretinopathy, varicose veins and glaucoma (reduced risk). Not associated with Mendelian disease.
Sources: Literature
Mendeliome v1.2628 OSM Bryony Thompson Marked gene: OSM as ready
Mendeliome v1.2628 OSM Bryony Thompson Gene: osm has been classified as Green List (High Evidence).
Mendeliome v1.2628 OSM Bryony Thompson Classified gene: OSM as Green List (high evidence)
Mendeliome v1.2628 OSM Bryony Thompson Gene: osm has been classified as Green List (High Evidence).
Mendeliome v1.2627 OSM Bryony Thompson gene: OSM was added
gene: OSM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OSM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSM were set to 39847438; 40309776; 17118758
Phenotypes for gene: OSM were set to bone marrow failure syndrome MONDO:0000159
Review for gene: OSM was set to GREEN
Added comment: 6 individuals with with OSM deficiency and an inherited severe bone marrow failure syndrome from 3 consanguineous families with 2 different homozygous LoF variants. Supporting zebrafish and mouse models.
Sources: Literature
Mendeliome v1.2626 RREB1 Zornitza Stark Publications for gene: RREB1 were set to 32938917; 38332451
Mendeliome v1.2625 TAF1C Zornitza Stark Classified gene: TAF1C as Green List (high evidence)
Mendeliome v1.2625 TAF1C Zornitza Stark Gene: taf1c has been classified as Green List (High Evidence).
Mendeliome v1.2624 GALNT14 Zornitza Stark Marked gene: GALNT14 as ready
Mendeliome v1.2624 GALNT14 Zornitza Stark Gene: galnt14 has been classified as Red List (Low Evidence).
Mendeliome v1.2624 GALNT14 Zornitza Stark gene: GALNT14 was added
gene: GALNT14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GALNT14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GALNT14 were set to 40153534
Phenotypes for gene: GALNT14 were set to IgA Nephropathy, susceptibility to, MONDO:0100555, GALNT14-related
Review for gene: GALNT14 was set to RED
Added comment: LoF variant identified in large pedigree, including 6 affected individuals. Also found in 3 unaffected relatives. Supportive mouse model.
Sources: Literature
Mendeliome v1.2623 FAAP100 Zornitza Stark Marked gene: FAAP100 as ready
Mendeliome v1.2623 FAAP100 Zornitza Stark Gene: faap100 has been classified as Green List (High Evidence).
Mendeliome v1.2623 FAAP100 Zornitza Stark Classified gene: FAAP100 as Green List (high evidence)
Mendeliome v1.2623 FAAP100 Zornitza Stark Gene: faap100 has been classified as Green List (High Evidence).
Mendeliome v1.2622 FAAP100 Zornitza Stark gene: FAAP100 was added
gene: FAAP100 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAAP100 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAAP100 were set to 40244696; 40232843
Phenotypes for gene: FAAP100 were set to Fanconi anaemia, MONDO:0019391, FAAP100-related
Review for gene: FAAP100 was set to GREEN
Added comment: PMID 40244696: reports two families with homozygous LoF variants. First family had 6 pregnancy losses and two infants with a severe phenotype characterised by multiple congenital anomalies. Second family had one liveborn child with multiple anomalies and a termination of pregnancy for multiple congenital anomalies. Supportive functional data. Third family reported in PMID 40232843, homozygous missense variant in a fetus with multiple congenital anomalies suggestive of FA. Functional data.
Sources: Literature
Mendeliome v1.2621 TM2D3 Zornitza Stark Marked gene: TM2D3 as ready
Mendeliome v1.2621 TM2D3 Zornitza Stark Gene: tm2d3 has been classified as Green List (High Evidence).
Mendeliome v1.2621 TM2D3 Zornitza Stark Classified gene: TM2D3 as Green List (high evidence)
Mendeliome v1.2621 TM2D3 Zornitza Stark Gene: tm2d3 has been classified as Green List (High Evidence).
Mendeliome v1.2620 TM2D3 Zornitza Stark gene: TM2D3 was added
gene: TM2D3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to Neurodevelopmental disorder, MONDO:0700092, TM2D3-related
Review for gene: TM2D3 was set to GREEN
Added comment: Four individuals from 4 unrelated families identified with biallelic variants in this gene. Supportive functional data.
Sources: Literature
Mendeliome v1.2619 SLK Zornitza Stark Marked gene: SLK as ready
Mendeliome v1.2619 SLK Zornitza Stark Gene: slk has been classified as Green List (High Evidence).
