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Congenital Diarrhoea v1.20 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Amber List (Moderate Evidence).
Congenital Diarrhoea v1.19 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
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.61 KLHL9 Zornitza Stark Publications for gene: KLHL9 were set to 20554658
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 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
Imprinting disorders v1.8 UHRF1 Zornitza Stark commented on gene: UHRF1: Second family reported with homozygous missense variant.
Imprinting disorders v1.8 UHRF1 Zornitza Stark Phenotypes for gene: UHRF1 were changed from Multi locus imprinting disturbance in offspring to Multi locus imprinting disturbance in offspring; Imprinting disorder
Imprinting disorders v1.7 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982
Imprinting disorders v1.6 UHRF1 Zornitza Stark Classified gene: UHRF1 as Amber List (moderate evidence)
Imprinting disorders v1.6 UHRF1 Zornitza Stark Gene: uhrf1 has been classified as Amber List (Moderate Evidence).
Imprinting disorders v1.5 UHRF1 Zornitza Stark edited their review of gene: UHRF1: Changed rating: AMBER; Changed publications: 40825131; Changed phenotypes: Imprinting disorder; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.269 RNF2 Zornitza Stark Classified gene: RNF2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.269 RNF2 Zornitza Stark Gene: rnf2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.268 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: 33864376, 40831499
Genetic Epilepsy v1.192 RNF2 Zornitza Stark Publications for gene: RNF2 were set to 33864376
Genetic Epilepsy v1.191 RNF2 Zornitza Stark Classified gene: RNF2 as Green List (high evidence)
Genetic Epilepsy v1.191 RNF2 Zornitza Stark Gene: rnf2 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.190 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: 33864376, 40831499
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
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Marked gene: CCDC93 as ready
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Classified gene: CCDC93 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v1.268 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.267 CCDC93 Zornitza Stark reviewed gene: CCDC93: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ritscher-Schinzel syndrome, MONDO:0019078, CCDC93-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Callosome v0.554 CCDC93 Zornitza Stark Marked gene: CCDC93 as ready
Callosome v0.554 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
Callosome v0.554 CCDC93 Zornitza Stark Classified gene: CCDC93 as Red List (low evidence)
Callosome v0.554 CCDC93 Zornitza Stark Gene: ccdc93 has been classified as Red List (Low Evidence).
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).
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Marked gene: COX18 as ready
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Classified gene: COX18 as Green List (high evidence)
Hereditary Neuropathy - complex v1.31 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v1.30 COX18 Zornitza Stark gene: COX18 was added
gene: COX18 was added to Hereditary Neuropathy - complex. Sources: Literature
Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX18 were set to 37468577; 40830826
Phenotypes for gene: COX18 were set to Mitochondrial disease (MONDO:0044970), COX18-related
Review for gene: COX18 was set to GREEN
Added comment: PMID 40830826: Two sibs presenting with early onset progressive axonal sensory-motor peripheral neuropathy Family 1 (consanguineous) - two sibs affected with axonal CMT and homozygous c.435-6A>G - NFE AF - 0.001531% Family 2 - 4 sibs affected with axonal CMT and homozygous Leu72Arg - MID PopMax AF - 0.07120% Family 3 - two sibs with axonal CMT and compound het variants confirmed in trans - Ala110Pro; Arg297Pro Functional assay on c.435-6A>G showed stable but defective COX18 isoform - impairs CIV assembly and activity resulting in the reduction of mitochondrial membrane potential.

Note earlier case report with multi-system mitochondrial disease, hence placing in this panel.
Sources: Literature
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).
Mitochondrial disease v0.996 COX18 Zornitza Stark Publications for gene: COX18 were set to PMID:37468577
Lysosomal Storage Disorder v1.21 SPNS1 Sangavi Sivagnanasundram gene: SPNS1 was added
gene: SPNS1 was added to Lysosomal Storage Disorder. 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: 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 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
Intellectual disability syndromic and non-syndromic v1.267 WDR18 Krithika Murali Marked gene: WDR18 as ready
Intellectual disability syndromic and non-syndromic v1.267 WDR18 Krithika Murali Gene: wdr18 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.267 WDR18 Krithika Murali gene: WDR18 was added
gene: WDR18 was added to Intellectual disability syndromic and non-syndromic. 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
Intellectual disability syndromic and non-syndromic v1.266 MIS18BP1 Krithika Murali Marked gene: MIS18BP1 as ready
Intellectual disability syndromic and non-syndromic v1.266 MIS18BP1 Krithika Murali Gene: mis18bp1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.266 MIS18BP1 Krithika Murali gene: MIS18BP1 was added
gene: MIS18BP1 was added to Intellectual disability syndromic and non-syndromic. 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 v1.2964 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
Mitochondrial disease v0.995 COX18 Zornitza Stark Classified gene: COX18 as Green List (high evidence)
Mitochondrial disease v0.995 COX18 Zornitza Stark Gene: cox18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.265 HYPK Zornitza Stark Marked gene: HYPK as ready
Intellectual disability syndromic and non-syndromic v1.265 HYPK Zornitza Stark Gene: hypk has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.265 HYPK Zornitza Stark gene: HYPK was added
gene: HYPK was added to Intellectual disability syndromic and non-syndromic. 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
Intellectual disability syndromic and non-syndromic v1.264 DDX39A Zornitza Stark Marked gene: DDX39A as ready
Intellectual disability syndromic and non-syndromic v1.264 DDX39A Zornitza Stark Gene: ddx39a has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.264 DDX39A Zornitza Stark gene: DDX39A was added
gene: DDX39A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DDX39A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX39A were set to 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
Intellectual disability syndromic and non-syndromic v1.263 ARID3A Zornitza Stark Marked gene: ARID3A as ready
Intellectual disability syndromic and non-syndromic v1.263 ARID3A Zornitza Stark Gene: arid3a has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.263 ARID3A Zornitza Stark gene: ARID3A was added
gene: ARID3A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARID3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID3A were set to 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
Intellectual disability syndromic and non-syndromic v1.262 PIK3C3 Zornitza Stark Marked gene: PIK3C3 as ready
Intellectual disability syndromic and non-syndromic v1.262 PIK3C3 Zornitza Stark Gene: pik3c3 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.262 PIK3C3 Zornitza Stark gene: PIK3C3 was added
gene: PIK3C3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PIK3C3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C3 were set to 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
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Marked gene: MED29 as ready
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.261 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.330 MED29 Zornitza Stark Marked gene: MED29 as ready
Microcephaly v1.330 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.330 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Microcephaly v1.330 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
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).
Cerebellar and Pontocerebellar Hypoplasia v1.86 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.86 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.85 MED29 Zornitza Stark Classified gene: MED29 as Amber List (moderate evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.85 MED29 Zornitza Stark Gene: med29 has been classified as Amber List (Moderate Evidence).
Miscellaneous Metabolic Disorders v1.50 GLYAT Zornitza Stark Marked gene: GLYAT as ready
Miscellaneous Metabolic Disorders v1.50 GLYAT Zornitza Stark Gene: glyat has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.50 GLYAT Zornitza Stark gene: GLYAT was added
gene: GLYAT was added to Miscellaneous Metabolic Disorders. 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 v1.2961 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
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark Marked gene: GLYAT as ready
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark Gene: glyat has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark changed review comment from: 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 edema and hypotonia and an improvement in her motor function and social interactions. Her serum glycine level was also normalized.
Sources: Literature; to: 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
Intellectual disability syndromic and non-syndromic v1.260 GLYAT Zornitza Stark gene: GLYAT was added
gene: GLYAT was added to Intellectual disability syndromic and non-syndromic. 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 edema 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
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Marked gene: TDRD12 as ready
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Classified gene: TDRD12 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.19 TDRD12 Zornitza Stark Gene: tdrd12 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.18 TDRD12 Zornitza Stark gene: TDRD12 was added
gene: TDRD12 was added to Infertility and Recurrent Pregnancy Loss. 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).
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Marked gene: CCDC189 as ready
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name CFAP119.
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Gene: ccdc189 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark Tag new gene name tag was added to gene: CCDC189.
Infertility and Recurrent Pregnancy Loss v1.17 CCDC189 Zornitza Stark gene: CCDC189 was added
gene: CCDC189 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
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.
Sources: Literature
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
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Genetic Epilepsy v1.190 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Microcephaly v1.329 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Microcephaly v1.329 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Microcephaly v1.329 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Microcephaly v1.329 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.189 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Genetic Epilepsy. 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
Microcephaly v1.328 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Microcephaly. 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
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Marked gene: C1orf109 as ready
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Classified gene: C1orf109 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.259 C1orf109 Zornitza Stark Gene: c1orf109 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.258 C1orf109 Zornitza Stark gene: C1orf109 was added
gene: C1orf109 was added to Intellectual disability syndromic and non-syndromic. 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
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Marked gene: ASAP2 as ready
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Classified gene: ASAP2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.257 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.256 ASAP2 Zornitza Stark gene: ASAP2 was added
gene: ASAP2 was added to Intellectual disability syndromic and non-syndromic. 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
Microcephaly v1.327 ASAP2 Zornitza Stark Marked gene: ASAP2 as ready
Microcephaly v1.327 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.327 ASAP2 Zornitza Stark Classified gene: ASAP2 as Amber List (moderate evidence)
Microcephaly v1.327 ASAP2 Zornitza Stark Gene: asap2 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.326 ASAP2 Zornitza Stark gene: ASAP2 was added
gene: ASAP2 was added to Microcephaly. 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
Intellectual disability syndromic and non-syndromic v1.255 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. Supportive functional data.
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 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
Microcephaly v1.325 RTF1 Zornitza Stark Marked gene: RTF1 as ready
Microcephaly v1.325 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Microcephaly v1.325 RTF1 Zornitza Stark Classified gene: RTF1 as Green List (high evidence)
Microcephaly v1.325 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Microcephaly v1.324 RTF1 Zornitza Stark gene: RTF1 was added
gene: RTF1 was added to Microcephaly. 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. 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
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Marked gene: RTF1 as ready
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Classified gene: RTF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.255 RTF1 Zornitza Stark Gene: rtf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.254 RTF1 Zornitza Stark gene: RTF1 was added
gene: RTF1 was added to Intellectual disability syndromic and non-syndromic. 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. Supportive functional data.
Sources: Literature
Genomic newborn screening: BabyScreen+ v1.136 SNTA1 Lilian Downie reviewed gene: SNTA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 12 MIM#612955; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.404 DAW1 Zornitza Stark Marked gene: DAW1 as ready
Fetal anomalies v1.404 DAW1 Zornitza Stark Gene: daw1 has been classified as Green List (High Evidence).
Fetal anomalies v1.404 DAW1 Zornitza Stark Classified gene: DAW1 as Green List (high evidence)
Fetal anomalies v1.404 DAW1 Zornitza Stark Gene: daw1 has been classified as Green List (High Evidence).
Fetal anomalies v1.403 DAW1 Zornitza Stark gene: DAW1 was added
gene: DAW1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DAW1 were set to Primary ciliary dyskinesia, with or without heterotaxy, MIM#620570
Review for gene: DAW1 was set to GREEN
Added comment: Biallelic variants identified in two unrelated families. Zebrafish model recapitulates PCD and heterotaxy phenotype.
Sources: Expert Review
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
Microcephaly v1.323 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Microcephaly. 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
Intellectual disability syndromic and non-syndromic v1.253 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Intellectual disability syndromic and non-syndromic. 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
Cerebellar and Pontocerebellar Hypoplasia v1.84 MED29 Sarah Milton gene: MED29 was added
gene: MED29 was added to Cerebellar and Pontocerebellar Hypoplasia. 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 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
Mitochondrial disease v0.994 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 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
Callosome v0.553 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
Callosome v0.553 CCDC93 Sarah Milton Deleted their review
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
Callosome v0.553 CCDC93 Sarah Milton gene: CCDC93 was added
gene: CCDC93 was added to Callosome. 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
Intellectual disability syndromic and non-syndromic v1.253 CCDC93 Sarah Milton gene: CCDC93 was added
gene: CCDC93 was added to Intellectual disability syndromic and non-syndromic. 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 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
Pulmonary Arterial Hypertension v1.43 ATP13A3 Zornitza Stark Mode of inheritance for gene: ATP13A3 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 v1.2947 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
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Marked gene: DLGAP5 as ready
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Classified gene: DLGAP5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.16 DLGAP5 Zornitza Stark Gene: dlgap5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.15 DLGAP5 Zornitza Stark gene: DLGAP5 was added
gene: DLGAP5 was added to Infertility and Recurrent Pregnancy Loss. 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
Retinitis pigmentosa v0.175 CREB3 Sarah Milton gene: CREB3 was added
gene: CREB3 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. 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
Cone-rod Dystrophy v0.56 CREB3 Sarah Milton gene: CREB3 was added
gene: CREB3 was added to Cone-rod Dystrophy. 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
Fetal anomalies v1.402 ISPD Zornitza Stark Marked gene: ISPD as ready
Fetal anomalies v1.402 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Fetal anomalies v1.402 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Fetal anomalies v1.402 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Marked gene: ISPD as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
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
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Genetic Epilepsy v1.188 ISPD Zornitza Stark Marked gene: ISPD as ready
Genetic Epilepsy v1.188 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Genetic Epilepsy v1.188 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Genetic Epilepsy v1.188 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Marked gene: ISPD as ready
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.96 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
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.
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Marked gene: ISPD as ready
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Hydrocephalus_Ventriculomegaly v0.128 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Marked gene: ISPD as ready
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.84 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Marked gene: ISPD as ready
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Congenital Disorders of Glycosylation v1.70 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Cataract v0.374 ISPD Zornitza Stark Marked gene: ISPD as ready
Cataract v0.374 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Cataract v0.374 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Cataract v0.374 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Lissencephaly and Band Heterotopia v1.21 ISPD Zornitza Stark Marked gene: ISPD as ready
Lissencephaly and Band Heterotopia v1.21 ISPD Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is CRPPA.
Lissencephaly and Band Heterotopia v1.21 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Lissencephaly and Band Heterotopia v1.21 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
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Marked gene: TRIM74 as ready
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Classified gene: TRIM74 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v1.253 TRIM74 Zornitza Stark Gene: trim74 has been classified as Red List (Low Evidence).
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).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 TRIM72 Zornitza Stark Marked gene: TRIM72 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 TRIM72 Zornitza Stark Gene: trim72 has been classified as Red List (Low Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.60 TRIM72 Zornitza Stark gene: TRIM72 was added
gene: TRIM72 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. 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 v1.2942 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
Intellectual disability syndromic and non-syndromic v1.252 ZNF496 Zornitza Stark Marked gene: ZNF496 as ready
Intellectual disability syndromic and non-syndromic v1.252 ZNF496 Zornitza Stark Gene: znf496 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.252 SCN3B Sarah Milton gene: SCN3B was added
gene: SCN3B was added to Intellectual disability syndromic and non-syndromic. 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 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
Intellectual disability syndromic and non-syndromic v1.252 XPO1 Sangavi Sivagnanasundram gene: XPO1 was added
gene: XPO1 was added to Intellectual disability syndromic and non-syndromic. 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 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
Aortopathy_Connective Tissue Disorders v1.96 TLN1 Elena Savva Publications for gene: TLN1 were set to 30888838; 39163585; 33092471
Aortopathy_Connective Tissue Disorders v1.96 TLN1 Elena Savva Publications for gene: TLN1 were set to 30888838
Aortopathy_Connective Tissue Disorders v1.95 TLN1 Elena Savva changed review comment from: Azizi (2024):
- describes missense variants and functionally analyzes only a SINGLE missense finding a measurable defect in features such as cell behaviour and movement.
- Missense that were analysed were the same variants described in the previous submission (Turley 2019). Functional studies showed some effects in wound healing assay, but not cell monolayer integrity - weak functional evidence; to: Azizi (2024):
- describes missense variants and functionally analyzes only a SINGLE missense finding a measurable defect in features such as cell behaviour and movement.
- Missense that were analysed were the same variants described in the previous submission (Turley 2019). Functional studies showed some effects in wound healing assay, but not cell monolayer integrity - weak functional evidence

Li (2021): Additional SNPs observed in a cohort with thoracic aortic aneurysm, no follow analysis of the variants (MAF, in silicos, functional etc.)
Intellectual disability syndromic and non-syndromic v1.252 ZNF496 Zornitza Stark gene: ZNF496 was added
gene: ZNF496 was added to Intellectual disability syndromic and non-syndromic. 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 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
Phagocyte Defects v1.42 MKL1 Zornitza Stark Phenotypes for gene: MKL1 were changed from Neutropaenia with combined immune deficiency to Inborn error of immunity, MONDO:0003778, MKL1-related
Phagocyte Defects v1.41 MKL1 Zornitza Stark edited their review of gene: MKL1: Changed phenotypes: Inborn error of immunity, MONDO:0003778, MKL1-related
Phagocyte Defects v1.41 MKL1 Zornitza Stark Publications for gene: MKL1 were set to 32128589; 26224645
Phagocyte Defects v1.40 MKL1 Zornitza Stark Classified gene: MKL1 as Green List (high evidence)
Phagocyte Defects v1.40 MKL1 Zornitza Stark Gene: mkl1 has been classified as Green List (High Evidence).
Phagocyte Defects v1.39 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
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
Chromosome Breakage Disorders v1.23 MARS Zornitza Stark Publications for gene: MARS were set to 33909043
Chromosome Breakage Disorders v1.22 MARS Zornitza Stark edited their review of gene: MARS: Changed publications: 40820264, 33909043
Chromosome Breakage Disorders v1.22 MARS Zornitza Stark Classified gene: MARS as Amber List (moderate evidence)
Chromosome Breakage Disorders v1.22 MARS Zornitza Stark Gene: mars has been classified as Amber List (Moderate Evidence).
Chromosome Breakage Disorders v1.21 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Second individual reported with this phenotype and a homozygous variant in this gene.; Changed rating: AMBER
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
Intellectual disability syndromic and non-syndromic v1.251 TRIM74 Sangavi Sivagnanasundram gene: TRIM74 was added
gene: TRIM74 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
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 DD.