Mendeliome v1.2619 SLK Zornitza Stark Classified gene: SLK as Green List (high evidence)
Mendeliome v1.2619 SLK Zornitza Stark Gene: slk has been classified as Green List (High Evidence).
Mendeliome v1.2618 SLK Zornitza Stark gene: SLK was added
gene: SLK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLK were set to 40347834
Phenotypes for gene: SLK were set to Neurodevelopmental disorder, MONDO:0700092, SLK-related
Review for gene: SLK was set to GREEN
Added comment: Three affected individuals from three unrelated families reported. Two of the families were consanguineous and homozygous LoF variants were present in the probands. Third individual had compound het missense variants. Functional data from a Drosophila model and transdifferentiated neurons.
Sources: Literature
Mendeliome v1.2617 ERBB2 Bryony Thompson Mode of inheritance for gene: ERBB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2616 ERBB2 Bryony Thompson Publications for gene: ERBB2 were set to
Mendeliome v1.2615 ERBB2 Bryony Thompson Phenotypes for gene: ERBB2 were changed from Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465 to Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465; Congenital heart disease - left ventricular outflow tract obstruction defects; MONDO:0005453
Mendeliome v1.2614 ERBB2 Bryony Thompson Mode of inheritance for gene: ERBB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2613 ERBB2 Bryony Thompson Classified gene: ERBB2 as Amber List (moderate evidence)
Mendeliome v1.2613 ERBB2 Bryony Thompson Gene: erbb2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2612 ERBB2 Eleanor Ludington reviewed gene: ERBB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 40329538; Phenotypes: Congenital heart disease - left ventricular outflow tract obstruction defects, MONDO:0005453; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2612 TAF1C Sangavi Sivagnanasundram edited their review of gene: TAF1C: Changed phenotypes: complex neurodevelopmental disorder, TAF1C-related, MONDO:0100038
Mendeliome v1.2612 TAF1C Sangavi Sivagnanasundram reviewed gene: TAF1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 40371665; Phenotypes: complex neurodevelopmental disorder, TAF1C-realted, MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2612 RREB1 Chirag Patel Classified gene: RREB1 as Green List (high evidence)
Mendeliome v1.2612 RREB1 Chirag Patel Gene: rreb1 has been classified as Green List (High Evidence).
Mendeliome v1.2611 RREB1 Chirag Patel reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40418122; Phenotypes: Rasopathy, MONDO:0021060, RREB1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2611 LEF1 Zornitza Stark Phenotypes for gene: LEF1 were changed from Syndromic disease, MONDO:0002254, LEF1-related to Ectodermal dysplasia 17 with or without limb malformations, MIM# 621224
Mendeliome v1.2610 LEF1 Zornitza Stark edited their review of gene: LEF1: Changed phenotypes: Ectodermal dysplasia 17 with or without limb malformations, MIM# 621224
Mendeliome v1.2610 GON4L Zornitza Stark reviewed gene: GON4L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Li-Takada-Miyake syndrome, MIM# 621212; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2610 GON4L Zornitza Stark Phenotypes for gene: GON4L were changed from complex neurodevelopmental disorder MONDO:0100038 to Li-Takada-Miyake syndrome, MIM# 621212
Mendeliome v1.2609 NKAP Elena Savva Mode of inheritance for gene: NKAP was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.2608 NKAP Elena Savva Phenotypes for gene: NKAP were changed from Intellectual disability to intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, MONDO:0026733, MIM#301039
Mendeliome v1.2607 NKAP Elena Savva Mode of inheritance for gene: NKAP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2606 FBXL7 Bryony Thompson Phenotypes for gene: FBXL7 were changed from Hennekam lymphangiectasia-lymphedema syndrome to Hennekam lymphangiectasia-lymphedema syndrome MONDO:0016256
Mendeliome v1.2605 FAAH2 Bryony Thompson Phenotypes for gene: FAAH2 were changed from to autism spectrum disorder MONDO:0005258
Mendeliome v1.2604 ESRP2 Bryony Thompson Phenotypes for gene: ESRP2 were changed from Cleft lip to Orofacial cleft MONDO:0000358
Mendeliome v1.2603 ERGIC3 Bryony Thompson Phenotypes for gene: ERGIC3 were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2602 ADAM10 Bryony Thompson Marked gene: ADAM10 as ready
Mendeliome v1.2602 ADAM10 Bryony Thompson Gene: adam10 has been classified as Green List (High Evidence).
Mendeliome v1.2602 ADAM10 Bryony Thompson Classified gene: ADAM10 as Green List (high evidence)
Mendeliome v1.2602 ADAM10 Bryony Thompson Gene: adam10 has been classified as Green List (High Evidence).
Mendeliome v1.2601 ADAM10 Bryony Thompson gene: ADAM10 was added
gene: ADAM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADAM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAM10 were set to 23666529; 30488468
Phenotypes for gene: ADAM10 were set to reticulate acropigmentation of Kitamura MONDO:0014234
Review for gene: ADAM10 was set to GREEN
Added comment: Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation. >5 families have been reported. Loss of function is the reported mechanism of disease.
Sources: Literature
Mendeliome v1.2600 IKBKG Bryony Thompson Tag technically challenging tag was added to gene: IKBKG.
Mendeliome v1.2600 MYCBP2 Zornitza Stark Classified gene: MYCBP2 as Red List (low evidence)
Mendeliome v1.2600 MYCBP2 Zornitza Stark Gene: mycbp2 has been classified as Red List (Low Evidence).
Mendeliome v1.2599 MYCBP2 Zornitza Stark reviewed gene: MYCBP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, MYCBP2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2599 DNAH12 Zornitza Stark Marked gene: DNAH12 as ready
Mendeliome v1.2599 DNAH12 Zornitza Stark Gene: dnah12 has been classified as Green List (High Evidence).
Mendeliome v1.2599 DNAH12 Zornitza Stark Classified gene: DNAH12 as Green List (high evidence)
Mendeliome v1.2599 DNAH12 Zornitza Stark Gene: dnah12 has been classified as Green List (High Evidence).
Mendeliome v1.2598 DNAH12 Zornitza Stark gene: DNAH12 was added
gene: DNAH12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH12 were set to 39071892; 40146200
Phenotypes for gene: DNAH12 were set to Spermatogenic failure 100, MIM# 621209
Review for gene: DNAH12 was set to GREEN
Added comment: Twelve individuals from 7 families and two mouse models support this association
Sources: Literature
Mendeliome v1.2597 BBIP1 Zornitza Stark Classified gene: BBIP1 as Green List (high evidence)
Mendeliome v1.2597 BBIP1 Zornitza Stark Gene: bbip1 has been classified as Green List (High Evidence).
Mendeliome v1.2596 BBIP1 Zornitza Stark edited their review of gene: BBIP1: Added comment: Third family with homozygous LoF variant reported; Changed rating: GREEN; Changed publications: 24026985, 32055034, 37239474
Mendeliome v1.2596 FAM177A1 Zornitza Stark Phenotypes for gene: FAM177A1 were changed from Neurodevelopmental disorder, MONDO_0100500, FAM177A1-related to Neurodevelopmental disorder with white matter abnormalities and gait disturbance, MIM# 621152
Mendeliome v1.2595 FAM177A1 Zornitza Stark reviewed gene: FAM177A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with white matter abnormalities and gait disturbance, MIM# 621152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2595 GTF3C3 Zornitza Stark Phenotypes for gene: GTF3C3 were changed from Neurodevelopmental disorder MONDO:0700092, GTF3C3-related to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MIM# 621201
Mendeliome v1.2594 GTF3C3 Zornitza Stark edited their review of gene: GTF3C3: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MIM# 621201
Mendeliome v1.2594 PTPMT1 Zornitza Stark Phenotypes for gene: PTPMT1 were changed from inborn mitochondrial metabolism disorder MONDO:0004069 to Neurodevelopmental disorder with ataxia and brain abnormalities, MIM# 621199
Mendeliome v1.2593 PTPMT1 Zornitza Stark reviewed gene: PTPMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with ataxia and brain abnormalities, MIM# 621199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2593 WNT3 Zornitza Stark commented on gene: WNT3: LIMITED by ClinGen.