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: 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
Autism v0.213 BAZ2B Zornitza Stark Classified gene: BAZ2B as Amber List (moderate evidence)
Autism v0.213 BAZ2B Zornitza Stark Gene: baz2b has been classified as Amber List (Moderate Evidence).
Autism v0.212 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Added comment: Classified as LIMITED by ClinGen.; Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v1.251 BAZ2B Zornitza Stark Phenotypes for gene: BAZ2B were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Intellectual disability syndromic and non-syndromic v1.250 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Autism v0.212 BAZ2B Zornitza Stark Phenotypes for gene: BAZ2B were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, BAZ2B-related
Autism v0.211 BAZ2B Zornitza Stark edited their review of gene: BAZ2B: 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
Vasculitis v0.87 TRAP1 Zornitza Stark Marked gene: TRAP1 as ready
Vasculitis v0.87 TRAP1 Zornitza Stark Gene: trap1 has been classified as Red List (Low Evidence).
Vasculitis v0.87 TRAP1 Zornitza Stark Classified gene: TRAP1 as Red List (low evidence)
Vasculitis v0.87 TRAP1 Zornitza Stark Gene: trap1 has been classified as Red List (Low Evidence).
Vasculitis v0.86 TRAP1 Zornitza Stark reviewed gene: TRAP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.402 TRAP1 Zornitza Stark Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to Syndromic disease, MONDO:0002254, TRAP1-related
Fetal anomalies v1.401 TRAP1 Zornitza Stark edited their review of gene: TRAP1: Changed phenotypes: Syndromic disease, MONDO:0002254, TRAP1-related
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
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.125 TRAP1 Zornitza Stark Phenotypes for gene: TRAP1 were changed from CAKUT; VACTERL to Syndromic disease, MONDO:0002254, TRAP1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.124 TRAP1 Zornitza Stark edited their review of gene: TRAP1: Changed phenotypes: Syndromic disease, MONDO:0002254, TRAP1-related
Hand and foot malformations v0.77 TP63 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen, lumped multiple entities together.; to: DEFINITIVE by ClinGen, lumped multiple entities together. Limb anomalies are a key feature.
Hand and foot malformations v0.77 TP63 Zornitza Stark Marked gene: TP63 as ready
Hand and foot malformations v0.77 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Hand and foot malformations v0.77 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Hay-Wells syndrome 106260; Rapp-Hodgkin syndrome 129400; Limb-mammary syndrome 603543; Split-hand/foot malformation 4 605289; Orofacial cleft 8 129400; ULT syndrome 103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 604292 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Hand and foot malformations v0.76 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.401 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
Fetal anomalies v1.400 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Clefting disorders v0.268 TP63 Zornitza Stark Marked gene: TP63 as ready
Clefting disorders v0.268 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Clefting disorders v0.268 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Orofacial cleft 8, EEC SYNDROME 3, Rapp Hodgkins syndrome, 129400; EEC3; Limb-mammary syndrome, 603543; AEC (Ankyloblepharon filiforme adnatum, Ectodermal defects and Clefting), Hay Wells syndrome 106260; EEC syndrome (Ectrodactyly, Ectodermal dysplasia and Clefting); ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3; Cleft lip; Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3, 604292 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Clefting disorders v0.267 TP63 Zornitza Stark commented on gene: TP63: DEFINITIVE by ClinGen, lumped multiple disorders.
Clefting disorders v0.267 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hair disorders v0.80 TP63 Zornitza Stark Marked gene: TP63 as ready
Hair disorders v0.80 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Hair disorders v0.80 TP63 Zornitza Stark Publications for gene: TP63 were set to 31332722
Hair disorders v0.79 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon-ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb-mammary syndrome to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Hair disorders v0.78 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Ectodermal Dysplasia v0.98 TP63 Zornitza Stark Marked gene: TP63 as ready
Ectodermal Dysplasia v0.98 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.98 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon-ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb-mammary syndrome to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Ectodermal Dysplasia v0.97 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v0.317 TP63 Zornitza Stark Marked gene: TP63 as ready
Skeletal dysplasia v0.317 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.317 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Hay-Wells syndrome 106260; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 604292; Limb-mammary syndrome 603543; Rapp-Hodgkin syndrome 129400; Orofacial cleft 8 129400; ULT syndrome 103285; Split-hand/foot malformation 4 605289 to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Skeletal dysplasia v0.316 TP63 Zornitza Stark Publications for gene: TP63 were set to
Skeletal dysplasia v0.315 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Intellectual disability syndromic and non-syndromic v1.250 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
Intellectual disability syndromic and non-syndromic v1.249 TP63 Zornitza Stark reviewed gene: TP63: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe Combined Immunodeficiency v1.11 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, MIM# 604292; lymphopaenia to TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
Severe Combined Immunodeficiency v1.10 TP63 Zornitza Stark edited their review of gene: TP63: Changed phenotypes: TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, MONDO:1040001
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
Leukodystrophy - paediatric v0.323 TOMM70 Zornitza Stark Phenotypes for gene: TOMM70 were changed from White matter abnormalities; Developmental delay; Regression; Movement disorder to Leukodystrophy, MONDO:0019046, TOMM70-related
Leukodystrophy - paediatric v0.322 TOMM70 Zornitza Stark edited their review of gene: TOMM70: Changed phenotypes: Leukodystrophy, MONDO:0019046, TOMM70-related
Mitochondrial disease v0.994 TOMM70 Zornitza Stark Phenotypes for gene: TOMM70 were changed from Severe anaemia; Lactic acidosis; Developmental delay to Mitochondrial disease, MONDO:0044970, TOMM70-related
Mitochondrial disease v0.993 TOMM70 Zornitza Stark edited their review of gene: TOMM70: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TOMM70-related
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.
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Marked gene: ARNTL as ready
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Classified gene: ARNTL as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.249 ARNTL Zornitza Stark Gene: arntl has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.248 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).
Genetic Epilepsy v1.188 CSMD3 Zornitza Stark Marked gene: CSMD3 as ready
Genetic Epilepsy v1.188 CSMD3 Zornitza Stark Gene: csmd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.188 CSMD3 Zornitza Stark Classified gene: CSMD3 as Green List (high evidence)
Genetic Epilepsy v1.188 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
Genomic newborn screening: BabyScreen+ v1.136 TNFSF11 Lilian Downie commented on gene: TNFSF11: This type of osteopetrosis is particularly difficult to treat PMID: 36031188
Intellectual disability syndromic and non-syndromic v1.248 TMPRSS7 Zornitza Stark gene: TMPRSS7 was added
gene: TMPRSS7 was added to Intellectual disability syndromic and non-syndromic. 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
Intellectual disability syndromic and non-syndromic v1.247 PPP1R2 Zornitza Stark Marked gene: PPP1R2 as ready
Intellectual disability syndromic and non-syndromic v1.247 PPP1R2 Zornitza Stark Gene: ppp1r2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.247 PPP1R2 Zornitza Stark gene: PPP1R2 was added
gene: PPP1R2 was added to Intellectual disability syndromic and non-syndromic. 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 v1.2928 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
Optic Atrophy v1.49 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Optic Atrophy v1.49 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Optic Atrophy v1.49 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Optic Atrophy v1.49 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Optic Atrophy v1.48 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Optic Atrophy. 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
Microcephaly v1.323 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Microcephaly v1.323 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Genetic Epilepsy v1.187 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.186 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Genetic Epilepsy. 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
Microcephaly v1.323 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Microcephaly v1.323 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Microcephaly v1.322 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Microcephaly. 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
Fetal anomalies v1.400 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Fetal anomalies v1.400 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Arthrogryposis v0.424 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Arthrogryposis v0.424 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Arthrogryposis v0.424 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Arthrogryposis v0.424 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Fetal anomalies v1.400 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Fetal anomalies v1.400 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Fetal anomalies v1.399 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Fetal anomalies. 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
Arthrogryposis v0.423 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Arthrogryposis. 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 v1.2927 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
Regression v0.585 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Regression v0.585 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Regression v0.585 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Regression v0.585 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Regression v0.584 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Regression. 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
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.246 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.245 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Intellectual disability syndromic and non-syndromic. 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
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Classified gene: BORCS5 as Green List (high evidence)
Lysosomal Storage Disorder v1.21 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Green List (High Evidence).
Lysosomal Storage Disorder v1.20 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Lysosomal Storage Disorder. 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
Osteopetrosis v0.38 BORCS5 Zornitza Stark Marked gene: BORCS5 as ready
Osteopetrosis v0.38 BORCS5 Zornitza Stark Gene: borcs5 has been classified as Red List (Low Evidence).
Osteopetrosis v0.38 BORCS5 Zornitza Stark Publications for gene: BORCS5 were set to 40621786; 7577667
Osteopetrosis v0.37 BORCS5 Zornitza Stark edited their review of gene: BORCS5: Changed publications: 40621786, 7577667, 40385417
Osteopetrosis v0.37 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Osteopetrosis. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40621786; 7577667
Phenotypes for gene: BORCS5 were set to Neuroaxonal dystrophy (NAD) with osteopetrosis syndrome (OMIM # 600329)
Review for gene: BORCS5 was set to RED
Added comment: Disease entity originally described in 1995 but genetic basis unknown. Report of consanguineous family with two affected fetuses, homozygous for same missense variant, p. Arg301His.

However, note 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
Genetic Epilepsy v1.185 CSMD3 Sarah Milton gene: CSMD3 was added
gene: CSMD3 was added to Genetic Epilepsy. 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 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
Phagocyte Defects v1.39 MMD2 Zornitza Stark Marked gene: MMD2 as ready
Phagocyte Defects v1.39 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.39 MMD2 Zornitza Stark edited their review of gene: MMD2: Changed rating: AMBER
Phagocyte Defects v1.39 MMD2 Zornitza Stark Classified gene: MMD2 as Amber List (moderate evidence)
Phagocyte Defects v1.39 MMD2 Zornitza Stark Gene: mmd2 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.38 MMD2 Zornitza Stark gene: MMD2 was added
gene: MMD2 was added to Phagocyte Defects. 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 GREEN
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 v1.2925 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
Intellectual disability syndromic and non-syndromic v1.244 ARNTL Sarah Milton gene: ARNTL was added
gene: ARNTL was added to Intellectual disability syndromic and non-syndromic. 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 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
Mitochondrial disease v0.993 FAM136A Zornitza Stark Marked gene: FAM136A as ready
Mitochondrial disease v0.993 FAM136A Zornitza Stark Gene: fam136a has been classified as Red List (Low Evidence).
Mitochondrial disease v0.993 FAM136A Zornitza Stark gene: FAM136A was added
gene: FAM136A was added to Mitochondrial disease. 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
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Marked gene: NCOA7 as ready
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Classified gene: NCOA7 as Green List (high evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.352 NCOA7 Zornitza Stark Gene: ncoa7 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.351 NCOA7 Zornitza Stark gene: NCOA7 was added
gene: NCOA7 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. 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
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.350 POU5F1 Zornitza Stark edited their review of gene: POU5F1: Added comment: Additional individual reported in PMID 40744326 with rare high impact variant, maintain Red rating for now.; Changed publications: 21273125, 40744326
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
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Marked gene: DNAH6 as ready
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Classified gene: DNAH6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.14 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.13 DNAH6 Zornitza Stark gene: DNAH6 was added
gene: DNAH6 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH6 were set to 37594300; 39192248; 37424858; 31676830; 29356036; 40592014
Phenotypes for gene: DNAH6 were set to Spermatogenic failure, MONDO:0004983, DNAH6-related
Review for gene: DNAH6 was set to GREEN
Added comment: More than 5 unrelated individuals reported with spermatogenic failure and bi-allelic variants in this gene.
Sources: Literature
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
Infertility and Recurrent Pregnancy Loss v1.12 DNAH2 Zornitza Stark Marked gene: DNAH2 as ready
Infertility and Recurrent Pregnancy Loss v1.12 DNAH2 Zornitza Stark Gene: dnah2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.12 DNAH2 Zornitza Stark Publications for gene: DNAH2 were set to 30811583; 32732226; 40592014
Infertility and Recurrent Pregnancy Loss v1.11 DNAH2 Zornitza Stark Classified gene: DNAH2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.11 DNAH2 Zornitza Stark Gene: dnah2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.10 DNAH2 Zornitza Stark gene: DNAH2 was added
gene: DNAH2 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH2 were set to 30811583; 32732226; 40592014
Phenotypes for gene: DNAH2 were set to Spermatogenic failure 45, MIM# 619094
Review for gene: DNAH2 was set to GREEN
Added comment: At least 3 unrelated families reported with biallelic variants and spermatogenic failure.
Sources: Literature
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
Monogenic Diabetes v0.145 PAX4 Zornitza Stark Phenotypes for gene: PAX4 were changed from Maturity-onset diabetes of the young, type IX MIM#612225 to Maturity-onset diabetes of the young, type IX MIM#612225; Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related
Monogenic Diabetes v0.144 PAX4 Zornitza Stark Publications for gene: PAX4 were set to 17426099; 14561778; 25951767; 21263211
Monogenic Diabetes v0.143 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
Monogenic Diabetes v0.142 PAX4 Zornitza Stark edited their review of gene: PAX4: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic Diabetes v0.142 PAX4 Zornitza Stark reviewed gene: PAX4: Rating: RED; Mode of pathogenicity: None; Publications: 40614820; Phenotypes: Transient neonatal diabetes mellitus, MONDO:0020525, PAX-4 related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.244 MAN2A2 Zornitza Stark Publications for gene: MAN2A2 were set to 36357165
Intellectual disability syndromic and non-syndromic v1.243 MAN2A2 Zornitza Stark Classified gene: MAN2A2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.243 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.242 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v1.242 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 publications: 36357165, 40628855
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).
Congenital Disorders of Glycosylation v1.70 MAN2A2 Zornitza Stark Publications for gene: MAN2A2 were set to 36357165
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
Congenital Disorders of Glycosylation v1.69 MAN2A2 Zornitza Stark Classified gene: MAN2A2 as Amber List (moderate evidence)
Congenital Disorders of Glycosylation v1.69 MAN2A2 Zornitza Stark Gene: man2a2 has been classified as Amber List (Moderate Evidence).
Congenital Disorders of Glycosylation v1.68 MAN2A2 Zornitza Stark edited their review of gene: MAN2A2: Changed rating: AMBER
Congenital Disorders of Glycosylation v1.68 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 publications: 36357165, 40628855
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Marked gene: CCDC186 as ready
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Classified gene: CCDC186 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.242 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.241 CCDC186 Zornitza Stark gene: CCDC186 was added
gene: CCDC186 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146; 37569695; 40633195
Phenotypes for gene: CCDC186 were set to Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Review for gene: CCDC186 was set to GREEN
Added comment: At least 3 unrelated families reported with bi-allelic LoF variants and a neurodevelopmental phenotype comprising ID and seizures, plus other more variable features.
Sources: Literature
Genetic Epilepsy v1.185 CCDC186 Zornitza Stark Phenotypes for gene: CCDC186 were changed from Epileptic encephalopathy to Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
Genetic Epilepsy v1.184 CCDC186 Zornitza Stark Publications for gene: CCDC186 were set to 33259146
Genetic Epilepsy v1.183 CCDC186 Zornitza Stark Classified gene: CCDC186 as Green List (high evidence)
Genetic Epilepsy v1.183 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.182 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.

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.; Changed rating: GREEN; Changed publications: 33259146, 37569695, 40633195; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CCDC186-related
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
Intellectual disability syndromic and non-syndromic v1.240 PCLO Zornitza Stark Publications for gene: PCLO were set to 25832664
Intellectual disability syndromic and non-syndromic v1.239 PCLO Zornitza Stark Classified gene: PCLO as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.239 PCLO Zornitza Stark Gene: pclo has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.238 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 v1.2906 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
Cerebellar and Pontocerebellar Hypoplasia v1.84 PCLO Zornitza Stark Publications for gene: PCLO were set to 25832664
Cerebellar and Pontocerebellar Hypoplasia v1.83 PCLO Zornitza Stark Classified gene: PCLO as Green List (high evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.83 PCLO Zornitza Stark Gene: pclo has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.82 PCLO Zornitza Stark edited their review of gene: PCLO: Changed rating: GREEN
Cerebellar and Pontocerebellar Hypoplasia v1.82 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 30287594: additional family with 5 affected sibs, compound het for LoF variants and PCH. Upgrade to GREEN.; Changed publications: 25832664, 40661989, 32122952, 30287594
Cerebellar and Pontocerebellar Hypoplasia v1.82 PCLO Zornitza Stark edited their review of gene: PCLO: Added comment: PMID 32122952: rat model consistent with human phenotype.; Changed publications: 25832664, 40661989, 32122952
Cerebellar and Pontocerebellar Hypoplasia v1.82 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.; Changed publications: 25832664, 40661989
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
Cholestasis v1.4 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
Cholestasis v1.3 LSR Zornitza Stark Publications for gene: LSR were set to 32303357; 30250217
Cholestasis v1.2 LSR Zornitza Stark Classified gene: LSR as Green List (high evidence)
Cholestasis v1.2 LSR Zornitza Stark Gene: lsr has been classified as Green List (High Evidence).
Cholestasis v1.1 LSR Zornitza Stark edited their review of gene: LSR: Added comment: PMID 40846272: further two patients with homozygous missense variants.; Changed publications: 32303357, 30250217, 40679108, 40846272
Cholestasis v1.1 LSR Zornitza Stark edited their review of gene: LSR: Added comment: 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; Changed phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, LSR-related, transient neonatal cholestasis, intellectual disability, short stature
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.350 IGSF10 Zornitza Stark Phenotypes for gene: IGSF10 were changed from delayed puberty; hypogonadotropic hypogonadism to Disorder of sex differentiation, MONDO:0002145, IGSF10-related; delayed puberty; hypogonadotropic hypogonadism
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.349 IGSF10 Zornitza Stark reviewed gene: IGSF10: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Disorder of sex differentiation, MONDO:0002145, IGSF10-related; Mode of inheritance: None
Fetal anomalies v1.398 TAF13 Zornitza Stark Phenotypes for gene: TAF13 were changed from Mental retardation, autosomal recessive 60, MIM# 617432; Microcephaly to Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Fetal anomalies v1.397 TAF13 Zornitza Stark Publications for gene: TAF13 were set to 28257693
Fetal anomalies v1.396 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, which may also be relevant to this panel.; Changed publications: 28257693, 40679298; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
Intellectual disability syndromic and non-syndromic v1.238 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
Intellectual disability syndromic and non-syndromic v1.237 TAF13 Zornitza Stark Publications for gene: TAF13 were set to 28257693
Intellectual disability syndromic and non-syndromic v1.236 TAF13 Zornitza Stark edited their review of gene: TAF13: Changed publications: 28257693, 40679298; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 60, MIM# 617432
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
Differences of Sex Development v1.14 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
Differences of Sex Development v1.13 IGSF10 Zornitza Stark edited their review of gene: IGSF10: Changed phenotypes: Disorder of sex differentiation, MONDO:0002145, IGSF10-related
Differences of Sex Development v1.13 IGSF10 Zornitza Stark Publications for gene: IGSF10 were set to 27137492; 31042289
Differences of Sex Development v1.12 IGSF10 Zornitza Stark edited their review of gene: IGSF10: Added comment: PMID 40700020 provides some functional data to support pathogenicity of R156L and E161K, maintain AMBER rating.; Changed publications: 27137492, 31042289, 40700020
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
Intellectual disability syndromic and non-syndromic v1.236 FAAH2 Zornitza Stark Phenotypes for gene: FAAH2 were changed from Neuropsychiatric disorder to Neurodevelopmental disorder, MONDO:0700092, FAAH2-related
Intellectual disability syndromic and non-syndromic v1.235 FAAH2 Zornitza Stark Publications for gene: FAAH2 were set to 25885783
Intellectual disability syndromic and non-syndromic v1.234 FAAH2 Zornitza Stark edited their review of gene: FAAH2: Added comment: Further case report of novel missense variant in an individual with a neurodevelopmental disorder, no supportive evidence.; Changed publications: 25885783, 40744325; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, FAAH2-related
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
Predominantly Antibody Deficiency v1.3 TNFSF12 Zornitza Stark Publications for gene: TNFSF12 were set to 23493554
Predominantly Antibody Deficiency v1.2 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
Predominantly Antibody Deficiency v1.1 TNFSF12 Zornitza Stark edited their review of gene: TNFSF12: Changed phenotypes: Inborn error of immunity, MONDO:0003778, TNFSF12-related
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
Hereditary Neuropathy - complex v1.29 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
Hereditary Neuropathy - complex v1.28 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
Intellectual disability syndromic and non-syndromic v1.234 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
Intellectual disability syndromic and non-syndromic v1.233 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 v1.2892 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
Intellectual disability syndromic and non-syndromic v1.233 SEPHS1 Zornitza Stark Phenotypes for gene: SEPHS1 were changed from Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related to Ververi-Brady syndrome 2, MIM# 621325
Intellectual disability syndromic and non-syndromic v1.232 SEPHS1 Zornitza Stark edited their review of gene: SEPHS1: Changed phenotypes: Ververi-Brady syndrome 2, MIM# 621325
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
Deafness_IsolatedAndComplex v1.221 TMTC2 Zornitza Stark Classified gene: TMTC2 as Red List (low evidence)
Deafness_IsolatedAndComplex v1.221 TMTC2 Zornitza Stark Gene: tmtc2 has been classified as Red List (Low Evidence).
Deafness_IsolatedAndComplex v1.220 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
Autism v0.211 TMPRSS9 Zornitza Stark Phenotypes for gene: TMPRSS9 were changed from autism spectrum disorder to Neurodevelopmental disorder, MONDO:0700092, TMPRSS9-related
Autism v0.210 TMPRSS9 Zornitza Stark edited their review of gene: TMPRSS9: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TMPRSS9-related
Mitochondrial disease v0.992 TMEM65 Zornitza Stark Phenotypes for gene: TMEM65 were changed from Mitochondrial disease, MONDO:0044970, TMEM65-related to Mitochondrial disease, MONDO:0044970, TMEM65-related
Mitochondrial disease v0.992 TMEM65 Zornitza Stark Phenotypes for gene: TMEM65 were changed from Mitochondrial encephalomyopathy to Mitochondrial disease, MONDO:0044970, TMEM65-related
Mitochondrial disease v0.991 TMEM65 Zornitza Stark edited their review of gene: TMEM65: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TMEM65-related
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
Combined Immunodeficiency v1.126 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
Combined Immunodeficiency v1.125 POLE2 Zornitza Stark edited their review of gene: POLE2: Changed phenotypes: Combined immunodeficiency MONDO:0015131, POLE2-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
Syndromic Retinopathy v0.230 PNPLA6 Zornitza Stark Marked gene: PNPLA6 as ready
Syndromic Retinopathy v0.230 PNPLA6 Zornitza Stark Gene: pnpla6 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.230 PNPLA6 Zornitza Stark Publications for gene: PNPLA6 were set to
Syndromic Retinopathy v0.229 PNPLA6 Zornitza Stark Phenotypes for gene: PNPLA6 were changed from to Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155
Syndromic Retinopathy v0.228 PNPLA6 Zornitza Stark Mode of inheritance for gene: PNPLA6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Syndromic Retinopathy v0.227 PNPLA6 Zornitza Stark edited their review of gene: PNPLA6: Changed phenotypes: Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome MONDO:0100155
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
Mitochondrial disease v0.991 PNPLA4 Zornitza Stark Phenotypes for gene: PNPLA4 were changed from to Mitochondrial disease (MONDO:0044970), PNPLA4-related
Mitochondrial disease v0.990 PNPLA4 Zornitza Stark edited their review of gene: PNPLA4: Changed phenotypes: Mitochondrial disease (MONDO:0044970), PNPLA4-related
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
Mitochondrial disease v0.990 TIMM22 Zornitza Stark Phenotypes for gene: TIMM22 were changed from hypotonia; gastroesophageal reflux disease to Mitochondrial disease, MONDO:0044970, TIMM22-related
Mitochondrial disease v0.989 TIMM22 Zornitza Stark edited their review of gene: TIMM22: Changed phenotypes: Mitochondrial disease, MONDO:0044970, TIMM22-related
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
Deafness_IsolatedAndComplex v1.220 THOC1 Zornitza Stark Phenotypes for gene: THOC1 were changed from Nonsyndromic hearing loss to Hearing loss disorder, MONDO:0005365, THOC1-related
Deafness_IsolatedAndComplex v1.219 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
Genomic newborn screening: BabyScreen+ v1.136 TPM1 Lilian Downie reviewed gene: TPM1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33642254; Phenotypes: Cardiomyopathy, hypertrophic, 3 MIM#115196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v1.232 TDGF1 Zornitza Stark Phenotypes for gene: TDGF1 were changed from to Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Intellectual disability syndromic and non-syndromic v1.231 TDGF1 Zornitza Stark edited their review of gene: TDGF1: Changed rating: RED; Changed phenotypes: Congenital nervous system disorder, MONDO:0002320, TDGF1-related
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
Holoprosencephaly and septo-optic dysplasia v1.21 TDGF1 Zornitza Stark Phenotypes for gene: TDGF1 were changed from Forebrain abnormalities to Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Holoprosencephaly and septo-optic dysplasia v1.20 TDGF1 Zornitza Stark edited their review of gene: TDGF1: Changed phenotypes: Congenital nervous system disorder, MONDO:0002320, TDGF1-related
Intellectual disability syndromic and non-syndromic v1.231 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
Intellectual disability syndromic and non-syndromic v1.230 TCF7L2 Zornitza Stark edited their review of gene: TCF7L2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCF7L2-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
Pituitary hormone deficiency v0.37 TCF7L1 Zornitza Stark Marked gene: TCF7L1 as ready
Pituitary hormone deficiency v0.37 TCF7L1 Zornitza Stark Gene: tcf7l1 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v0.37 TCF7L1 Zornitza Stark Phenotypes for gene: TCF7L1 were changed from No OMIM number; pituitary hormone deficiency to Combined pituitary deficiencies, genetic form, MONDO:0013099, TCF7L1-related
Pituitary hormone deficiency v0.36 TCF7L1 Zornitza Stark Classified gene: TCF7L1 as Red List (low evidence)
Pituitary hormone deficiency v0.36 TCF7L1 Zornitza Stark Gene: tcf7l1 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v0.35 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 v1.2879 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
Genomic newborn screening: BabyScreen+ v1.136 VCL Lilian Downie reviewed gene: VCL: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32516855; Phenotypes: Cardiomyopathy, dilated, 1W MIM#611407; 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
Dystonia - isolated/combined v1.41 NIT1 Zornitza Stark Phenotypes for gene: NIT1 were changed from Cerebrovascular disorder, NIT1-related (MONDO:0011057) to Brain small vessel disease 4, MIM# 621313
Dystonia - isolated/combined v1.40 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
Stroke v1.24 NIT1 Zornitza Stark Phenotypes for gene: NIT1 were changed from Cerebrovascular disorder, NIT1-related (MONDO:0011057) to Brain small vessel disease 4, MIM# 621313
Stroke v1.23 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
Disorders of immune dysregulation v1.23 NLRP1 Zornitza Stark Marked gene: NLRP1 as ready
Disorders of immune dysregulation v1.23 NLRP1 Zornitza Stark Gene: nlrp1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.23 NLRP1 Zornitza Stark Phenotypes for gene: NLRP1 were changed from Autoinflammation with arthritis and dyskeratosis to Autoinflammation with arthritis and dyskeratosis, MIM# 617388
Disorders of immune dysregulation v1.22 NLRP1 Zornitza Stark Classified gene: NLRP1 as Green List (high evidence)
Disorders of immune dysregulation v1.22 NLRP1 Zornitza Stark Gene: nlrp1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.21 NLRP1 Zornitza Stark reviewed gene: NLRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammation with arthritis and dyskeratosis, MIM# 617388; Mode of inheritance: None
Genetic Epilepsy v1.182 NALCN Zornitza Stark Phenotypes for gene: NALCN were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MIM#615419) to Congenital contractures of the limbs and face, hypotonia, and developmental delay - MIM#616266; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 - MIM#615419
Genetic Epilepsy v1.181 NALCN Zornitza Stark Publications for gene: NALCN were set to 30167850
Genetic Epilepsy v1.180 NALCN Zornitza Stark Mode of inheritance for gene: NALCN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.179 NALCN Zornitza Stark reviewed gene: NALCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 25683120, 35388452, 28327206, 27473021, 27558372; Phenotypes: Congenital contractures of the limbs and face, hypotonia, and developmental delay - MIM#616266, Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 - MIM#615419; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Disorders of immune dysregulation v1.21 NLRP1 Peter McNaughton gene: NLRP1 was added
gene: NLRP1 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: NLRP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NLRP1 were set to PMID: 27965258
Phenotypes for gene: NLRP1 were set to Autoinflammation with arthritis and dyskeratosis
Review for gene: NLRP1 was set to GREEN
Added comment: Given overlap autoinflammatory / auto-immune phenotype with arthritis, thyroiditis, cytopaenias, hepatosplenomegaly should be included in immune dysregulation panel in addition to autoinflammatory panel.
Sources: Literature
Ataxia v1.46 CSNK2B Zornitza Stark Marked gene: CSNK2B as ready
Ataxia v1.46 CSNK2B Zornitza Stark Gene: csnk2b has been classified as Green List (High Evidence).
Ataxia v1.46 CSNK2B Zornitza Stark Phenotypes for gene: CSNK2B were changed from intellectual disability; ataxia; epilepsy to Poirier-Bienvenu neurodevelopmental syndrome , MIM#618732
Ataxia v1.45 CSNK2B Zornitza Stark Classified gene: CSNK2B as Green List (high evidence)
Ataxia v1.45 CSNK2B Zornitza Stark Gene: csnk2b has been classified as Green List (High Evidence).
Ataxia v1.44 CSNK2B Boris Keren gene: CSNK2B was added
gene: CSNK2B was added to Ataxia - paediatric. Sources: Literature
Mode of inheritance for gene: CSNK2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK2B were set to PMID: 34041744
Phenotypes for gene: CSNK2B were set to intellectual disability; ataxia; epilepsy
Penetrance for gene: CSNK2B were set to Complete
Review for gene: CSNK2B was set to GREEN
Added comment: PMID: 34041744. 25 patients with mostly de novo LoF or missenses and NDD. 25% have ataxia
Sources: Literature
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.33 PDE4D Zornitza Stark Marked gene: PDE4D as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.33 PDE4D Zornitza Stark Gene: pde4d has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.33 PDE4D Zornitza Stark Phenotypes for gene: PDE4D were changed from to Acrodysostosis 2, with or without hormone resistance, MIM# 614613
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.32 PDE4D Zornitza Stark Publications for gene: PDE4D were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.31 PDE4D Zornitza Stark Mode of inheritance for gene: PDE4D was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.30 PRKAR1A Zornitza Stark Marked gene: PRKAR1A as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.30 PRKAR1A Zornitza Stark Gene: prkar1a has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.30 PRKAR1A Zornitza Stark Phenotypes for gene: PRKAR1A were changed from to Acrodysostosis 1, with or without hormone resistance, MIM# 101800
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.29 PRKAR1A Zornitza Stark Publications for gene: PRKAR1A were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.28 PRKAR1A Zornitza Stark Mode of inheritance for gene: PRKAR1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.27 GNAS Zornitza Stark Marked gene: GNAS as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.27 GNAS Zornitza Stark Gene: gnas has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.27 GNAS Zornitza Stark Phenotypes for gene: GNAS were changed from to Pseudohypoparathyroidism Ia (103580) AD; Pseudohypoparathyroidism Ib (603233) AD; Pseudohypoparathyroidism Ic (612462) AD; Pseudopseudohypoparathyroidism (612463); Osseous heteroplasia, progressive (166350) AD; Pituitary adenoma 3, multiple types, somatic (617686)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.26 GNAS Zornitza Stark Mode of inheritance for gene: GNAS was changed from Unknown to Other
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.25 PTHLH Zornitza Stark Marked gene: PTHLH as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.25 PTHLH Zornitza Stark Gene: pthlh has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.25 PTHLH Zornitza Stark Phenotypes for gene: PTHLH were changed from to Brachydactyly, type E2, MIM# 613382
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.24 PTHLH Zornitza Stark Publications for gene: PTHLH were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.23 HOXD13 Zornitza Stark Marked gene: HOXD13 as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.23 HOXD13 Zornitza Stark Gene: hoxd13 has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.23 HOXD13 Zornitza Stark Phenotypes for gene: HOXD13 were changed from to Brachydactyly, type E, 113300
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.22 HOXD13 Zornitza Stark Publications for gene: HOXD13 were set to
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.21 HOXD13 Zornitza Stark Mode of inheritance for gene: HOXD13 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.20 TBCE Zornitza Stark Marked gene: TBCE as ready
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.20 TBCE Zornitza Stark Gene: tbce has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.20 TBCE Zornitza Stark Phenotypes for gene: TBCE were changed from to Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.19 TBCE Zornitza Stark Mode of inheritance for gene: TBCE was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Hyperinsulinism v1.48 CDKN1C Zornitza Stark Marked gene: CDKN1C as ready
Hyperinsulinism v1.48 CDKN1C Zornitza Stark Gene: cdkn1c has been classified as Green List (High Evidence).
Hyperinsulinism v1.48 ADK Zornitza Stark Marked gene: ADK as ready
Hyperinsulinism v1.48 ADK Zornitza Stark Gene: adk has been classified as Green List (High Evidence).
Hyperinsulinism v1.48 FAH Zornitza Stark Marked gene: FAH as ready
Hyperinsulinism v1.48 FAH Zornitza Stark Gene: fah has been classified as Green List (High Evidence).
Hyperinsulinism v1.48 EIF2S3 Zornitza Stark Publications for gene: EIF2S3 were set to
Hyperinsulinism v1.47 HRAS Zornitza Stark Marked gene: HRAS as ready
Hyperinsulinism v1.47 HRAS Zornitza Stark Gene: hras has been classified as Green List (High Evidence).
Hyperinsulinism v1.47 TRMT10A Zornitza Stark Publications for gene: TRMT10A were set to
Hyperinsulinism v1.46 YARS Zornitza Stark Marked gene: YARS as ready
Hyperinsulinism v1.46 YARS Zornitza Stark Gene: yars has been classified as Red List (Low Evidence).
Hereditary Neuropathy_CMT - isolated v1.61 PLEKHG5 Zornitza Stark Phenotypes for gene: PLEKHG5 were changed from HMSN, dHMN/dSMA; 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
Hereditary Neuropathy_CMT - isolated v1.60 PLEKHG5 Zornitza Stark edited their review of gene: PLEKHG5: Added comment: Lumped by ClinGen.; Changed phenotypes: hereditary peripheral neuropathy MONDO:0020127, PLEKHG5-related
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
Familial hypoparathyroidism v1.7 TBX1 Zornitza Stark Marked gene: TBX1 as ready
Familial hypoparathyroidism v1.7 TBX1 Zornitza Stark Gene: tbx1 has been classified as Green List (High Evidence).
Familial hypoparathyroidism v1.7 TBX1 Zornitza Stark Publications for gene: TBX1 were set to PMID: 20301696, 16684884, 14585638, 30137364
Pain syndromes v0.36 PLEKHN1 Zornitza Stark Phenotypes for gene: PLEKHN1 were changed from Sensory Neuropathy to Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related
Pain syndromes v0.35 PLEKHN1 Zornitza Stark edited their review of gene: PLEKHN1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pain syndromes v0.35 PLEKHN1 Zornitza Stark reviewed gene: PLEKHN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary sensory and autonomic neuropathy, MONDO:0015364, PLEKHN1-related; Mode of inheritance: None
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
Genetic Epilepsy v1.179 TRIO Zornitza Stark Mode of inheritance for gene: TRIO was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Susceptibility to Viral Infections v1.1 TAOK2 Zornitza Stark Phenotypes for gene: TAOK2 were changed from Generalized verrucosis; abnormal T cell activation to Inborn error of immunity, MONDO:0003778, TAOK2-related
Susceptibility to Viral Infections v1.0 TAOK2 Zornitza Stark reviewed gene: TAOK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, TAOK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mackenzie's Mission_Reproductive Carrier Screening v0.110 SYP Zornitza Stark Phenotypes for gene: SYP were changed from Mental retardation, X-linked 96, 300802 (3) to Intellectual developmental disorder, X-linked 96, MIM# 300802
Mackenzie's Mission_Reproductive Carrier Screening v0.109 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
Intellectual disability syndromic and non-syndromic v1.230 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
Intellectual disability syndromic and non-syndromic v1.229 SYP Zornitza Stark edited their review of gene: SYP: Changed phenotypes: Intellectual developmental disorder, X-linked 96, MIM# 300802
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
Ciliopathies v1.81 SUFU Zornitza Stark Phenotypes for gene: SUFU were changed from Joubert syndrome 32, MIM#617757; SUFU-related neurodevelopmental disorder, Joubert-like to Joubert syndrome 32, MIM#617757; Neurodevelopmental disorder, MONDO:0700092, SUFU-related
Osteogenesis Imperfecta and Osteoporosis v1.8 SUCO Zornitza Stark Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta to Osteogenesis imperfecta, MONDO:0019019, SUCO-related
Osteogenesis Imperfecta and Osteoporosis v1.7 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 v1.2870 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
Autoinflammatory Disorders v2.13 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
Autoinflammatory Disorders v2.12 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Deafness_IsolatedAndComplex v1.219 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
Deafness_IsolatedAndComplex v1.218 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
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
Inflammatory bowel disease v0.125 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
Inflammatory bowel disease v0.124 STXBP3 Zornitza Stark edited their review of gene: STXBP3: Changed phenotypes: Inborn error of immunity, MONDO:0003778, STXBP3-related
Polydactyly v0.288 RBM10 Zornitza Stark Mode of inheritance for gene: RBM10 was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v1.178 TRIO Chris Ciotta reviewed gene: TRIO: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32109419, 28796471; Phenotypes: Intellectual developmental disorder, autosomal dominant 44, with microcephaly (MIM#617061), Intellectual developmental disorder, autosomal dominant 63, with macrocephaly (MIM#618825), Syndromic intellectual disability (MONDO:0000508), TRIO-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v1.396 SRGAP1 Zornitza Stark Phenotypes for gene: SRGAP1 were changed from congenital anomalies of the kidney and urinary tract to CAKUT, MONDO:0019719, SRGAP1-related
Fetal anomalies v1.395 SRGAP1 Zornitza Stark reviewed gene: SRGAP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: CAKUT, MONDO:0019719, SRGAP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.124 SRGAP1 Zornitza Stark Phenotypes for gene: SRGAP1 were changed from CAKUT to CAKUT, MONDO:0019719, SRGAP1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.123 SRGAP1 Zornitza Stark edited their review of gene: SRGAP1: Changed phenotypes: CAKUT, MONDO:0019719, SRGAP1-related
Aortopathy_Connective Tissue Disorders v1.95 TLN1 Elena Savva reviewed gene: TLN1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 39163585, 30888838; Phenotypes: Idiopathic spontaneous coronary artery dissection MONDO:0007385; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Marked gene: NOTCH3 as ready
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Gene: notch3 has been classified as Amber List (Moderate Evidence).
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Classified gene: NOTCH3 as Amber List (moderate evidence)
Lipodystrophy_Lipoatrophy v1.24 NOTCH3 Zornitza Stark Gene: notch3 has been classified as Amber List (Moderate Evidence).
Lipodystrophy_Lipoatrophy v1.23 NOTCH3 Zornitza Stark gene: NOTCH3 was added
gene: NOTCH3 was added to Lipodystrophy_Lipoatrophy. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 39652711
Phenotypes for gene: NOTCH3 were set to Lipodystrophy, familial partial, type 1, MIM#608600
Review for gene: NOTCH3 was set to AMBER
Added comment: Three families reported with novel missense variants in NOTCH3 and partial lipodystrophy. Variant segregated with phenotype in 4 affected individuals of one family but no additional supportive data presented. Some functional data to suggest GoF mechanism.
Sources: Literature
Hyperthyroidism v0.24 Chirag Patel Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease
Osteopetrosis v0.36 Chirag Patel Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital
Osteopetrosis v0.35 SGMS2 Chirag Patel Classified gene: SGMS2 as Red List (low evidence)
Osteopetrosis v0.35 SGMS2 Chirag Patel Gene: sgms2 has been classified as Red List (Low Evidence).
Osteopetrosis v0.35 SGMS2 Chirag Patel Classified gene: SGMS2 as Red List (low evidence)
Osteopetrosis v0.35 SGMS2 Chirag Patel Gene: sgms2 has been classified as Red List (Low Evidence).
Osteopetrosis v0.34 SGMS2 Chirag Patel reviewed gene: SGMS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Marked gene: COPZ1 as ready
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Classified gene: COPZ1 as Amber List (moderate evidence)
Phagocyte Defects v1.37 COPZ1 Zornitza Stark Gene: copz1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.36 COPZ1 Zornitza Stark gene: COPZ1 was added
gene: COPZ1 was added to Phagocyte Defects. 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
Familial hypoparathyroidism v1.6 Chirag Patel Panel types changed to Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease
Familial hypoparathyroidism v1.5 TBX1 Chirag Patel Classified gene: TBX1 as Green List (high evidence)
Familial hypoparathyroidism v1.5 TBX1 Chirag Patel Gene: tbx1 has been classified as Green List (High Evidence).
Familial hypoparathyroidism v1.4 TBX1 Chirag Patel gene: TBX1 was added
gene: TBX1 was added to Familial hypoparathyroidism. Sources: Expert list,Literature
Mode of inheritance for gene: TBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX1 were set to PMID: 20301696, 16684884, 14585638, 30137364
Phenotypes for gene: TBX1 were set to DiGeorge syndrome MIM# 188400; Velocardiofacial syndrome MIM# 192430; Decreased T cells; Hypoparathyroidism; Conotruncal cardiac malformation; velopalatal insufficiency; abnormal facies (cleft palate, prominent tubular nose etc); intellectual disability; Immunodeficiency; thymic hypoplasia or aplasia with resultant T‐cell dysfunction; renal anomalies; autoimmunity
Review for gene: TBX1 was set to GREEN
Added comment: Well-established disease-gene association with DiGeorge syndrome and Velocardiofacial syndrome; multiple mouse models Most common micro-deletion syndrome (22q11.2 Deletion Syndrome) which can lead to diverse clinical features comprising a triad of immunodeficiency, hypoparathyroidism, and congenital heart defect in addition to renal anomalies, autoimmunity.