Mendeliome v1.2593 PPP2R5C Zornitza Stark Phenotypes for gene: PPP2R5C were changed from Neurodevelopmental disorder, PPP2R5C-related (MONDO:070092); macrocephaly; intellectual disability to Houge-Janssens syndrome 4, MIM# 621185
Mendeliome v1.2592 PPP2R5C Zornitza Stark reviewed gene: PPP2R5C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Houge-Janssens syndrome 4, MIM# 621185; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2592 SCO2 Zornitza Stark Mode of inheritance for gene: SCO2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2591 MMAB Sangavi Sivagnanasundram reviewed gene: MMAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 24813872; Phenotypes: methylmalonic aciduria, cblB type MONDO:0009614; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2591 SEPT4 Zornitza Stark reviewed gene: SEPT4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 99, MIM# 621194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2591 ABCC8 Zornitza Stark Phenotypes for gene: ABCC8 were changed from Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800 to Maturity-onset diabetes of the young, type 12, MIM# 621196; Diabetes mellitus, noninsulin-dependent MIM#125853; Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Diabetes mellitus, transient neonatal 2 MIM#610374; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450; Hypoglycemia of infancy, leucine-sensitive MIM#240800
Mendeliome v1.2590 MRPL49 Zornitza Stark Phenotypes for gene: MRPL49 were changed from Mitochondrial disease, MONDO:0044970, MRPL49-related to Combined oxidative phosphorylation deficiency 60, MIM# 621195
Mendeliome v1.2589 MRPL49 Zornitza Stark edited their review of gene: MRPL49: Changed phenotypes: Combined oxidative phosphorylation deficiency 60, MIM# 621195
Mendeliome v1.2589 IDH3G Zornitza Stark Phenotypes for gene: IDH3G were changed from X-linked retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa 99, MIM# 301148
Mendeliome v1.2588 IDH3G Zornitza Stark reviewed gene: IDH3G: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 99, MIM# 301148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2588 MAN2B1 Sangavi Sivagnanasundram reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18651971, 9158146, 9758606, 9915946, 22161967; Phenotypes: alpha-mannosidosis MONDO:0009561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LYST Sangavi Sivagnanasundram edited their review of gene: LYST: Changed publications: 8896560, 9215680, 31906877, 9215679, 26499269, 24112114, 28145517
Mendeliome v1.2588 LYST Sangavi Sivagnanasundram reviewed gene: LYST: Rating: GREEN; Mode of pathogenicity: None; Publications: 8896560, 9215680, 31906877, 9215679, 26499269, 24112114, 28145517); Phenotypes: Chediak-Higashi syndrome MONDO:0008963; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LYRM7 Sangavi Sivagnanasundram reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24014394, 26912632; Phenotypes: mitochondrial disease, LYRM7-related MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LPAR6 Sangavi Sivagnanasundram reviewed gene: LPAR6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18297072, 18297070, 18461368; Phenotypes: LPAR6-related hypotrichosis/woolly hair with or without hypotrichosis, MONDO:MONDO:0800312; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2588 LSM1 Zornitza Stark Phenotypes for gene: LSM1 were changed from Neurodevelopmental disorder, MONDO:0700092, LSM1-related to FICUS syndrome, MIM# 621193
Mendeliome v1.2587 LSM1 Zornitza Stark edited their review of gene: LSM1: Changed phenotypes: FICUS syndrome, MIM# 621193
Mendeliome v1.2587 CERS1 Zornitza Stark Marked gene: CERS1 as ready
Mendeliome v1.2587 CERS1 Zornitza Stark Gene: cers1 has been classified as Green List (High Evidence).
Mendeliome v1.2587 CERS1 Zornitza Stark Classified gene: CERS1 as Green List (high evidence)
Mendeliome v1.2587 CERS1 Zornitza Stark Gene: cers1 has been classified as Green List (High Evidence).
Mendeliome v1.2586 DBF4 Zornitza Stark Marked gene: DBF4 as ready
Mendeliome v1.2586 DBF4 Zornitza Stark Gene: dbf4 has been classified as Red List (Low Evidence).
Mendeliome v1.2586 DBF4 Zornitza Stark Classified gene: DBF4 as Red List (low evidence)
Mendeliome v1.2586 DBF4 Zornitza Stark Gene: dbf4 has been classified as Red List (Low Evidence).
Mendeliome v1.2585 GINS4 Zornitza Stark Marked gene: GINS4 as ready
Mendeliome v1.2585 GINS4 Zornitza Stark Gene: gins4 has been classified as Red List (Low Evidence).
Mendeliome v1.2585 GINS4 Zornitza Stark Classified gene: GINS4 as Red List (low evidence)
Mendeliome v1.2585 GINS4 Zornitza Stark Gene: gins4 has been classified as Red List (Low Evidence).
Mendeliome v1.2584 ARSI Zornitza Stark Marked gene: ARSI as ready
Mendeliome v1.2584 ARSI Zornitza Stark Gene: arsi has been classified as Red List (Low Evidence).