Hypoparathyroidism and subsequent hypocalcemia is present in 17%-60% of persons with 22q11.2DS and is typically most serious in the neonatal period.
Sources: Expert list, Literature
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
Genomic newborn screening: ICoNS v0.7 F9 Jorune Balciuniene gene: F9 was added
gene: F9 was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: F9 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: F9 were set to Hemophilia B
Penetrance for gene: F9 were set to Complete
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark changed review comment from: Discussed at ICoNS Gene List Subcommittee meeting on 22/08/2025.

Originally excluded by BabyScreen+ study due to concerns about mappability especially on ES. On further assessment, issue is less pronounced on WGS and subsequently upgraded.

Therefore there is full consensus to include this gene in gNBS studies.; to: Discussed at ICoNS Gene List Subcommittee meeting on 22/08/2025.

Originally excluded by BabyScreen+ study due to concerns about mappability especially on ES. On further assessment, issue is less pronounced on WGS and gene subsequently included in the study.

Therefore there is full consensus to include this gene in gNBS studies.
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark Marked gene: CBS as ready
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark Gene: cbs has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.7 CBS Zornitza Stark Publications for gene: CBS were set to
Genomic newborn screening: ICoNS v0.6 CBS Zornitza Stark Classified gene: CBS as Green List (high evidence)
Genomic newborn screening: ICoNS v0.6 CBS Zornitza Stark Gene: cbs has been classified as Green List (High Evidence).
Genomic newborn screening: ICoNS v0.5 CBS Zornitza Stark reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27778219; Phenotypes: Homocystinuria, B6-responsive and nonresponsive types MIM#236200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hyperinsulinism v1.43 YARS Chirag Patel gene: YARS was added
gene: YARS was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: YARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YARS were set to PMID: 33490854
Phenotypes for gene: YARS were set to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, MIM# 619418
Review for gene: YARS was set to RED
Added comment: Multisystemic disorder characterized by cholestatic hepatitis, poor feeding, poor overall growth, and hypoglycemia apparent from infancy. Most have variable global developmental delay. Additional common features include sensorineural deafness and retinal abnormalities with visual defects. Some patients have pancreatic dysfunction, hypothyroidism, and primary amenorrhea.

PMID: 33490854- only 1 case of hyperinsulinaemic hypoglycaemia,
Sources: Literature
Hyperinsulinism v1.42 TRMT10A Chirag Patel Classified gene: TRMT10A as Red List (low evidence)
Hyperinsulinism v1.42 TRMT10A Chirag Patel Gene: trmt10a has been classified as Red List (Low Evidence).
Hyperinsulinism v1.41 TRMT10A Chirag Patel reviewed gene: TRMT10A: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 25053765; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hyperinsulinism v1.41 MPI Chirag Patel Classified gene: MPI as Red List (low evidence)
Hyperinsulinism v1.41 MPI Chirag Patel Gene: mpi has been classified as Red List (Low Evidence).
Hyperinsulinism v1.40 MPI Chirag Patel reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29531722; Phenotypes: ; Mode of inheritance: None
Hyperinsulinism v1.40 HRAS Chirag Patel Classified gene: HRAS as Green List (high evidence)
Hyperinsulinism v1.40 HRAS Chirag Patel Gene: hras has been classified as Green List (High Evidence).
Hyperinsulinism v1.39 HRAS Chirag Patel gene: HRAS was added
gene: HRAS was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HRAS were set to PMID: 16278907, 25668678, 33224014, 37454648, 37065762
Phenotypes for gene: HRAS were set to Costello syndrome MONDO:0009026
Review for gene: HRAS was set to GREEN
Added comment: Well established gene-disease association.

Neonatal hypoglycemia is quite common (44%), but hyperinsulinemic hypoglycemia has only occasionally been documented.
Sources: Literature
Hyperinsulinism v1.38 EIF2S3 Chirag Patel reviewed gene: EIF2S3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 30878599; Phenotypes: MEHMO syndrome, MIM# 300148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hyperinsulinism v1.38 FAH Chirag Patel Classified gene: FAH as Green List (high evidence)
Hyperinsulinism v1.38 FAH Chirag Patel Gene: fah has been classified as Green List (High Evidence).
Hyperinsulinism v1.37 FAH Chirag Patel gene: FAH was added
gene: FAH was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAH were set to PMID: 15877201
Phenotypes for gene: FAH were set to Tyrosinemia type I MONDO:0010161
Review for gene: FAH was set to GREEN
Added comment: Well established gene-disease association.

PMID: 15877201 reported 3 individuals with Tyrosinaemia type I and acute liver dysfunction. Hyperinsulinemic hypoglycemia was seen in early infancy and all were successfully treated with diazoxide and chlorthiazide, with treatment gradually withdrawn. The mechanism of pancreatic dysfunction is unknown but may be related to accumulation of toxic metabolites.
Sources: Literature
Hyperinsulinism v1.36 ADK Chirag Patel Publications for gene: ADK were set to PMID: 26642971, 21963049
Hyperinsulinism v1.35 CDKN1C Chirag Patel Publications for gene: CDKN1C were set to
Hyperinsulinism v1.34 CDKN1C Chirag Patel Classified gene: CDKN1C as Green List (high evidence)
Hyperinsulinism v1.34 CDKN1C Chirag Patel Gene: cdkn1c has been classified as Green List (High Evidence).
Hyperinsulinism v1.33 CDKN1C Chirag Patel gene: CDKN1C was added
gene: CDKN1C was added to Hyperinsulinism. Sources: Expert list
Mode of inheritance for gene: CDKN1C was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Phenotypes for gene: CDKN1C were set to Beckwith-Wiedemann syndrome due to CDKN1C mutation MONDO:0016476
Review for gene: CDKN1C was set to GREEN
Added comment: Well established gene-disease association.
Hyperinsulinaemic hypoglycemia well documented.
Sources: Expert list
Hyperinsulinism v1.32 ADK Chirag Patel Classified gene: ADK as Green List (high evidence)
Hyperinsulinism v1.32 ADK Chirag Patel Gene: adk has been classified as Green List (High Evidence).
Hyperinsulinism v1.31 ADK Chirag Patel gene: ADK was added
gene: ADK was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: ADK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADK were set to PMID: 26642971, 21963049
Phenotypes for gene: ADK were set to Adenosine kinase deficiency MONDO:0100255
Review for gene: ADK was set to GREEN
Added comment: A rare inborn error of metabolism characterized by persistent hypermethioninemia with increased levels of S-adenosylmethionine and S-adenosylhomocysteine which manifests with encephalopathy, severe global developmental delay, mild to severe liver dysfunction, hypotonia and facial dysmorphism. Epileptic seizures, hypoglycemia and/or cardiac defects may be associated.

PMID: 26642971 reported 11 patients from 8 families.
9/11 had recurrent hypoglycemia (4 in neonatal period).
-3/9 had hyperinsulinism as the underlying cause (not studied in most other cases).
-2/11 were treated with diazoxide with good response.
Sources: Literature
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.18 Chirag Patel Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Classified gene: TBCE as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Gene: tbce has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Classified gene: TBCE as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.17 TBCE Chirag Patel Gene: tbce has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 TBCE Chirag Patel reviewed gene: TBCE: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Classified gene: HOXD13 as Green List (high evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Gene: hoxd13 has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Classified gene: HOXD13 as Green List (high evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.16 HOXD13 Chirag Patel Gene: hoxd13 has been classified as Green List (High Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.15 HDAC4 Chirag Patel Classified gene: HDAC4 as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.15 HDAC4 Chirag Patel Gene: hdac4 has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HDAC4 Chirag Patel reviewed gene: HDAC4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel reviewed gene: HOXD13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34777468, 12649808; Phenotypes: Brachydactyly, type E, 113300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel Deleted their review
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PTHLH Chirag Patel changed review comment from: Type E brachydactyly with shortening mainly of the metacarpals and metatarsals, but in some cases the phalanges as well. Some individuals have moderate short stature and round facies but do not have ectopic ossification or intellectual disability.

Phenotype similar to Albright Hereditary Osteodystrophy but no hormone resistance.; to: Established gene-disease association, multiple families reported.

Type E brachydactyly with shortening mainly of the metacarpals and metatarsals, but in some cases the phalanges as well. Some individuals have moderate short stature and round facies but do not have ectopic ossification or intellectual disability.

Phenotype similar to Albright Hereditary Osteodystrophy but no hormone resistance.
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PTHLH Chirag Patel reviewed gene: PTHLH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20015959, 34897794, 29947179, 28211986; Phenotypes: Brachydactyly, type E2, MIM# 613382; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PRMT7 Chirag Patel reviewed gene: PRMT7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26437029, 27718516, 30513135; Phenotypes: Short stature, brachydactyly, intellectual developmental disability, and seizures, MIM# 617157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel changed review comment from: Not associated with Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy; to: Not associated with Pseudohypoparathyroidism or Albright Hereditary Osteodystrophy
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 GNAS Chirag Patel reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudohypoparathyroidism Ia (103580) AD, Pseudohypoparathyroidism Ib (603233) AD, Pseudohypoparathyroidism Ic (612462) AD, Pseudopseudohypoparathyroidism (612463), Osseous heteroplasia, progressive (166350) AD, Pituitary adenoma 3, multiple types, somatic (617686); Mode of inheritance: Other
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PRKAR1A Chirag Patel reviewed gene: PRKAR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 21651393, 22464250; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 PDE4D Chirag Patel reviewed gene: PDE4D: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22464250, 22464252, 23033274, 24203977; Phenotypes: Acrodysostosis 2, with or without hormone resistance, MIM# 614613; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel Classified gene: HOXD13 as Red List (low evidence)
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.14 HOXD13 Chirag Patel Gene: hoxd13 has been classified as Red List (Low Evidence).
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.13 HOXD13 Chirag Patel reviewed gene: HOXD13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachydactyly, type E 113300, Brachydactyly, type D, MIM# 113200, Syndactyly, type V, MIM# 186300 Synpolydactyly 1, MIM# 186000, Brachydactyly-syndactyly syndrome, MIM# 610713; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), 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
Cataract v0.374 SRD5A3 Rachel Wong reviewed gene: SRD5A3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34925443; Phenotypes: nystagmus, retinal dystrophy, autism, anxiety, ataxia, learning difficulties; 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
Intellectual disability syndromic and non-syndromic v1.229 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
Intellectual disability syndromic and non-syndromic v1.228 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
Intellectual disability syndromic and non-syndromic v1.228 SPOP Zornitza Stark edited their review of gene: SPOP: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SPOP-related
Deafness_IsolatedAndComplex v1.218 SPATC1L Zornitza Stark Phenotypes for gene: SPATC1L were changed from Deafness to Hearing loss disorder, MONDO:0005365 SPATC1L-related
Deafness_IsolatedAndComplex v1.217 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed phenotypes: Hearing loss disorder, MONDO:0005365 SPATC1L-related
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
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.349 SOHLH2 Zornitza Stark Phenotypes for gene: SOHLH2 were changed from Premature ovarian failure to Inherited premature ovarian failure MONDO:0019852, SOHLH2-related
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.348 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
Dilated Cardiomyopathy v1.43 SOD2 Zornitza Stark Phenotypes for gene: SOD2 were changed from Lethal neonatal dilated cardiomyopathy to Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related
Dilated Cardiomyopathy v1.42 SOD2 Zornitza Stark edited their review of gene: SOD2: Changed phenotypes: Dilated cardiomyopathy MONDO:0005021, lethal neonatal, SOD2-related
Intellectual disability syndromic and non-syndromic v1.228 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
Intellectual disability syndromic and non-syndromic v1.227 SOBP Zornitza Stark edited their review of gene: SOBP: Changed phenotypes: Impaired intellectual development, anterior maxillary protrusion, and strabismus, MIM# 613671
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
Intellectual disability syndromic and non-syndromic v1.227 SNX27 Zornitza Stark Phenotypes for gene: SNX27 were changed from intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, SNX27-related
Intellectual disability syndromic and non-syndromic v1.226 SNX27 Zornitza Stark edited their review of gene: SNX27: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SNX27-related
Genetic Epilepsy v1.178 SNX27 Zornitza Stark Phenotypes for gene: SNX27 were changed from intellectual disability; seizures to Neurodevelopmental disorder MONDO:0700092, SNX27-related
Genetic Epilepsy v1.177 SNX27 Zornitza Stark edited their review of gene: SNX27: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SNX27-related
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
Pain syndromes v0.35 SMPDL3A Zornitza Stark Phenotypes for gene: SMPDL3A were changed from Sensory Neuropathy to Sensory Neuropathy MONDO:0002321, SMPDL3A-related
Pain syndromes v0.34 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 v1.2855 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)
Intellectual disability syndromic and non-syndromic v1.226 SMARCD1 Zornitza Stark Phenotypes for gene: SMARCD1 were changed from no OMIM number yet to Neurodevelopmental disorder MONDO:0700092, SMARCD1-related
Intellectual disability syndromic and non-syndromic v1.225 SMARCD1 Zornitza Stark reviewed gene: SMARCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCD1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Intellectual disability syndromic and non-syndromic v1.225 SMARCA5 Zornitza Stark Phenotypes for gene: SMARCA5 were changed from Neurodevelopmental disorder; microcephaly; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Intellectual disability syndromic and non-syndromic v1.224 SMARCA5 Zornitza Stark edited their review of gene: SMARCA5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Microcephaly v1.321 SMARCA5 Zornitza Stark Phenotypes for gene: SMARCA5 were changed from Neurodevelopmental disorder; microcephaly; dysmorphic features to Neurodevelopmental disorder MONDO:0700092, SMARCA5-related
Microcephaly v1.320 SMARCA5 Zornitza Stark edited their review of gene: SMARCA5: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, SMARCA5-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
Fetal anomalies v1.395 SLIT3 Zornitza Stark Phenotypes for gene: SLIT3 were changed from Congenital diaphragmatic hernia to Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Fetal anomalies v1.394 SLIT3 Zornitza Stark reviewed gene: SLIT3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related; Mode of inheritance: None
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
Congenital diaphragmatic hernia v1.17 SLIT3 Zornitza Stark Phenotypes for gene: SLIT3 were changed from Congenital diaphragmatic hernia to Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Congenital diaphragmatic hernia v1.16 SLIT3 Zornitza Stark edited their review of gene: SLIT3: Changed phenotypes: Congenital diaphragmatic hernia MONDO:0005711, SLIT3-related
Fetal anomalies v1.394 SLIT2 Zornitza Stark Phenotypes for gene: SLIT2 were changed from CAKUT; vesicoureteric reflux to CAKUT MONDO:0019719, SLIT2-related
Fetal anomalies v1.393 SLIT2 Zornitza Stark reviewed gene: SLIT2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: CAKUT MONDO:0019719, SLIT2-related; Mode of inheritance: None
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
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.123 SLIT2 Zornitza Stark Phenotypes for gene: SLIT2 were changed from CAKUT to CAKUT MONDO:0019719, SLIT2-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.122 SLIT2 Zornitza Stark edited their review of gene: SLIT2: Changed phenotypes: CAKUT MONDO:0019719, SLIT2-related
Mitochondrial disease v0.989 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 v1.2848 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
Fetal anomalies v1.393 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
Intellectual disability syndromic and non-syndromic v1.224 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
Intellectual disability syndromic and non-syndromic v1.223 SLC6A17 Zornitza Stark edited their review of gene: SLC6A17: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 48, MIM# 616269
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
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Marked gene: DAAM2 as ready
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Added comment: Comment when marking as ready: Downgraded to RED as only one plausible family.
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Gene: daam2 has been classified as Red List (Low Evidence).
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Classified gene: DAAM2 as Red List (low evidence)
Differences of Sex Development v1.12 DAAM2 Zornitza Stark Gene: daam2 has been classified as Red List (Low Evidence).
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
Osteogenesis Imperfecta and Osteoporosis v1.7 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
Osteogenesis Imperfecta and Osteoporosis v1.6 WNT1 Zornitza Stark Publications for gene: WNT1 were set to 23499309; 23499310; 23656646; 26671912
Callosome v0.553 MAP1B Zornitza Stark Marked gene: MAP1B as ready
Callosome v0.553 MAP1B Zornitza Stark Gene: map1b has been classified as Green List (High Evidence).
Callosome v0.553 MAP1B Zornitza Stark Phenotypes for gene: MAP1B were changed from corpus callosum to Periventricular nodular heterotopia 9, MIM# 618918
Callosome v0.552 MAP1B Zornitza Stark Classified gene: MAP1B as Green List (high evidence)
Callosome v0.552 MAP1B Zornitza Stark Gene: map1b has been classified as Green List (High Evidence).
Callosome v0.551 MAP1B Zornitza Stark reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Periventricular nodular heterotopia 9, MIM# 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Disorders of immune dysregulation v1.21 MAP4K1 Zornitza Stark Marked gene: MAP4K1 as ready
Disorders of immune dysregulation v1.21 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.21 MAP4K1 Zornitza Stark Phenotypes for gene: MAP4K1 were changed from Immune dysregulation to Inborn error of immunity, MONDO:0003778, MAP4K1-related
Disorders of immune dysregulation v1.20 MAP4K1 Zornitza Stark Classified gene: MAP4K1 as Green List (high evidence)
Disorders of immune dysregulation v1.20 MAP4K1 Zornitza Stark Gene: map4k1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v1.19 MAP4K1 Zornitza Stark changed review comment from: One multiplex family with 8 affected individuals and one family with single individual affected, extensive functional data.; to: One multiplex family with 8 affected individuals and one family with single individual affected, extensive functional data. Borderline Amber/Green.
Disorders of immune dysregulation v1.19 MAP4K1 Zornitza Stark reviewed gene: MAP4K1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, MAP4K1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pierre Robin Sequence v0.52 MN1 Zornitza Stark Marked gene: MN1 as ready
Pierre Robin Sequence v0.52 MN1 Zornitza Stark Gene: mn1 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.52 MN1 Zornitza Stark Phenotypes for gene: MN1 were changed from to Cleft palate; CEBALID syndrome, MIM# 618774
Pierre Robin Sequence v0.51 MN1 Zornitza Stark Publications for gene: MN1 were set to
Pierre Robin Sequence v0.50 MN1 Zornitza Stark Mode of inheritance for gene: MN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pierre Robin Sequence v0.49 MN1 Zornitza Stark reviewed gene: MN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33351141, 31834374, 33351070, 15870292; Phenotypes: Cleft palate, CEBALID syndrome, MIM# 618774; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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.
Clefting disorders v0.267 MN1 Zornitza Stark Publications for gene: MN1 were set to 33351141; 31834374; 33351070
Clefting disorders v0.266 MN1 Zornitza Stark Classified gene: MN1 as Green List (high evidence)
Clefting disorders v0.266 MN1 Zornitza Stark Gene: mn1 has been classified as Green List (High Evidence).
Clefting disorders v0.265 MN1 Sarah Milton reviewed gene: MN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33351070, 31834374, 31834374, 15870292; Phenotypes: Cleft palate, MONDO:0016064, MN1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Transplant Co-Morbidity v0.19 CHST14 Zornitza Stark Marked gene: CHST14 as ready
Transplant Co-Morbidity v0.19 CHST14 Zornitza Stark Gene: chst14 has been classified as Green List (High Evidence).
Transplant Co-Morbidity v0.19 CHST14 Zornitza Stark Mode of inheritance for gene: CHST14 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.57 CHST14 Zornitza Stark Mode of inheritance for gene: CHST14 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.56 CHST14 Zornitza Stark edited their review of gene: CHST14: Changed phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1, MIM# 601776; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v1.19 MAP4K1 Peter McNaughton gene: MAP4K1 was added
gene: MAP4K1 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: MAP4K1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K1 were set to PMID: 40716650
Phenotypes for gene: MAP4K1 were set to Immune dysregulation
Penetrance for gene: MAP4K1 were set to Incomplete
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.
Sources: Literature
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Marked gene: ARHGAP36 as ready
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Classified gene: ARHGAP36 as Amber List (moderate evidence)
Ectodermal Dysplasia v0.97 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.96 ARHGAP36 Zornitza Stark gene: ARHGAP36 was added
gene: ARHGAP36 was added to Ectodermal Dysplasia. 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
Genomic newborn screening: ICoNS v0.5 CBS Lilian Downie gene: CBS was added
gene: CBS was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: CBS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CBS were set to Homocystinuria, B6-responsive and nonresponsive types MIM#236200
Added comment: Well established gene-disease association.