Mendeliome v1.2584 ARSI Zornitza Stark Classified gene: ARSI as Red List (low evidence)
Mendeliome v1.2584 ARSI Zornitza Stark Gene: arsi has been classified as Red List (Low Evidence).
Mendeliome v1.2583 ADGRB3 Zornitza Stark Marked gene: ADGRB3 as ready
Mendeliome v1.2583 ADGRB3 Zornitza Stark Gene: adgrb3 has been classified as Red List (Low Evidence).
Mendeliome v1.2583 ADGRB3 Zornitza Stark Classified gene: ADGRB3 as Red List (low evidence)
Mendeliome v1.2583 ADGRB3 Zornitza Stark Gene: adgrb3 has been classified as Red List (Low Evidence).
Mendeliome v1.2582 BRCC3 Zornitza Stark Marked gene: BRCC3 as ready
Mendeliome v1.2582 BRCC3 Zornitza Stark Gene: brcc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2582 BRCC3 Zornitza Stark Classified gene: BRCC3 as Amber List (moderate evidence)
Mendeliome v1.2582 BRCC3 Zornitza Stark Gene: brcc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2581 BRCC3 Zornitza Stark Tag SV/CNV tag was added to gene: BRCC3.
Mendeliome v1.2581 SH3BP4 Zornitza Stark Marked gene: SH3BP4 as ready
Mendeliome v1.2581 SH3BP4 Zornitza Stark Gene: sh3bp4 has been classified as Red List (Low Evidence).
Mendeliome v1.2581 SH3BP4 Zornitza Stark Classified gene: SH3BP4 as Red List (low evidence)
Mendeliome v1.2581 SH3BP4 Zornitza Stark Gene: sh3bp4 has been classified as Red List (Low Evidence).
Mendeliome v1.2580 WDR48 Zornitza Stark Marked gene: WDR48 as ready
Mendeliome v1.2580 WDR48 Zornitza Stark Gene: wdr48 has been classified as Red List (Low Evidence).
Mendeliome v1.2580 WDR48 Zornitza Stark Classified gene: WDR48 as Red List (low evidence)
Mendeliome v1.2580 WDR48 Zornitza Stark Gene: wdr48 has been classified as Red List (Low Evidence).
Mendeliome v1.2579 SNRPA Zornitza Stark Marked gene: SNRPA as ready
Mendeliome v1.2579 SNRPA Zornitza Stark Gene: snrpa has been classified as Red List (Low Evidence).
Mendeliome v1.2579 SNRPA Zornitza Stark Classified gene: SNRPA as Red List (low evidence)
Mendeliome v1.2579 SNRPA Zornitza Stark Gene: snrpa has been classified as Red List (Low Evidence).
Mendeliome v1.2578 ZFR Zornitza Stark Marked gene: ZFR as ready
Mendeliome v1.2578 ZFR Zornitza Stark Gene: zfr has been classified as Red List (Low Evidence).
Mendeliome v1.2578 ZFR Zornitza Stark Classified gene: ZFR as Red List (low evidence)
Mendeliome v1.2578 ZFR Zornitza Stark Gene: zfr has been classified as Red List (Low Evidence).
Mendeliome v1.2577 ZNF674 Zornitza Stark Marked gene: ZNF674 as ready
Mendeliome v1.2577 ZNF674 Zornitza Stark Gene: znf674 has been classified as Red List (Low Evidence).
Mendeliome v1.2577 ZNF674 Zornitza Stark Classified gene: ZNF674 as Red List (low evidence)
Mendeliome v1.2577 ZNF674 Zornitza Stark Gene: znf674 has been classified as Red List (Low Evidence).
Mendeliome v1.2576 ZNF674 Zornitza Stark Tag disputed tag was added to gene: ZNF674.
Mendeliome v1.2576 FAAHP1 Zornitza Stark Marked gene: FAAHP1 as ready
Mendeliome v1.2576 FAAHP1 Zornitza Stark Gene: faahp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2576 FAAHP1 Zornitza Stark Classified gene: FAAHP1 as Red List (low evidence)
Mendeliome v1.2576 FAAHP1 Zornitza Stark Gene: faahp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2575 ERN1 Zornitza Stark Marked gene: ERN1 as ready
Mendeliome v1.2575 ERN1 Zornitza Stark Gene: ern1 has been classified as Red List (Low Evidence).
Mendeliome v1.2575 ERN1 Zornitza Stark Classified gene: ERN1 as Red List (low evidence)
Mendeliome v1.2575 ERN1 Zornitza Stark Gene: ern1 has been classified as Red List (Low Evidence).