Multi-system disorder, onset can be in infancy - highly variable.
In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature.

Homozygous for the p.I278T can be asymptomatic throughout life or have isolated thromboembolism.

Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219.

Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids

Paediatric actionable gene by ClinGen.
Sources: Expert list
Genomic newborn screening: ICoNS v0.4 AK2 Lilian Downie reviewed gene: AK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19043416, 19043417, 40654267; Phenotypes: Reticular dysgenesis MIM#267500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
Hair disorders v0.78 ARHGAP36 Zornitza Stark Marked gene: ARHGAP36 as ready
Hair disorders v0.78 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Hair disorders v0.78 ARHGAP36 Zornitza Stark Publications for gene: ARHGAP36 were set to
Hair disorders v0.77 ARHGAP36 Zornitza Stark changed review comment from: 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.

AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.

Sources: Expert Review; to: 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
Hair disorders v0.77 ARHGAP36 Zornitza Stark edited their review of gene: ARHGAP36: Changed publications: 35986704, 40015599; Changed phenotypes: Bazex-Dupre-Christol syndrome, MIM# 301845
Hair disorders v0.77 ARHGAP36 Zornitza Stark changed review comment from: 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.
Sources: Expert Review; to: 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.

AMBER rating until we decide how to handle regulatory region information in PanelApp Aus -- coding region variants not reported.

Sources: Expert Review
Hair disorders v0.77 ARHGAP36 Zornitza Stark Classified gene: ARHGAP36 as Amber List (moderate evidence)
Hair disorders v0.77 ARHGAP36 Zornitza Stark Gene: arhgap36 has been classified as Amber List (Moderate Evidence).
Hair disorders v0.76 ARHGAP36 Zornitza Stark gene: ARHGAP36 was added
gene: ARHGAP36 was added to Hair disorders. 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)
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.
Sources: Expert Review
Callosome v0.551 MAP1B Boris Keren edited their review of gene: MAP1B: Changed publications: PMID: 31317654, PMID: 30150678
Callosome v0.551 MAP1B Boris Keren reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31317654, 30150678; Phenotypes: intellectual disability, corpus callosum dysgenesis, corpus callosum hypoplasia, seizures, microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Callosome v0.551 MAP1B Boris Keren gene: MAP1B was added
gene: MAP1B was added to Callosome. Sources: Literature
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1B were set to PMID: 30150678; PMID: 31317654
Phenotypes for gene: MAP1B were set to corpus callosum
Penetrance for gene: MAP1B were set to Incomplete
Mode of pathogenicity for gene: MAP1B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Osteogenesis Imperfecta and Osteoporosis v1.5 WNT1 Chirag Patel reviewed gene: WNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27005318, 25010833, 30246918, 30283887; Phenotypes: Osteoporosis MONDO:0005298; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v1.136 GFAP Lilian Downie reviewed gene: GFAP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Alexander disease, MIM#203450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Intellectual disability syndromic and non-syndromic v1.223 YWHAZ Zornitza Stark Phenotypes for gene: YWHAZ were changed from Intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related
Intellectual disability syndromic and non-syndromic v1.222 YWHAZ Zornitza Stark Classified gene: YWHAZ as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.222 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.221 YWHAZ Zornitza Stark reviewed gene: YWHAZ: Rating: AMBER; Mode of pathogenicity: None; Publications: 31024343, 35143101, 35501409, 22124272, 26207352; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, YWHAZ-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bone Marrow Failure v1.123 THRA Zornitza Stark Marked gene: THRA as ready
Bone Marrow Failure v1.123 THRA Zornitza Stark Gene: thra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.123 THRA Zornitza Stark Classified gene: THRA as Amber List (moderate evidence)
Bone Marrow Failure v1.123 THRA Zornitza Stark Gene: thra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.122 THRA Zornitza Stark gene: THRA was added
gene: THRA was added to Bone Marrow Failure. Sources: Expert Review
Mode of inheritance for gene: THRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: THRA were set to Hypothyroidism, congenital, nongoitrous, 6, MIM# 614450
Review for gene: THRA was set to AMBER
Added comment: Over 10 sequence variants (including truncating nonsense and frameshift as well as missense) have been reported in the literature in association with consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia, delayed dentition and constipation) and specific facial features. Milder outcomes for missense variants and more severe phenotype manifestations for truncating variants have been observed.

Most of the variants are located in the last exon of the THRA isoform 1 (NM_199334.5; a shorter isoform) affecting the C-terminal ligand binding domain with nonsense and frameshift variants predicted to escape nonsense mediated decay. These variants are either de novo or inherited from an affected parent. A few pedigrees are also available with segregation data. Truncating variants appear to have near complete penetrance whereas missense variants may be associated with variable expressivity (Family C - PMID: 27144938).

Note routine TFTs can be normal.

We have identified multiple individuals internally with pathogenic de novo variants in this gene and macrocytic anaemia.

AMBER rating as only one lineage affected. However, the above patients tested through haematology.
Sources: Expert Review
Red cell disorders v1.33 THRA Zornitza Stark Marked gene: THRA as ready
Red cell disorders v1.33 THRA Zornitza Stark Gene: thra has been classified as Green List (High Evidence).
Red cell disorders v1.33 THRA Zornitza Stark Classified gene: THRA as Green List (high evidence)
Red cell disorders v1.33 THRA Zornitza Stark Gene: thra has been classified as Green List (High Evidence).
Red cell disorders v1.32 THRA Zornitza Stark gene: THRA was added
gene: THRA was added to Red cell disorders. Sources: Expert Review
Mode of inheritance for gene: THRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: THRA were set to Hypothyroidism, congenital, nongoitrous, 6, MIM# 614450
Review for gene: THRA was set to GREEN
Added comment: Over 10 sequence variants (including truncating nonsense and frameshift as well as missense) have been reported in the literature in association with consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia, delayed dentition and constipation) and specific facial features. Milder outcomes for missense variants and more severe phenotype manifestations for truncating variants have been observed.

Most of the variants are located in the last exon of the THRA isoform 1 (NM_199334.5; a shorter isoform) affecting the C-terminal ligand binding domain with nonsense and frameshift variants predicted to escape nonsense mediated decay. These variants are either de novo or inherited from an affected parent. A few pedigrees are also available with segregation data. Truncating variants appear to have near complete penetrance whereas missense variants may be associated with variable expressivity (Family C - PMID: 27144938).

Note routine TFTs can be normal.

We have identified multiple individuals internally with pathogenic de novo variants in this gene and macrocytic anaemia.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v1.221 THRA Zornitza Stark reviewed gene: THRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypothyroidism congenital nongoitrous 6 (MIM 614450); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2837 RUSC2 Zornitza Stark commented on gene: RUSC2: LIMITED by ClinGen but note multiple P/LP ClinVar submissions
Callosome v0.551 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX to Alsahan-Harris syndrome, MIM#621307; Orofaciodigital syndrome type IX, MIM#258865
Callosome v0.550 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566
Callosome v0.549 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Callosome v0.549 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Callosome v0.548 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, anencephaly and ACC, 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.

Note previous reports of individuals characterised as having OFD, similarly affected by midline brain abnormalities, including ACC, again supporting the notion of a spectrum.; Changed rating: GREEN; Changed publications: 24285566, 31130284, 36826837, 32573025; Changed phenotypes: Alsahan-Harris syndrome, MIM#621307, Orofaciodigital syndrome type IX, MIM#258865
Ciliopathies v1.80 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX, MIM#258865 to Orofaciodigital syndrome type IX, MIM#258865; Alsahan-Harris syndrome, MIM#621307; Retinitis pigmentosa 100, MIM# 621280
Ciliopathies v1.79 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 36826837; 40319332
Ciliopathies v1.78 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.

At the milder end of the spectrum, note PMIDs 37768732 and 39930170, associating variants in this gene and RP.; Changed publications: 24285566, 32573025, 32060556, 31130284, 36826837, 40319332, 31130284, 36826837, 37768732, 39930170; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865, Alsahan-Harris syndrome, MIM#621307, Retinitis pigmentosa 100, MIM# 621280
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.221 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.220 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 36826837; 40319332
Phenotypes for gene: TBC1D32 were set to Orofacial digital syndrome type IX, MIM#258865
Review for gene: TBC1D32 was set to GREEN
Added comment: Multiple affected individuals reported from unrelated families. Midline brain abnormalities are a feature and DD/ID is variable.
Sources: Expert Review
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Holoprosencephaly and septo-optic dysplasia v1.20 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Holoprosencephaly and septo-optic dysplasia v1.19 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed rating: GREEN
Holoprosencephaly and septo-optic dysplasia v1.19 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Holoprosencephaly and septo-optic dysplasia. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 31130284; 36826837; 32573025
Phenotypes for gene: TBC1D32 were set to Alsahan-Harris syndrome, MIM#621307; Orofaciodigital syndrome type IX, MIM#258865
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.

Note previous reports of individuals characterised as having OFD, similarly affected by midline brain abnormalities, again supporting the notion of a spectrum.
Sources: Expert Review
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Anophthalmia_Microphthalmia_Coloboma v1.50 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Anophthalmia_Microphthalmia_Coloboma v1.49 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Anophthalmia_Microphthalmia_Coloboma. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 31130284; 36826837; 32573025
Phenotypes for gene: TBC1D32 were set to Alsahan-Harris syndrome, MIM#621307
Review for gene: TBC1D32 was set to GREEN
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.
Sources: Expert Review
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
Fetal anomalies v1.392 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX, MIM#258865 to Alsahan-Harris syndrome, MIM#621307; Orofaciodigital syndrome type IX, MIM#258865
Fetal anomalies v1.391 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284; 36826837; 40319332
Fetal anomalies v1.390 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed publications: 31130284, 32573025, 36826837, 24285566, 32060556, 31130284, 39930170, 36826837, 40319332
Fetal anomalies v1.390 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed phenotypes: Alsahan-Harris syndrome, MIM#621307, Orofaciodigital syndrome type IX, MIM#258865
Fetal anomalies v1.390 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: In addition, 6 fetuses from 5 unrelated families reported with a very severe fetal phenotype, characterised by severe brain defects, 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: 31130284, 32573025, 36826837; Changed phenotypes: Alsahan-Harris syndrome, MIM#621307
Fetal anomalies v1.390 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofacial digital syndrome type IX to Orofaciodigital syndrome type IX, MIM#258865
Fetal anomalies v1.389 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 32573025; 32060556; 31130284
Fetal anomalies v1.388 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, 36826837, 40319332; Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865
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
Ciliopathies v1.78 TBC1D32 Zornitza Stark Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome type IX to Orofaciodigital syndrome type IX, MIM#258865
Ciliopathies v1.77 TBC1D32 Zornitza Stark Publications for gene: TBC1D32 were set to 24285566; 32573025; 32060556; 31130284
Ciliopathies v1.76 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Added comment: PMIDs 36826837 and 40319332: four more individuals reported.; Changed publications: 24285566, 32573025, 32060556, 31130284, 36826837, 40319332
Ciliopathies v1.76 TBC1D32 Zornitza Stark edited their review of gene: TBC1D32: Changed phenotypes: Orofaciodigital syndrome type IX, MIM#258865
Callosome v0.548 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Callosome v0.548 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.315 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Skeletal dysplasia v0.315 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Polydactyly v0.287 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Polydactyly v0.287 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Hydrocephalus_Ventriculomegaly v0.128 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Hydrocephalus_Ventriculomegaly v0.128 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Skeletal Dysplasia_Fetal v0.233 HYLS1 Chirag Patel Classified gene: HYLS1 as Green List (high evidence)
Skeletal Dysplasia_Fetal v0.233 HYLS1 Chirag Patel Gene: hyls1 has been classified as Green List (High Evidence).
Fetal anomalies v1.388 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal Dysplasia_Fetal v0.232 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hydrocephalus_Ventriculomegaly v0.127 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Polydactyly v0.286 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v0.314 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting disorders v0.265 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Callosome v0.547 HYLS1 Chirag Patel reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome MONDO:0006037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Deafness_IsolatedAndComplex v1.217 SLC9A1 Chirag Patel Classified gene: SLC9A1 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.217 SLC9A1 Chirag Patel Gene: slc9a1 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.216 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 v1.2833 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).
Ataxia v1.44 SLC9A1 Chirag Patel Classified gene: SLC9A1 as Green List (high evidence)
Ataxia v1.44 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
Ataxia v1.43 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
Deafness_IsolatedAndComplex v1.216 ESRP1 Chirag Patel Classified gene: ESRP1 as Red List (low evidence)
Deafness_IsolatedAndComplex v1.216 ESRP1 Chirag Patel Gene: esrp1 has been classified as Red List (Low Evidence).
Deafness_IsolatedAndComplex v1.215 ESRP1 Chirag Patel reviewed gene: ESRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pulmonary Fibrosis_Interstitial Lung Disease v0.90 NHP2 Chirag Patel gene: NHP2 was added
gene: NHP2 was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Expert Review
Mode of inheritance for gene: NHP2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NHP2 were set to Dyskeratosis congenita, autosomal recessive 2 MONDO:0013519
Review for gene: NHP2 was set to RED
Added comment: ClinGen 'limited' classification.