Mendeliome v1.2574 AGXT2 Zornitza Stark Marked gene: AGXT2 as ready
Mendeliome v1.2574 AGXT2 Zornitza Stark Gene: agxt2 has been classified as Red List (Low Evidence).
Mendeliome v1.2574 AGXT2 Zornitza Stark Classified gene: AGXT2 as Red List (low evidence)
Mendeliome v1.2574 AGXT2 Zornitza Stark Gene: agxt2 has been classified as Red List (Low Evidence).
Mendeliome v1.2573 SLC29A1 Zornitza Stark Marked gene: SLC29A1 as ready
Mendeliome v1.2573 SLC29A1 Zornitza Stark Gene: slc29a1 has been classified as Red List (Low Evidence).
Mendeliome v1.2573 SLC29A1 Zornitza Stark Classified gene: SLC29A1 as Red List (low evidence)
Mendeliome v1.2573 SLC29A1 Zornitza Stark Gene: slc29a1 has been classified as Red List (Low Evidence).
Mendeliome v1.2572 PLK1 Zornitza Stark Phenotypes for gene: PLK1 were changed from Epilepsy; microcephaly; intellectual disability to Neurodevelopmental disorder, PLK1-related, MONDO:0700092
Mendeliome v1.2571 PLOD3 Zornitza Stark Phenotypes for gene: PLOD3 were changed from to Lysyl hydroxylase 3 deficiency, MIM#612394; Bone fragility with contractures, arterial rupture, and deafness (BCARD syndrome) MONDO:0012892
Mendeliome v1.2570 PLOD3 Zornitza Stark Publications for gene: PLOD3 were set to
Mendeliome v1.2569 PLXNA2 Zornitza Stark Phenotypes for gene: PLXNA2 were changed from Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology to Complex neurodevelopmental disorder, PLXNA2-related, MONDO:0100038
Mendeliome v1.2568 RECQL Zornitza Stark Phenotypes for gene: RECQL were changed from Photosensitivity; facial dysmorphism; xeropthalmia; skeletal abnormalities to RECON progeroid syndrome MONDO:0957266
Mendeliome v1.2567 RFX3 Zornitza Stark Phenotypes for gene: RFX3 were changed from ID, ASD, ADHD to RFX3-related neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2566 RFX4 Zornitza Stark Phenotypes for gene: RFX4 were changed from ID, ASD, ADHD to RFX4-related neurodevelopmental disorder, MONDO:0700092
Mendeliome v1.2565 ROBO4 Zornitza Stark Publications for gene: ROBO4 were set to 30455415; 32748548
Mendeliome v1.2564 ROBO4 Rylee Peters reviewed gene: ROBO4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36855159; Phenotypes: Aortic valve disease 8 MIM#618496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2564 AMOTL1 Zornitza Stark Phenotypes for gene: AMOTL1 were changed from Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related to Craniofaciocardiohepatic syndrome, MIM# 621192
Mendeliome v1.2563 AMOTL1 Zornitza Stark edited their review of gene: AMOTL1: Changed phenotypes: Craniofaciocardiohepatic syndrome, MIM# 621192
Mendeliome v1.2563 LSM7 Zornitza Stark Phenotypes for gene: LSM7 were changed from leukodystrophy MONDO:0019046, LRM7-related to Leukodystrophy and cerebellar atrophy, MIM# 621191
Mendeliome v1.2562 LSM7 Zornitza Stark reviewed gene: LSM7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy and cerebellar atrophy, MIM# 621191; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2562 RFX4 Sangavi Sivagnanasundram reviewed gene: RFX4: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RFX4-related neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: None
Mendeliome v1.2562 RFX3 Sangavi Sivagnanasundram reviewed gene: RFX3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RFX3-related neurodevelopmental disorder MONDO:0700092; Mode of inheritance: None
Mendeliome v1.2562 RECQL Sangavi Sivagnanasundram reviewed gene: RECQL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: RECON progeroid syndrome MONDO:0957266; Mode of inheritance: None
Mendeliome v1.2562 PYCR1 Sangavi Sivagnanasundram reviewed gene: PYCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive cutis laxa type 2B MONDO:0013051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2562 PLXNA2 Sangavi Sivagnanasundram reviewed gene: PLXNA2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Complex neurodevelopmental disorder, PLXNA2-related, MONDO:0100038; Mode of inheritance: None
Mendeliome v1.2562 PLOD3 Sangavi Sivagnanasundram reviewed gene: PLOD3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Bone fragility with contractures, arterial rupture, and deafness (BCARD syndrome) MONDO:0012892; Mode of inheritance: None