NHP2 ribonucleoprotein (NHP2) was first reported in relation to autosomal recessive dyskeratosis congenita in 2008 (Vulliamy et al., PMID 18523010). NHP2 biallelic variant carriers present with features common to other monogenic telomere biology disorders (TBD) like: oral leukoplakia, reticular skin pigmentation, nail dystrophy, bone marrow failure, intellectual disability, and short telomeres. Variation in other telomere related genes like TERT and TERC have been shown to be related to interstitial lung disease (ILD), but to date ILD has not been observed for this gene-disease entity (PMID 38718684). Seven variants (6 missense, and 1 stop-loss extension) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data from 3 different publications describing a total of 4 probands with ages of onset being reported in both childhood and adulthood. Additionally, 4 families have been reported with heterozygous variant carriers that have presented with features consistent with TBD. The ClinGen Interstitial Lung Disease GCEP has decided to exclude heterozygous cases from this curation due to high population frequencies and/or lack of sufficient detail regarding genotyping. If, however, more convincing data of autosomal dominant inheritance becomes available, the curated entity and classification will be revisited. This gene-disease relationship is supported by protein interaction data, a yeast model and functional alteration in non-patient cells; PMID 11160879, 11074001, 37440454). Experimental data demonstrated that variant NHP2 is related to a decrease in the expression of TERC, and that expression of variant NHP2 and interaction with NOP10 and DKC1 were reduced. The mechanism is unclear but thought to be LOF. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date April 15, 2025 (SOP 11). This gene-disease pair was originally evaluated by the General GCEP on June 1, 2017. It was reevaluated on August 1, 2025. Although additional case and experimental evidence (PMIDs: 37440454, 31985013) was published, the classification did not change.
Sources: Expert Review
Hypertrophic cardiomyopathy_HCM v1.7 JPH2 Chirag Patel Classified gene: JPH2 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.7 JPH2 Chirag Patel Gene: jph2 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.6 JPH2 Chirag Patel reviewed gene: JPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypertrophic cardiomyopathy MONDO:0005045; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Classified gene: SLC25A4 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Gene: slc25a4 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Classified gene: SLC25A4 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.6 SLC25A4 Chirag Patel Gene: slc25a4 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.5 SLC25A4 Chirag Patel reviewed gene: SLC25A4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive MONDO:0014175; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy_HCM v1.5 FXN Chirag Patel Classified gene: FXN as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v1.5 FXN Chirag Patel Gene: fxn has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v1.4 FXN Chirag Patel reviewed gene: FXN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Friedreich ataxia MIM#229300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v1.136 MYL2 Zornitza Stark Marked gene: MYL2 as ready
Genomic newborn screening: BabyScreen+ v1.136 MYL2 Zornitza Stark Gene: myl2 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v1.136 MYL2 Zornitza Stark Phenotypes for gene: MYL2 were changed from Cardiomyopathy, familial hypertrophic, 10 to Cardiomyopathy, hypertrophic, 10, MIM# 608758
Genomic newborn screening: BabyScreen+ v1.135 MYL2 Zornitza Stark reviewed gene: MYL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, hypertrophic, 10, MIM# 608758; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.135 LMNA Zornitza Stark Marked gene: LMNA as ready
Genomic newborn screening: BabyScreen+ v1.135 LMNA Zornitza Stark Gene: lmna has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.135 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from Charcot-Marie-Tooth disease; Emery-Dreifuss muscular dystrophy 2; Dilated cardiomyopathy to Cardiomyopathy, dilated, 1A, MIM# 115200
Genomic newborn screening: BabyScreen+ v1.134 LMNA Zornitza Stark Classified gene: LMNA as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.134 LMNA Zornitza Stark Gene: lmna has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.133 LMNA Zornitza Stark reviewed gene: LMNA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1A, MIM# 115200; Mode of inheritance: None
Genomic newborn screening: BabyScreen+ v1.133 KRIT1 Zornitza Stark Marked gene: KRIT1 as ready
Genomic newborn screening: BabyScreen+ v1.133 KRIT1 Zornitza Stark Gene: krit1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.133 KRIT1 Zornitza Stark Publications for gene: KRIT1 were set to PMID: 30061145, 20301470, 27561926
Genomic newborn screening: BabyScreen+ v1.132 KRIT1 Zornitza Stark Classified gene: KRIT1 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.132 KRIT1 Zornitza Stark Gene: krit1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.131 KRIT1 Zornitza Stark reviewed gene: KRIT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral cavernous malformations-1 MIM#116860; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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.
Genomic newborn screening: BabyScreen+ v1.131 KCNE1 Zornitza Stark Marked gene: KCNE1 as ready
Genomic newborn screening: BabyScreen+ v1.131 KCNE1 Zornitza Stark Gene: kcne1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.131 KCNE1 Zornitza Stark Phenotypes for gene: KCNE1 were changed from Long QT syndrome-5; Jervell and Lange-Nielsen syndrome to Long QT syndrome 5, MIM# 613695
Genomic newborn screening: BabyScreen+ v1.130 KCNE1 Zornitza Stark Classified gene: KCNE1 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.130 KCNE1 Zornitza Stark Gene: kcne1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.129 KCNE1 Zornitza Stark reviewed gene: KCNE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 5, MIM# 613695; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v1.129 GPD1L Zornitza Stark Marked gene: GPD1L as ready
Genomic newborn screening: BabyScreen+ v1.129 GPD1L Zornitza Stark Gene: gpd1l has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.129 GPD1L Zornitza Stark Phenotypes for gene: GPD1L were changed from Brugada syndrome to Brugada syndrome 2, MIM# 611777
Genomic newborn screening: BabyScreen+ v1.128 GPD1L Zornitza Stark Classified gene: GPD1L as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.128 GPD1L Zornitza Stark Gene: gpd1l has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.127 GPD1L Zornitza Stark reviewed gene: GPD1L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brugada syndrome 2, MIM# 611777; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.127 GJA5 Zornitza Stark Marked gene: GJA5 as ready
Genomic newborn screening: BabyScreen+ v1.127 GJA5 Zornitza Stark Gene: gja5 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.127 GJA5 Zornitza Stark Phenotypes for gene: GJA5 were changed from Atrial fibrillation to Atrial fibrillation, familial, 11, MIM# 614049
Genomic newborn screening: BabyScreen+ v1.126 GJA5 Zornitza Stark Classified gene: GJA5 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.126 GJA5 Zornitza Stark Gene: gja5 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.125 GJA5 Zornitza Stark reviewed gene: GJA5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial fibrillation, familial, 11, OMIM# 614049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.125 DES Zornitza Stark Marked gene: DES as ready
Genomic newborn screening: BabyScreen+ v1.125 DES Zornitza Stark Gene: des has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.125 DES Zornitza Stark Phenotypes for gene: DES were changed from Myopathy, myofibrillar; Cardiomyopathy, dilated to Cardiomyopathy, dilated, 1I, MIM# 604765
Genomic newborn screening: BabyScreen+ v1.124 DES Zornitza Stark Classified gene: DES as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.124 DES Zornitza Stark Gene: des has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.123 DES Zornitza Stark reviewed gene: DES: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1I, MIM# 604765; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.123 CRYAB Zornitza Stark Marked gene: CRYAB as ready
Genomic newborn screening: BabyScreen+ v1.123 CRYAB Zornitza Stark Gene: cryab has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.123 CRYAB Zornitza Stark Phenotypes for gene: CRYAB were changed from Myofibrillar myopathy; Cardiomyopathy, dilated to Cardiomyopathy, dilated, 1II MIM#615184
Genomic newborn screening: BabyScreen+ v1.122 CRYAB Zornitza Stark Classified gene: CRYAB as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v1.122 CRYAB Zornitza Stark Gene: cryab has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v1.121 CRYAB Zornitza Stark reviewed gene: CRYAB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, dilated, 1II MIM#615184; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v1.121 CACNA1C Zornitza Stark Marked gene: CACNA1C as ready
Genomic newborn screening: BabyScreen+ v1.121 CACNA1C Zornitza Stark Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v1.121 CACNA1C Zornitza Stark reviewed gene: CACNA1C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 8, MIM# 618447, Timothy syndrome, MIM# 601005; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Disorders of immune dysregulation v1.19 RC3H1 Zornitza Stark Marked gene: RC3H1 as ready
Disorders of immune dysregulation v1.19 RC3H1 Zornitza Stark Gene: rc3h1 has been classified as Red List (Low Evidence).
Disorders of immune dysregulation v1.19 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from to Inborn error of immunity, MONDO:0003778, RC3H1-related
Disorders of immune dysregulation v1.18 RC3H1 Zornitza Stark Classified gene: RC3H1 as Red List (low evidence)
Disorders of immune dysregulation v1.18 RC3H1 Zornitza Stark Gene: rc3h1 has been classified as Red List (Low Evidence).
Disorders of immune dysregulation v1.17 RC3H1 Zornitza Stark reviewed gene: RC3H1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, RC3H1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.989 PMPCA Zornitza Stark Marked gene: PMPCA as ready
Mitochondrial disease v0.989 PMPCA Zornitza Stark Gene: pmpca has been classified as Green List (High Evidence).
Mitochondrial disease v0.989 PMPCA Zornitza Stark Phenotypes for gene: PMPCA were changed from to Spinocerebellar ataxia, autosomal recessive 2, MIM# 213200
Mitochondrial disease v0.988 PMPCA Zornitza Stark Publications for gene: PMPCA were set to
Mitochondrial disease v0.987 PMPCA Zornitza Stark Mode of inheritance for gene: PMPCA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.219 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
Intellectual disability syndromic and non-syndromic v1.218 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
Intellectual disability syndromic and non-syndromic v1.217 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 v1.2825 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
Intellectual disability syndromic and non-syndromic v1.217 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
Intellectual disability syndromic and non-syndromic v1.216 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679
Intellectual disability syndromic and non-syndromic v1.215 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed publications: 40210679, 40442284; Changed phenotypes: Developmental and epileptic encephalopathy 119, MIM# 621304
Genetic Epilepsy v1.177 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
Genetic Epilepsy v1.176 RNU2-2P Zornitza Stark Publications for gene: RNU2-2P were set to 40210679
Genetic Epilepsy v1.175 RNU2-2P Zornitza Stark edited their review of gene: RNU2-2P: Changed publications: 40210679, 40442284; Changed phenotypes: Developmental and epileptic encephalopathy 119, MIM# 621304
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
Disorders of immune dysregulation v1.17 RC3H1 Peter McNaughton gene: RC3H1 was added
gene: RC3H1 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: RC3H1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RC3H1 were set to PMID: 40769319
Review for gene: RC3H1 was set to AMBER
Added comment: 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.
Previous single case of HLH in PMID: 31636267 though this patient was homozygous nonsense.
Sources: Literature
Fetal anomalies v1.388 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Fetal anomalies v1.387 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
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
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.150 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Anophthalmia_Microphthalmia_Coloboma v1.48 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Syndromic disease, MONDO:0002254, NR6A1-related to Oculovertebral syndrome, MIM# 621277
Anophthalmia_Microphthalmia_Coloboma v1.47 NR6A1 Zornitza Stark edited their review of gene: NR6A1: Changed phenotypes: Oculovertebral syndrome, MIM# 621277
Fetal anomalies v1.387 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Fetal anomalies v1.387 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
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).
Ciliopathies v1.76 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Ciliopathies v1.76 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Zornitza Stark Marked gene: TMEM17 as ready
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Zornitza Stark Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Marked gene: BLOC1S1 as ready
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Classified gene: BLOC1S1 as Green List (high evidence)
Leukodystrophy - paediatric v0.322 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.321 BLOC1S1 Zornitza Stark reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic Atrophy v1.47 BLOC1S1 Zornitza Stark Marked gene: BLOC1S1 as ready
Optic Atrophy v1.47 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Optic Atrophy v1.47 BLOC1S1 Zornitza Stark Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Optic Atrophy v1.46 BLOC1S1 Zornitza Stark Classified gene: BLOC1S1 as Green List (high evidence)
Optic Atrophy v1.46 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Optic Atrophy v1.45 BLOC1S1 Zornitza Stark reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.175 BLOC1S1 Zornitza Stark Marked gene: BLOC1S1 as ready
Genetic Epilepsy v1.175 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.175 BLOC1S1 Zornitza Stark Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Genetic Epilepsy v1.174 BLOC1S1 Zornitza Stark Classified gene: BLOC1S1 as Green List (high evidence)
Genetic Epilepsy v1.174 BLOC1S1 Zornitza Stark Gene: bloc1s1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.173 BLOC1S1 Zornitza Stark reviewed gene: BLOC1S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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).
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Marked gene: ST5 as ready
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Classified gene: ST5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.215 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.214 ST5 Zornitza Stark Tag new gene name tag was added to gene: ST5.
Genetic Epilepsy v1.173 ST5 Zornitza Stark Marked gene: ST5 as ready
Genetic Epilepsy v1.173 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.173 ST5 Zornitza Stark Classified gene: ST5 as Green List (high evidence)
Genetic Epilepsy v1.173 ST5 Zornitza Stark Gene: st5 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.172 ST5 Zornitza Stark Tag new gene name tag was added to gene: ST5.
Fetal anomalies v1.387 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Fetal anomalies v1.387 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.386 FRYL Zornitza Stark edited their review of gene: FRYL: Added comment: Published literature re-reviewed:
A number of variants reported in currently published gene discovery paper were not absent in gnomAD v4.

Loss of function is the proposed mechanism of disease however too many NMD predicted variants throughout the gene in gnomAD v4 to be consistent with rare disease.

Functional studies performed in drosophila using FRY orthologue, however, humans have two paralogous genes - FRY and FRYL. As such, difficult to translate this model to implications in human disease or even judge to what extent it recapitulates the human phenotype.

Note multiple isoforms for FRYL however no clear paucity of NMD predicted variants in the population within one region of the gene.

Requires further literature to establish gene disease association.; Changed rating: AMBER
Congenital Heart Defect v0.451 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Congenital Heart Defect v0.451 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.450 FRYL Zornitza Stark edited their review of gene: FRYL: Added comment: Published literature re-reviewed:
A number of variants reported in currently published gene discovery paper were not absent in gnomAD v4.

Loss of function is the proposed mechanism of disease however too many NMD predicted variants throughout the gene in gnomAD v4 to be consistent with rare disease.

Functional studies performed in drosophila using FRY orthologue, however, humans have two paralogous genes - FRY and FRYL. As such, difficult to translate this model to implications in human disease or even judge to what extent it recapitulates the human phenotype.

Note multiple isoforms for FRYL however no clear paucity of NMD predicted variants in the population within one region of the gene.

Requires further literature to establish gene disease association.; Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v1.214 FRYL Zornitza Stark Classified gene: FRYL as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.214 FRYL Zornitza Stark Gene: fryl has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.213 FRYL Zornitza Stark edited their review of gene: FRYL: Added comment: Published literature re-reviewed:
A number of variants reported in currently published gene discovery paper were not absent in gnomAD v4.

Loss of function is the proposed mechanism of disease however too many NMD predicted variants throughout the gene in gnomAD v4 to be consistent with rare disease.

Functional studies performed in drosophila using FRY orthologue, however, humans have two paralogous genes - FRY and FRYL. As such, difficult to translate this model to implications in human disease or even judge to what extent it recapitulates the human phenotype.

Note multiple isoforms for FRYL however no clear paucity of NMD predicted variants in the population within one region of the gene.

Requires further literature to establish gene disease association.; Changed rating: AMBER
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).
Skeletal dysplasia v0.314 OGFRL1 Zornitza Stark Marked gene: OGFRL1 as ready
Skeletal dysplasia v0.314 OGFRL1 Zornitza Stark Gene: ogfrl1 has been classified as Red List (Low Evidence).
Skeletal dysplasia v0.314 OGFRL1 Zornitza Stark gene: OGFRL1 was added
gene: OGFRL1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: OGFRL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGFRL1 were set to 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 v1.2818 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
Genetic Epilepsy v1.172 ST5 Rylee Peters gene: ST5 was added
gene: ST5 was added to Genetic Epilepsy. 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
Intellectual disability syndromic and non-syndromic v1.213 ST5 Rylee Peters gene: ST5 was added
gene: ST5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ST5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ST5 were set to 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 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
Genetic Epilepsy v1.172 BLOC1S1 Rylee Peters gene: BLOC1S1 was added
gene: BLOC1S1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Phenotypes for gene: BLOC1S1 were set to Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related
Review for gene: BLOC1S1 was set to GREEN
Added comment: 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.
Sources: Literature
Optic Atrophy v1.45 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.
Sources: Literature; 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.
Sources: Literature
Leukodystrophy - paediatric v0.321 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.
Sources: Literature; 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.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.213 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 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.
Optic Atrophy v1.45 BLOC1S1 Rylee Peters gene: BLOC1S1 was added
gene: BLOC1S1 was added to Optic Atrophy. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Phenotypes for gene: BLOC1S1 were set to Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related
Review for gene: BLOC1S1 was set to GREEN
Added comment: 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.
Sources: Literature
Leukodystrophy - paediatric v0.321 BLOC1S1 Rylee Peters gene: BLOC1S1 was added
gene: BLOC1S1 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Phenotypes for gene: BLOC1S1 were set to Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related
Review for gene: BLOC1S1 was set to GREEN
Added comment: 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.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.213 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 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
Repeat Disorders v0.267 THAP11_SCA51_CAG Bryony Thompson edited their review of STR: THAP11_SCA51_CAG: Changed publications: 15368101, 24677642, 34165550, 38113319, 40459937, 39651830, 37148549
Repeat Disorders v0.267 THAP11_SCA51_CAG Bryony Thompson Publications for STR: THAP11_SCA51_CAG were set to 15368101; 24677642; 34165550; 38113319; 40459937; 39651830
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Renal Ciliopathies and Nephronophthisis v1.33 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Polydactyly v0.286 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Polydactyly v0.286 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Ciliopathies v1.76 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Ciliopathies v1.76 TMEM17 Chirag Patel Gene: tmem17 has been classified as Amber List (Moderate Evidence).
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).
Renal Ciliopathies and Nephronophthisis v1.32 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Renal Ciliopathies and Nephronophthisis. 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
Polydactyly v0.285 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Polydactyly. 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
Ciliopathies v1.75 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Ciliopathies. 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
Fetal anomalies v1.386 TMEM17 Chirag Patel Classified gene: TMEM17 as Amber List (moderate evidence)
Fetal anomalies v1.386 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
Fetal anomalies v1.385 TMEM17 Chirag Patel gene: TMEM17 was added
gene: TMEM17 was added to Fetal anomalies. 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
Autoimmune Lymphoproliferative Syndrome v1.8 IKZF1 Peter McNaughton gene: IKZF1 was added
gene: IKZF1 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKZF1 were set to PMID: 32654692
Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873; recurrent bacterial respiratory infections; Thrombocytopaenia; immunodeficiency; Hypogammaglobulinaemia; decrease B-cells; decrease B-cell differentiation; decrease memory B/T cells; Low Ig; pneumocystis early CID onset; Immune dysregulation
Review for gene: IKZF1 was set to GREEN
Added comment: ~30% of patients present with ALPS like autoimmunity +/- lymphoproliferation.
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
Intellectual disability syndromic and non-syndromic v1.213 CHTF18 Zornitza Stark Marked gene: CHTF18 as ready
Intellectual disability syndromic and non-syndromic v1.213 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.213 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
Intellectual disability syndromic and non-syndromic v1.212 CHTF18 Zornitza Stark Classified gene: CHTF18 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.212 CHTF18 Zornitza Stark Gene: chtf18 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.211 CHTF18 Zornitza Stark edited their review of gene: CHTF18: Changed phenotypes: Neurodevelopmental disorder MONDO#0700092, CHTF18-related
Intellectual disability syndromic and non-syndromic v1.211 CHTF18 Zornitza Stark reviewed gene: CHTF18: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoimmune Lymphoproliferative Syndrome v1.8 PIK3R1 Zornitza Stark Marked gene: PIK3R1 as ready
Autoimmune Lymphoproliferative Syndrome v1.8 PIK3R1 Zornitza Stark Gene: pik3r1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.8 PIK3R1 Zornitza Stark Phenotypes for gene: PIK3R1 were changed from APDS to Immunodeficiency 36, MIM# 616005
Autoimmune Lymphoproliferative Syndrome v1.7 PIK3R1 Zornitza Stark Classified gene: PIK3R1 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.7 PIK3R1 Zornitza Stark Gene: pik3r1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.6 PIK3CD Zornitza Stark Marked gene: PIK3CD as ready
Autoimmune Lymphoproliferative Syndrome v1.6 PIK3CD Zornitza Stark Gene: pik3cd has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.6 PIK3CD Zornitza Stark Phenotypes for gene: PIK3CD were changed from APDS to Immunodeficiency 14B, autosomal recessive, MIM# 619281; Immunodeficiency 14A, autosomal dominant, MIM# 615513
Autoimmune Lymphoproliferative Syndrome v1.5 PIK3CD Zornitza Stark Classified gene: PIK3CD as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.5 PIK3CD Zornitza Stark Gene: pik3cd has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.4 NFKB1 Zornitza Stark Marked gene: NFKB1 as ready
Autoimmune Lymphoproliferative Syndrome v1.4 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.4 NFKB1 Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576
Autoimmune Lymphoproliferative Syndrome v1.3 NFKB1 Zornitza Stark Classified gene: NFKB1 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.3 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.2 NFKB2 Zornitza Stark Marked gene: NFKB2 as ready
Autoimmune Lymphoproliferative Syndrome v1.2 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Autoimmune Lymphoproliferative Syndrome v1.2 NFKB2 Zornitza Stark Phenotypes for gene: NFKB2 were changed from to Immunodeficiency, common variable, 10 MIM# 615577
Autoimmune Lymphoproliferative Syndrome v1.1 NFKB2 Zornitza Stark Classified gene: NFKB2 as Green List (high evidence)
Autoimmune Lymphoproliferative Syndrome v1.1 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.211 KDM2B Zornitza Stark Publications for gene: KDM2B were set to 36322151
Intellectual disability syndromic and non-syndromic v1.210 KDM2B Zornitza Stark 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 v1.2813 KDM2B Zornitza Stark Publications for gene: KDM2B were set to 36322151
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Marked gene: KDM2B as ready
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Gene: kdm2b has been classified as Green List (High Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Classified gene: KDM2B as Green List (high evidence)
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.149 KDM2B Zornitza Stark Gene: kdm2b has been classified as Green List (High Evidence).
Callosome v0.547 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Callosome v0.547 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Callosome v0.547 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Callosome v0.547 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Genetic Epilepsy v1.172 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.210 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
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).
Microcephaly v1.320 SNW1 Zornitza Stark Marked gene: SNW1 as ready
Microcephaly v1.320 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Microcephaly v1.320 SNW1 Zornitza Stark Classified gene: SNW1 as Green List (high evidence)
Microcephaly v1.320 SNW1 Zornitza Stark Gene: snw1 has been classified as Green List (High Evidence).
Callosome v0.546 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Callosome. 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
Fetal anomalies v1.384 PDCD6IP Zornitza Stark Publications for gene: PDCD6IP were set to 32286682
Fetal anomalies v1.383 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Fetal anomalies v1.383 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Fetal anomalies v1.382 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Added comment: Additional individual with homozygous truncating variant, mild ID, microcephaly and mild thrombocytopenia.
p.Arg322* - present in gnomAD (NFE AF - 0.0006%).; Changed rating: GREEN; Changed publications: https://doi.org/10.1111/cge.70025
Microcephaly v1.319 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Microcephaly. 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
Intellectual disability syndromic and non-syndromic v1.209 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Intellectual disability syndromic and non-syndromic. 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
Genetic Epilepsy v1.171 SNW1 Lucy Spencer gene: SNW1 was added
gene: SNW1 was added to Genetic Epilepsy. 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
Intellectual disability syndromic and non-syndromic v1.209 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.209 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.208 PDCD6IP Zornitza Stark edited their review of gene: PDCD6IP: Added comment: Additional individual with homozygous truncating variant, mild ID, microcephaly and mild thrombocytopenia.
p.Arg322* - present in gnomAD (NFE AF - 0.0006%).; Changed rating: GREEN; Changed publications: https://doi.org/10.1111/cge.70025
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
Microcephaly v1.319 PDCD6IP Zornitza Stark Classified gene: PDCD6IP as Green List (high evidence)
Microcephaly v1.319 PDCD6IP Zornitza Stark Gene: pdcd6ip has been classified as Green List (High Evidence).
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.148 KDM2B Lucy Spencer gene: KDM2B was added
gene: KDM2B was added to Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 40420380; 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#0700092, KDM2B-related
Review for gene: KDM2B was set to GREEN
Added comment: 5/19 patients with variants in the CxxC domain were reported to have unilateral renal agenesis along with the typical syndromic ID phenotype associated with this gene.
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).
Autoimmune Lymphoproliferative Syndrome v1.0 NFKB2 Peter McNaughton gene: NFKB2 was added
gene: NFKB2 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: NFKB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFKB2 were set to PMID: 39644063
Review for gene: NFKB2 was set to GREEN
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.0 NFKB1 Peter McNaughton gene: NFKB1 was added
gene: NFKB1 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: NFKB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFKB1 were set to PMID: 39644063
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.0 PIK3CD Peter McNaughton gene: PIK3CD was added
gene: PIK3CD was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: PIK3CD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PIK3CD were set to PMID: 39644063
Phenotypes for gene: PIK3CD were set to APDS
Review for gene: PIK3CD was set to GREEN
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Autoimmune Lymphoproliferative Syndrome v1.0 PIK3R1 Peter McNaughton gene: PIK3R1 was added
gene: PIK3R1 was added to Autoimmune Lymphoproliferative Syndrome. Sources: Literature
Mode of inheritance for gene: PIK3R1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3R1 were set to PMID: 39644063
Phenotypes for gene: PIK3R1 were set to APDS
Review for gene: PIK3R1 was set to GREEN
Added comment: Recommended as part of genetic workup for ALPS as patients commonly present with cytopaenias and lymphoproliferation.
Sources: Literature
Cardiac conduction disease v1.0 POPDC2 Bryony Thompson Marked gene: POPDC2 as ready
Cardiac conduction disease v1.0 POPDC2 Bryony Thompson Gene: popdc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.208 CHTF18 Sangavi Sivagnanasundram gene: CHTF18 was added
gene: CHTF18 was added to Intellectual disability syndromic and non-syndromic. 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 AMBER
Added comment: Only two individuals reported with ID/DD:
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 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
Microcephaly v1.318 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 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
Congenital Disorders of Glycosylation v1.68 SLC37A4 Zornitza Stark Publications for gene: SLC37A4 were set to 32884905; 33728255
Intellectual disability syndromic and non-syndromic v1.208 SV2A Zornitza Stark Publications for gene: SV2A were set to PMID: 37985816
Intellectual disability syndromic and non-syndromic v1.207 SV2A Ava Stevenson reviewed gene: SV2A: Rating: AMBER; Mode of pathogenicity: None; Publications: 36350923, 37861890; Phenotypes: Developmental and epileptic encephalopathy 113 (MIM#620772), AR, Neurodevelopmental disorder, MONDO:0700092, SV2A-related, AD; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Repeat Disorders v0.266 THAP11_SCA51_CAG Bryony Thompson changed review comment from: 7 individuals from 2 Chinese families with SCA (1 was pre-ataxic) and a THAP11 CAG (polyQ) expansion. 45 repeats was the lowest number of repeats in an affected individual. A 46/29 CAG THAP11 genotype has also been identified in an individual with ataxia of European ancestry, that also had a CACNA1A pathogenic expansion which causes SCA6. Analysis of the 1000 genomes cohort (n=2504), suggests a normal range between 19-39. Also, a supporting mouse model and functional assays support a toxic aggregation mechanism of disease.
Further probands/families are required to confirm the gene-disease association.
Sources: Other; to: 7 individuals from 2 Chinese families with SCA (1 was pre-ataxic) and a THAP11 CAG (polyQ) expansion. 45 repeats was the lowest number of repeats in an affected individual and the number of CAA interruptions had been reduced from 5/6 to 3. Expanded alleles have been identified in individuals with neurodevelopmental phenotypes, other neurodegenerative phenotypes, and an individual with ataxia who also had a CACNA1A (SCA6) pathogenic expansion. However, all these individuals had 5/6 CAA interruptions instead of 3 that were reported in the initial Chinese families. Suggesting the number of CAA interruptions is associated with pathogenicity of the repeat expansion. Analysis of the 1000 genomes cohort (n=2504), suggests a normal range between 19-39. Also, a supporting mouse model and functional assays support a toxic aggregation mechanism of disease. Further probands/families are required to confirm the gene-disease association.
Sources: Other
Repeat Disorders v0.266 THAP11_SCA51_CAG Bryony Thompson Phenotypes for STR: THAP11_SCA51_CAG were changed from Spinocerebellar ataxia 51, MIM# 620947 to Spinocerebellar ataxia 51 MONDO:0975800
Repeat Disorders v0.265 THAP11_SCA51_CAG Bryony Thompson edited their review of STR: THAP11_SCA51_CAG: Changed publications: 15368101, 24677642, 34165550, 38113319, 40459937, 39651830; Changed phenotypes: Spinocerebellar ataxia 51 MONDO:0975800
Repeat Disorders v0.265 THAP11_SCA51_CAG Bryony Thompson Publications for STR: THAP11_SCA51_CAG were set to 15368101; 24677642; 34165550; 38113319; 37148549; 39651830
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Classified gene: ERCC1 as Green List (high evidence)
Liver Failure_Paediatric v1.26 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Liver Failure_Paediatric v1.25 ERCC1 Zornitza Stark gene: ERCC1 was added
gene: ERCC1 was added to Liver Failure_Paediatric. Sources: Literature
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 encodes a part of a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair.

Additional literature published further defining phenotypic spectrum.
Now more than 7 individuals from 4 families who present with a multi system disorder including progressive cholestatic hepatic dysfunction (100%) which required transplantation in some. 4 individuals developed hepatocellular carcinoma.
Other features included: photosensitivity, growth restriction, renal impairment/nephrocalcinosis and mild developmental issues.

LOF proposed mechanism with supportive functional studies including western blot from affected individual's fibroblasts showing reduced ERCC1 levels, reduced DNA repair following UV radiation, abnormal chromosomal breakage in response to mitomycin C.

Variant types include missense, splice site, deletion and NMD predicted. Some missense variants proposed to be hypomorphic.
Sources: Literature
Growth failure v1.78 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Growth failure v1.78 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Growth failure v1.78 ERCC1 Zornitza Stark Classified gene: ERCC1 as Green List (high evidence)
Growth failure v1.78 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
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
Cholestasis v1.1 ERCC1 Zornitza Stark Marked gene: ERCC1 as ready
Cholestasis v1.1 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Cholestasis v1.1 ERCC1 Zornitza Stark Classified gene: ERCC1 as Green List (high evidence)
Cholestasis v1.1 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.171 ATG2A Zornitza Stark Marked gene: ATG2A as ready
Genetic Epilepsy v1.171 ATG2A Zornitza Stark Gene: atg2a has been classified as Red List (Low Evidence).
Genetic Epilepsy v1.171 ATG2A Zornitza Stark commented on gene: ATG2A: 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.
Genetic Epilepsy v1.171 ATG2A Zornitza Stark gene: ATG2A was added
gene: ATG2A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG2A were set to 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: Sources: Literature
Regression v0.583 ATG2A Zornitza Stark Marked gene: ATG2A as ready
Regression v0.583 ATG2A Zornitza Stark Gene: atg2a has been classified as Red List (Low Evidence).
Regression v0.583 ATG2A Zornitza Stark gene: ATG2A was added
gene: ATG2A was added to Regression. Sources: Literature
Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG2A were set to 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
Fetal anomalies v1.382 SMAD5 Zornitza Stark Marked gene: SMAD5 as ready
Fetal anomalies v1.382 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Fetal anomalies v1.382 SMAD5 Zornitza Stark Classified gene: SMAD5 as Green List (high evidence)
Fetal anomalies v1.382 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Fetal anomalies v1.381 SMAD5 Zornitza Stark gene: SMAD5 was added
gene: SMAD5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD5 were set to 40619738
Phenotypes for gene: SMAD5 were set to Congenital heart disease, MONDO:0005453, SMAD5-related
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 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 v1.2807 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).
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Marked gene: SMAD5 as ready
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Classified gene: SMAD5 as Green List (high evidence)
Congenital Heart Defect v0.450 SMAD5 Zornitza Stark Gene: smad5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.449 SMAD5 Sarah Milton gene: SMAD5 was added
gene: SMAD5 was added to Congenital Heart Defect. 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 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/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
Skeletal dysplasia v0.313 TNFRSF11B Bryony Thompson Marked gene: TNFRSF11B as ready
Skeletal dysplasia v0.313 TNFRSF11B Bryony Thompson Gene: tnfrsf11b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Marked gene: TNFRSF11B as ready
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Gene: tnfrsf11b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Classified gene: TNFRSF11B as Green List (high evidence)
Osteogenesis Imperfecta and Osteoporosis v1.5 TNFRSF11B Bryony Thompson Gene: tnfrsf11b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v1.4 TNFRSF11B Bryony Thompson gene: TNFRSF11B was added
gene: TNFRSF11B was added to Osteogenesis Imperfecta and Osteoporosis. Sources: Literature
Mode of inheritance for gene: TNFRSF11B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TNFRSF11B were set to 24743232; 40735895; 29578045; 33559312; 33989379; 35412619; 14672344
Phenotypes for gene: TNFRSF11B were set to juvenile Paget disease MONDO:0009394; chondrocalcinosis 1 MONDO:0010917
Review for gene: TNFRSF11B was set to GREEN
gene: TNFRSF11B was marked as current diagnostic
Added comment: Fractures and osteoporosis can be a features of both Paget disease and chondrocalcinosis. Biallelic loss-of-function variants cause Paget disease, and a single monoallelic recurrent stoploss variant is associated with chondrocalcinosis.
Sources: Literature
Skeletal dysplasia v0.313 TNFRSF11B Bryony Thompson Phenotypes for gene: TNFRSF11B were changed from Paget disease of bone 5, juvenile-onset 239000; Paget disease of bone 5, juvenile-onset 239000 to juvenile Paget disease MONDO:0009394; chondrocalcinosis 1 MONDO:0010917
Skeletal dysplasia v0.312 TNFRSF11B Bryony Thompson Publications for gene: TNFRSF11B were set to
Skeletal dysplasia v0.311 TNFRSF11B Bryony Thompson Mode of inheritance for gene: TNFRSF11B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v0.310 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; Current diagnostic: yes
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
Renal Tubulopathies and related disorders v1.18 ATP6V0A4 Krithika Murali Marked gene: ATP6V0A4 as ready
Renal Tubulopathies and related disorders v1.18 ATP6V0A4 Krithika Murali Gene: atp6v0a4 has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.18 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 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
Ciliary Dyskinesia v1.55 CFAP43 Zornitza Stark Classified gene: CFAP43 as Amber List (moderate evidence)
Ciliary Dyskinesia v1.55 CFAP43 Zornitza Stark Gene: cfap43 has been classified as Amber List (Moderate Evidence).
Ciliary Dyskinesia v1.54 CFAP43 Zornitza Stark Tag disputed tag was added to gene: CFAP43.
Ciliary Dyskinesia v1.54 CFAP43 Zornitza Stark edited their review of gene: CFAP43: Added comment: DISPUTED by ClinGen for biallelic disease.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliary Dyskinesia v1.54 DNAH6 Zornitza Stark Classified gene: DNAH6 as Red List (low evidence)
Ciliary Dyskinesia v1.54 DNAH6 Zornitza Stark Gene: dnah6 has been classified as Red List (Low Evidence).
Ciliary Dyskinesia v1.53 DNAH6 Zornitza Stark commented on gene: DNAH6: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH6 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:008758.
Ciliary Dyskinesia v1.53 DNAH6 Zornitza Stark edited their review of gene: DNAH6: Added comment: DISPUTED by ClinGen.; Changed rating: RED
Ciliary Dyskinesia v1.53 DNAH8 Zornitza Stark Classified gene: DNAH8 as Red List (low evidence)
Ciliary Dyskinesia v1.53 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Red List (Low Evidence).
Ciliary Dyskinesia v1.52 DNAH8 Zornitza Stark Tag disputed tag was added to gene: DNAH8.
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Marked gene: NFIA as ready
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Gene: nfia has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Classified gene: NFIA as Green List (high evidence)
Polymicrogyria and Schizencephaly v0.197 NFIA Zornitza Stark Gene: nfia has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.196 NFIA Zornitza Stark gene: NFIA was added
gene: NFIA was added to Polymicrogyria and Schizencephaly. Sources: Expert Review
Mode of inheritance for gene: NFIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFIA were set to 27081522; 28452798; 33973697; 36553517
Phenotypes for gene: NFIA were set to Brain malformations with or without urinary tract defects, MIM#613735
Review for gene: NFIA was set to GREEN
Added comment: Spectrum of brain malformations reported in multiple inviduals including polymicrogyria.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v1.207 RNU5A-1 Zornitza Stark Marked gene: RNU5A-1 as ready
Intellectual disability syndromic and non-syndromic v1.207 RNU5A-1 Zornitza Stark Gene: rnu5a-1 has been classified as Amber List (Moderate Evidence).
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).
Intellectual disability syndromic and non-syndromic v1.207 RNU5A-1 Zornitza Stark Classified gene: RNU5A-1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.207 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
Intellectual disability syndromic and non-syndromic v1.206 RNU5A-1 Zornitza Stark gene: RNU5A-1 was added
gene: RNU5A-1 was added to Intellectual disability syndromic and non-syndromic. 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
Disorders of immune dysregulation v1.17 AMFR Zornitza Stark Marked gene: AMFR as ready
Disorders of immune dysregulation v1.17 AMFR Zornitza Stark Gene: amfr has been classified as Red List (Low Evidence).
Disorders of immune dysregulation v1.17 AMFR Zornitza Stark gene: AMFR was added
gene: AMFR was added to Disorders of immune dysregulation. Sources: Expert Review
Mode of inheritance for gene: AMFR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMFR were set to 38277122
Phenotypes for gene: AMFR were set to Inborn error of immunity, MONDO:0003778, AMFR-related
Review for gene: AMFR was set to RED
Added comment: 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.
Sources: Expert Review
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
Combined Immunodeficiency v1.125 ASXL1 Zornitza Stark Marked gene: ASXL1 as ready
Combined Immunodeficiency v1.125 ASXL1 Zornitza Stark Gene: asxl1 has been classified as Red List (Low Evidence).
Combined Immunodeficiency v1.125 ASXL1 Zornitza Stark gene: ASXL1 was added
gene: ASXL1 was added to Combined Immunodeficiency. Sources: Literature
Mode of inheritance for gene: ASXL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASXL1 were set to 40742536
Phenotypes for gene: ASXL1 were set to Combined immunodeficiency, MONDO:0015131, ASXL1-related
Review for gene: ASXL1 was set to RED
Added comment: 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.
Sources: Literature
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
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Marked gene: RCC1 as ready
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Classified gene: RCC1 as Green List (high evidence)
Hereditary Neuropathy_CMT - isolated v1.60 RCC1 Zornitza Stark Gene: rcc1 has been classified as Green List (High Evidence).
Hereditary Neuropathy_CMT - isolated v1.59 RCC1 Zornitza Stark gene: RCC1 was added
gene: RCC1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Expert list
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 list
Growth failure v1.77 ERCC1 Sarah Milton gene: ERCC1 was added
gene: ERCC1 was added to Growth failure. Sources: Literature
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to PMID: 40684071
Phenotypes for gene: ERCC1 were set to Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 encodes a part of a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair.