Mendeliome v1.2562 PLK1 Sangavi Sivagnanasundram reviewed gene: PLK1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, PLK1-related, MONDO:0700092; Mode of inheritance: None
Mendeliome v1.2562 SLC29A1 Sangavi Sivagnanasundram edited their review of gene: SLC29A1: Changed rating: RED
Mendeliome v1.2562 SLC29A1 Sangavi Sivagnanasundram gene: SLC29A1 was added
gene: SLC29A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC29A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC29A1 were set to 35955904; 25896650
Phenotypes for gene: SLC29A1 were set to Disorders of ectonucleotide and nucleic acid metabolism; Equilibrative nucleoside transporter 1 deficiency MONDO:0019052
Review for gene: SLC29A1 was set to AMBER
Added comment: This gene-disease association is an inborn error of metabolism known as disorders of ectonucleotide and nucleic acid metabolism. More evidence is required to support the gene-disease association. - https://iembase.com/disorder/783

PMID: 35955904
Homozygous Glu391Lys responsible for the A-negative blood time in people of African ancestry however is not shown to alter the protein function. Affected individuals will likely not have any phenotypes except the A- blood type. Missense variant is present in gnomAD v4.1 (GrpMax FAF - 1.159% in African/African American Population)

PMID: 25896650
3 sibs of European ancestry identified with homozygous c.589+1G>C (rare on gnomAD v4.1 for AR gene)
No severe phenotype was observed however periarticular and ectopic mineralization was observed which important regarding bone homeostasis.
Sources: Literature
Mendeliome v1.2562 AGXT2 Sangavi Sivagnanasundram gene: AGXT2 was added
gene: AGXT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGXT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGXT2 were set to 21572414
Phenotypes for gene: AGXT2 were set to beta-aminoisobutyric acid, urinary excretion of MONDO:0008860
Review for gene: AGXT2 was set to RED
Added comment: This gene-disease association needs further evidence to support pathogenicity.

PMID: 21572414
GWAS study identified common SNP (V140I - https://gnomad.broadinstitute.org/variant/5-35037010-C-T?dataset=gnomad_r4) showing the strongest association with BAIB in the present study.
Sources: Literature
Mendeliome v1.2562 ERN1 Sangavi Sivagnanasundram gene: ERN1 was added
gene: ERN1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ERN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ERN1 were set to Immune Dysregulation, MONDO:0005046
Review for gene: ERN1 was set to RED
Added comment: No new evidence to support gene-disease association. Review copied from Disorders of immune dysregulation Panel:
"On the IUIS 2024 update for IEIs as a gene associated with an AD disease of immune dysregulation, I cannot find any evidence of Mendelian disease."
Sources: Expert Review
Mendeliome v1.2562 FAAHP1 Sangavi Sivagnanasundram gene: FAAHP1 was added
gene: FAAHP1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FAAHP1 was set to Unknown
Publications for gene: FAAHP1 were set to 30929760
Phenotypes for gene: FAAHP1 were set to Pain insensitivity
Review for gene: FAAHP1 was set to RED
Added comment: Review from Pain Syndromes Panel:
"This is a pseudogene. A single case with pain insensitivity has been reported with co-inheritance of a microdeletion in dorsal root ganglia and brain-expressed pseudogene and a common functional SNP in FAAH (rs324420 ) conferring reduced expression and activity."
Sources: Expert Review
Mendeliome v1.2562 ZNF674 Sangavi Sivagnanasundram gene: ZNF674 was added
gene: ZNF674 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZNF674 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZNF674 were set to https://search.clinicalgenome.org/CCID:006588
Phenotypes for gene: ZNF674 were set to X-linked intellectual disability MONDO:0100284
Review for gene: ZNF674 was set to RED
Added comment: Classified DISPUTED by ClinGen ID and Autism GCEP on 04/05/2021 - https://search.clinicalgenome.org/CCID:006588
Sources: Expert Review
Mendeliome v1.2562 ZFR Sangavi Sivagnanasundram gene: ZFR was added
gene: ZFR was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFR were set to 24482476
Phenotypes for gene: ZFR were set to hereditary spastic paraplegia, MONDO:0019064
Review for gene: ZFR was set to RED
Added comment: No new proband/evidence supporting gene-disease association.

Review copied from HSP paediatric panel:
"A single family reported with a homozygous variant."
Sources: Expert Review
Mendeliome v1.2562 SNRPA Sangavi Sivagnanasundram gene: SNRPA was added
gene: SNRPA was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SNRPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNRPA were set to 29437235
Phenotypes for gene: SNRPA were set to complex neurodevelopmental disorder, SNRPA-related MONDO:0100038
Review for gene: SNRPA was set to RED
Added comment: No new reported probands supporting the gene-disease association.

Review copied from ID panel:
"1 report of concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in 2 female siblings with 3 homozygous missense variants in SNRPA. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. No functional studies."
Sources: Expert Review
Mendeliome v1.2562 WDR48 Sangavi Sivagnanasundram gene: WDR48 was added
gene: WDR48 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: WDR48 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR48 were set to 24482476
Phenotypes for gene: WDR48 were set to Hereditary spastic paraplegia MONDO:0015150
Review for gene: WDR48 was set to RED
Added comment: Gene Reviews - https://www.ncbi.nlm.nih.gov/books/NBK1509/
SPG60 - paediatric onset of complex HSP.
Polyneuropathy and DD are the typical onset of symptoms

No new reported probands - review copied from HSP paediatric panel:
"A single family reported with a homozygous in-frame deletion."
Sources: Expert Review
Mendeliome v1.2562 SH3BP4 Sangavi Sivagnanasundram gene: SH3BP4 was added
gene: SH3BP4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SH3BP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SH3BP4 were set to 24627108
Phenotypes for gene: SH3BP4 were set to Peripheral neuropathy, MONDO:0005244
Review for gene: SH3BP4 was set to RED
Added comment: No new information supportive of gene-disease association.

Review copied from Hereditary Neuropathy_CMT - isolated Panel:
"A single family reported with inherited peripheral neuropathy, with no functional analyses."
Sources: Expert Review
Mendeliome v1.2562 BRCC3 Sangavi Sivagnanasundram gene: BRCC3 was added
gene: BRCC3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: BRCC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: BRCC3 were set to 21596366; 33868155; 35815106; 39552268
Phenotypes for gene: BRCC3 were set to MoyaMoya Disease, syndromic, MONDO:0016820
Review for gene: BRCC3 was set to AMBER
Added comment: The same common ~26kb Xq28 deletion was identified in all affected individuals below. No other evidence of any SNVs.

Additional probands with MoyaMoya:
PMID: 35815106 & 39552268
Two unrelated individuals with MoyaMoya and other neurodevelopmental features.
A hemizygous ~26kb Xq28 deletion was identified in both individuals

------------------------------
Review from CVM panel:
“PMID 21596366: three unrelated families with multiple affected males segregating a deletion involving MTCP1 and BRCC3. Positional approach used. Supportive zebrafish model, knockdown of BRCC3; angiogenesis affected.

PMID 33868155, additional report of affected male, with similar deletion.

No reports of SNVs identified, including in ClinVar.”
Sources: Expert Review
Mendeliome v1.2562 ADGRB3 Sangavi Sivagnanasundram gene: ADGRB3 was added
gene: ADGRB3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ADGRB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADGRB3 were set to 30659260; 18628273
Phenotypes for gene: ADGRB3 were set to Intellectual disability MONDO:0001071
Review for gene: ADGRB3 was set to RED
Added comment: No new information supportive of gene-disease association. Review copied from ID panel:

"Single family with intragenic bi-allelic duplications and ID reported; association studies with schizophrenia."
Sources: Expert Review
Mendeliome v1.2562 ARSI Sangavi Sivagnanasundram gene: ARSI was added
gene: ARSI was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ARSI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSI were set to 24482476
Phenotypes for gene: ARSI were set to Complex spastic paraplegia, MONDO:0015150
Review for gene: ARSI was set to RED
Added comment: No new information supporting gene-disease association.

Review from HSP paediatric panel - "Single family reported"
Sources: Expert Review
Mendeliome v1.2562 GINS4 Sangavi Sivagnanasundram gene: GINS4 was added
gene: GINS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: GINS4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS4 were set to 36345943
Phenotypes for gene: GINS4 were set to combined immunodeficiency MONDO:0015131
Review for gene: GINS4 was set to RED
Added comment: No further information has been published to support the gene-disease association.

Review copied from Combined Immunodeficiency panel:
"2 affected siblings with compound het variants are reported in a single family."
Sources: Expert Review