Additional literature published further defining phenotypic spectrum.
Now more than 7 individuals from 4 families who present with a multi system disorder including progressive cholestatic hepatic dysfunction (100%) which required transplantation in some. 4 individuals developed hepatocellular carcinoma.
Other features included: photosensitivity, growth restriction, renal impairment/nephrocalcinosis and mild developmental issues.

LOF proposed mechanism with supportive functional studies including western blot from affected individual's fibroblasts showing reduced ERCC1 levels, reduced DNA repair following UV radiation, abnormal chromosomal breakage in response to mitomycin C.

Variant types include missense, splice site, deletion and NMD predicted. Some missense variants proposed to be hypomorphic.
Sources: Literature
Cholestasis v1.0 ERCC1 Sarah Milton gene: ERCC1 was added
gene: ERCC1 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to PMID: 40684071
Phenotypes for gene: ERCC1 were set to Hepatorenal syndrome, MONDO:0001382, ERCC1-related
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 encodes a part of a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair.

Additional literature published further defining phenotypic spectrum.
Now more than 7 individuals from 4 families who present with a multi system disorder including progressive cholestatic hepatic dysfunction (100%) which required transplantation in some. 4 individuals developed hepatocellular carcinoma.
Other features included: photosensitivity, growth restriction, renal impairment/nephrocalcinosis and mild developmental issues.

LOF proposed mechanism with supportive functional studies including western blot from affected individual's fibroblasts showing reduced ERCC1 levels, reduced DNA repair following UV radiation, abnormal chromosomal breakage in response to mitomycin C.

Variant types include missense, splice site, deletion and NMD predicted. Some missense variants proposed to be hypomorphic.
Sources: Literature
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
Retinitis pigmentosa v0.175 TBC1D32 Zornitza Stark Marked gene: TBC1D32 as ready
Retinitis pigmentosa v0.175 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Retinitis pigmentosa v0.175 TBC1D32 Zornitza Stark Classified gene: TBC1D32 as Green List (high evidence)
Retinitis pigmentosa v0.175 TBC1D32 Zornitza Stark Gene: tbc1d32 has been classified as Green List (High Evidence).
Retinitis pigmentosa v0.174 TBC1D32 Zornitza Stark gene: TBC1D32 was added
gene: TBC1D32 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Expert Review
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 37768732; 39930170
Phenotypes for gene: TBC1D32 were set to Retinitis pigmentosa 100, MIM# 621280
Review for gene: TBC1D32 was set to GREEN
Added comment: PMID 37768732: 4 individuals from three unrelated families with bi-allelic variants. Some supportive functional data.
PMID 39930170: fourth family reported.

Biallelic variants in this gene are also associated with a multi-system ciliopathy.
Sources: Expert Review
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Marked gene: DNHD1 as ready
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Gene: dnhd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Classified gene: DNHD1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Gene: dnhd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.8 DNHD1 Zornitza Stark edited their review of gene: DNHD1: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v1.8 DNHD1 Zornitza Stark gene: DNHD1 was added
gene: DNHD1 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNHD1 were set to 34932939
Phenotypes for gene: DNHD1 were set to Spermatogenic failure 65, MIM# 619712
Added comment: Biallelic DNHD1 variants identified in 8 unrelated probands with asthenoteratozoospermia, reduced sperm motility and abnormal sperm morphology. DNHD1 knockout mice were infertile and had significantly reduced sperm concentration and motility rates, consistent with human individuals.
Sources: Literature
Genetic Epilepsy v1.170 BSN Zornitza Stark Phenotypes for gene: BSN were changed from Epilepsy MONDO:0005027 to Neurodevelopmental disorder (MONDO:0700092), BSN-related
Genetic Epilepsy v1.169 BSN Zornitza Stark edited their review of gene: BSN: Added comment: Guzman et al 2025: Described 12 additional patients with missense (3/12) and premature termination variants (9/12) which included de novo and inherited variants, suggesting incomplete penetrance.

They assessed all reported patients (n=29) which revealed common clinical characteristics including epilepsy(13/29), febrile seizures (7/29), generalised tonic-clonic seizures (5/29), and focal-onset seizures (3/29). Behavioural phenotypes were present in almost half of all individuals (14/29), which included ADHD (7/29) and autistic behaviour (5/29). Additional common features included developmental delay (11/29), obesity (10/29), and delayed speech (8/29). In adults with BSN PTVs, milder features were common, suggesting phenotypic variability, including a range of individuals without obvious neurodevelopmental features (7/29).; Changed rating: GREEN; Changed publications: 40393460; Changed phenotypes: Neurodevelopmental disorder (MONDO:0700092), BSN-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Marked gene: BSN as ready
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Classified gene: BSN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.205 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.204 BSN Zornitza Stark gene: BSN was added
gene: BSN was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review
Mode of inheritance for gene: BSN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BSN were set to 40393460
Phenotypes for gene: BSN were set to Neurodevelopmental disorder (MONDO:0700092), BSN-related
Review for gene: BSN was set to GREEN
Added comment: Guzman et al 2025: Described 12 additional patients with missense (3/12) and premature termination variants (9/12) which included de novo and inherited variants, suggesting incomplete penetrance.

They assessed all reported patients (n=29) which revealed common clinical characteristics including epilepsy(13/29), febrile seizures (7/29), generalised tonic-clonic seizures (5/29), and focal-onset seizures (3/29). Behavioural phenotypes were present in almost half of all individuals (14/29), which included ADHD (7/29) and autistic behaviour (5/29). Additional common features included developmental delay (11/29), obesity (10/29), and delayed speech (8/29). In adults with BSN PTVs, milder features were common, suggesting phenotypic variability, including a range of individuals without obvious neurodevelopmental features (7/29).
Sources: Expert Review
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Marked gene: FGF10 as ready
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Gene: fgf10 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Classified gene: FGF10 as Green List (high evidence)
Pulmonary Fibrosis_Interstitial Lung Disease v0.89 FGF10 Zornitza Stark Gene: fgf10 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.88 FGF10 Zornitza Stark gene: FGF10 was added
gene: FGF10 was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Expert list
Mode of inheritance for gene: FGF10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGF10 were set to 30639323; 30429870; 9916808
Phenotypes for gene: FGF10 were set to Lacrimoauriculodentodigital (LAAD) syndrome - pulmonary hypoplasia
Review for gene: FGF10 was set to GREEN
Added comment: Association with pulmonary hypoplasia and interstitial lung disease reported in multiple families.
Sources: Expert list
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
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.148 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Craniofacial microsomia MONDO:0015397 to Syndromic disease, MONDO:0002254, NR6A1-related
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.147 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
Anophthalmia_Microphthalmia_Coloboma v1.47 NR6A1 Zornitza Stark Phenotypes for gene: NR6A1 were changed from Craniofacial microsomia MONDO:0015397 to Syndromic disease, MONDO:0002254, NR6A1-related
Anophthalmia_Microphthalmia_Coloboma v1.46 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
Fetal anomalies v1.380 NR6A1 Zornitza Stark Marked gene: NR6A1 as ready
Fetal anomalies v1.380 NR6A1 Zornitza Stark Gene: nr6a1 has been classified as Green List (High Evidence).
Fetal anomalies v1.380 NR6A1 Zornitza Stark Classified gene: NR6A1 as Green List (high evidence)
Fetal anomalies v1.380 NR6A1 Zornitza Stark Gene: nr6a1 has been classified as Green List (High Evidence).
Fetal anomalies v1.379 NR6A1 Zornitza Stark gene: NR6A1 was added
gene: NR6A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR6A1 were set to 39606382
Phenotypes for gene: NR6A1 were set to Syndromic disease, MONDO:0002254, NR6A1-related
Review for gene: NR6A1 was set to GREEN
Added comment: 6 unrelated families with heterozygous rare variants (missense, nonsense, frameshift, or large deletion) with incomplete penetrance and variable expressivity. Colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities characterised the phenotype of the families. Also, supporting zebrafish model. Loss of function is the expected mechanism of disease.
Sources: Literature
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
Stroke v1.23 NOTCH2 Zornitza Stark Marked gene: NOTCH2 as ready
Stroke v1.23 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Stroke v1.23 NOTCH2 Zornitza Stark Classified gene: NOTCH2 as Green List (high evidence)
Stroke v1.23 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Stroke v1.22 NOTCH2 Zornitza Stark gene: NOTCH2 was added
gene: NOTCH2 was added to Stroke. Sources: Expert Review
Mode of inheritance for gene: NOTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2 were set to 30761079; 38400955; 25465847
Phenotypes for gene: NOTCH2 were set to Alagille syndrome 2 610205
Review for gene: NOTCH2 was set to GREEN
Added comment: Multiple reports of vascular abnormalities and stroke in Alagille syndrome, can be difficult to diagnose clinically.
Sources: Expert Review
Stroke v1.21 JAG1 Zornitza Stark Marked gene: JAG1 as ready
Stroke v1.21 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Stroke v1.21 JAG1 Zornitza Stark Classified gene: JAG1 as Green List (high evidence)
Stroke v1.21 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Stroke v1.20 JAG1 Zornitza Stark gene: JAG1 was added
gene: JAG1 was added to Stroke. Sources: Expert Review
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to 30761079; 38400955; 25465847
Phenotypes for gene: JAG1 were set to Alagille syndrome 1, MIM# 118450
Review for gene: JAG1 was set to GREEN
Added comment: Multiple reports of vascular abnormalities and stroke in Alagille syndrome, can be difficult to diagnose clinically.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Marked gene: SMAD6 as ready
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Gene: smad6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Classified gene: SMAD6 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.203 SMAD6 Zornitza Stark Gene: smad6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Marked gene: DNAH10 as ready
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Classified gene: DNAH10 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.6 DNAH10 Zornitza Stark gene: DNAH10 was added
gene: DNAH10 was added to Infertility and Recurrent Pregnancy Loss. Sources: Expert list
Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH10 were set to 34237282
Phenotypes for gene: DNAH10 were set to Spermatogenic failure 56, MIM# 619515
Review for gene: DNAH10 was set to GREEN
Added comment: 4x families with 5 affecteds (chets and homs - 4 missense and 2 fs). Knockout mouse models were infertile and showed significant reduction in count and motility compared to heterozygous mice
Sources: Expert list
Intellectual disability syndromic and non-syndromic v1.202 CRBN Elena Savva Phenotypes for gene: CRBN were changed from Intellectual developmental disorder, autosomal recessive 2, MIM# 607417 to Intellectual developmental disorder, autosomal recessive 2, MIM# 607417
Intellectual disability syndromic and non-syndromic v1.202 CRBN Elena Savva Phenotypes for gene: CRBN were changed from Mental retardation, autosomal recessive 2, MIM# 607417 to Intellectual developmental disorder, autosomal recessive 2, MIM# 607417
Intellectual disability syndromic and non-syndromic v1.201 CRBN Elena Savva Mode of inheritance for gene: CRBN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy - adult onset v0.150 C1R Zornitza Stark Classified gene: C1R as Green List (high evidence)
Leukodystrophy - adult onset v0.150 C1R Zornitza Stark Gene: c1r has been classified as Green List (High Evidence).
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
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Marked gene: ZNF597 as ready
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Classified gene: ZNF597 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
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
Infertility and Recurrent Pregnancy Loss v1.4 SYCP3 Zornitza Stark Classified gene: SYCP3 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.4 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.3 SYCP3 Zornitza Stark reviewed gene: SYCP3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
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).
Infertility and Recurrent Pregnancy Loss v1.3 KPNA7 Zornitza Stark Classified gene: KPNA7 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.3 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.2 KPNA7 Zornitza Stark reviewed gene: KPNA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 17, #MIM 620319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
Infertility and Recurrent Pregnancy Loss v1.2 GGN Zornitza Stark reviewed gene: GGN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
Infertility and Recurrent Pregnancy Loss v1.2 FOXD1 Zornitza Stark Phenotypes for gene: FOXD1 were changed from Recurrent pregnancy loss and repeated implantation failure susceptibility to Recurrent pregnancy loss and repeated implantation failure susceptibility, MONDO:0000144, FOXD1-related
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).
Infertility and Recurrent Pregnancy Loss v1.1 ELL3 Zornitza Stark reviewed gene: ELL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Leukodystrophy - adult onset v0.149 C1R Leah Frajman reviewed gene: C1R: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 37323685; Phenotypes: Ehlers-Danlos syndrome, periodontal type, 1 MIM#130080, leukoencephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v1.1 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Genetic Epilepsy v1.169 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Genetic Epilepsy v1.168 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 v1.2733 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
Autism v0.210 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Autism v0.209 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
Intellectual disability syndromic and non-syndromic v1.200 MARK2 Zornitza Stark Phenotypes for gene: MARK2 were changed from Neurodevelopmental disorder MONDO:0700092 to Intellectual developmental disorder, autosomal dominant 76, MIM# 621285
Intellectual disability syndromic and non-syndromic v1.199 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
Genomic newborn screening: ICoNS v0.4 TCN2 David Eckstein gene: TCN2 was added
gene: TCN2 was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: TCN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TCN2 were set to PMID: 24305960
Phenotypes for gene: TCN2 were set to Transcobalamin II deficiency, MIM#275350
Penetrance for gene: TCN2 were set to Complete
Review for gene: TCN2 was set to GREEN
Added comment: Well established gene-disease association https://medlineplus.gov/genetics/condition/transcobalamin-deficiency/

Haploinsufficiency Score = 30 https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11653

Transcobalamin II deficiency (TCN2D) is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities or death (1).

Diagnosis: Diagnosis is based on laboratory findings showing pancytopenia (or isolated megaloblastic anemia or combined anemia and leucopenia) and accumulation of homocysteine and methylmalonic acid. Methionine concentration may be reduced. Serum cobalamin levels are typically not low (most circulating cobalamin bound to haptocorrin). Reduction of unsaturated B12 binding capacity (test must be carried out before starting treatment with vitamin B12) and Holo- TC levels are observed. Diagnosis is confirmed by quantification of total transcobalamin in serum or plasma or by genetic screening of TCN2. Postnatal diagnosis may be achieved by screening newborn serum by tandem mass spectroscopy to detect the presence of C3-carnitines derived from methylmalonic acid. (Orphanet https://www.orpha.net/en/disease/detail/859#)

Treatment: Multiple case reports indicate good therapeutic effects from Vitamin B12 administration (2, 3). The BNF recommends hydroxocobalamin vs cyanocobalamin for this lifelong treatment*. Orphanet indicates that (t)reatment of TC involves maintenance of a very high serum cobalamin concentration (1,000-10,000 pg/ml) by intramuscular (IM) administration of hydroxocobalamin. Oral treatment or treatment with cyanocobalamin instead of hydroxocobalamin may result in poorer outcomes. Treatment with IM hydroxocobalamin at least once a week is recommended, with monitoring of biochemical and hematological parameters to ensure that treatment is effective. Follow-up into adulthood for asymptomatic children who continue to have abnormal metabolite excretion is recommended. (Orphanet https://www.orpha.net/en/disease/detail/859#)

* this was cited in a BMJ article https://www.bmj.com/content/349/bmj.g5389.full but I can’t access the BNF to provide a direct citation.

Included in BabyScreen+, BeginNGS, Guardian, Generation, EarlyCheck

Panels with this gene
• Bone Marrow Failure
• Mendeliome
• Combined Immunodeficiency
• Intellectual disability syndromic and non-syndromic
• Mackenzie's Mission_Reproductive Carrier Screening
• Red cell disorders
• Fetal anomalies
• Prepair 1000+
• Genomic newborn screening: BabyScreen+
• Prepair 500+
• Vitamin metabolism disorders
• Genomic newborn screening: ICoNS

Full citations
1. https://www.omim.org/entry/275350?search=%22transcobalamin%20ii%20deficiency%22&highlight=%22transcobalamin%20ii%20deficiency%22#8

2. Martino, F., Magenta, A., Troccoli, M.L. et al. Long-term outcome of a patient with Transcobalamin deficiency caused by the homozygous c.1115_1116delCA mutation in TCN2 gene: a case report. Ital J Pediatr 47, 54 (2021). https://doi.org/10.1186/s13052-021-01007-6

3. Trakadis YJ, Alfares A, Bodamer OA, Buyukavci M, Christodoulou J, Connor P, Glamuzina E, Gonzalez-Fernandez F, Bibi H, Echenne B, Manoli I, Mitchell J, Nordwall M, Prasad C, Scaglia F, Schiff M, Schrewe B, Touati G, Tchan MC, Varet B, Venditti CP, Zafeiriou D, Rupar CA, Rosenblatt DS, Watkins D, Braverman N. Update on transcobalamin deficiency: clinical presentation, treatment and outcome. J Inherit Metab Dis. 2014 May;37(3):461-73. doi: https://doi.org/10.1007/s10545-013-9664-5. Epub 2013 Dec 5. PMID: 24305960.
Sources: Expert list
Infertility and Recurrent Pregnancy Loss v1.0 ZNF597 Jasmine Chew edited their review of gene: ZNF597: Changed publications: 19968752, 28157578, 32576657
Infertility and Recurrent Pregnancy Loss v1.0 ZNF597 Jasmine Chew gene: ZNF597 was added
gene: ZNF597 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature,Research
Mode of inheritance for gene: ZNF597 was set to Other
Publications for gene: ZNF597 were set to 28157578; 28157578; 2576657
Mode of pathogenicity for gene: ZNF597 was set to Other
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: Literature, Research
Infertility and Recurrent Pregnancy Loss v1.0 Zornitza Stark promoted panel to version 1.0
Infertility and Recurrent Pregnancy Loss v0.232 Zornitza Stark Panel name changed from Infertility and Pregnancy Loss to Infertility and Recurrent Pregnancy Loss
Panel status changed from internal to public
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Marked gene: NLRP14 as ready
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Phenotypes for gene: NLRP14 were changed from Oocyte maturation defect and early embryo arrest to Inherited oocyte maturation defect, MONDO:0014769, NLRP14-related and early embryo arrest
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Marked gene: GALT as ready
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Gene: galt has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Phenotypes for gene: GALT were changed from Premature ovarian failure to Galactosaemia, MIM# 230400; Premature ovarian failure
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Marked gene: POLR3B as ready
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Classified gene: POLR3B as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Marked gene: POLG as ready
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Gene: polg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Phenotypes for gene: POLG were changed from Premature ovarian failure to POLG-related disorders; Premature ovarian failure
Infertility and Recurrent Pregnancy Loss v0.227 POLG Zornitza Stark Classified gene: POLG as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.227 POLG Zornitza Stark Gene: polg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Marked gene: MTHFR as ready
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Gene: mthfr has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Phenotypes for gene: MTHFR were changed from Recurrent pregnancy loss susceptibility to Homocystinuria due to MTHFR deficiency MIM#236250; Recurrent pregnancy loss susceptibility
Infertility and Recurrent Pregnancy Loss v0.225 MTHFR Zornitza Stark Classified gene: MTHFR as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.225 MTHFR Zornitza Stark Gene: mthfr has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Marked gene: LMNA as ready
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from Female infertility, premature ovarian insufficiency to Laminopathy; Female infertility, premature ovarian insufficiency
Infertility and Recurrent Pregnancy Loss v0.223 LMNA Zornitza Stark Classified gene: LMNA as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.223 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Marked gene: IKBKG as ready
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Gene: ikbkg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Classified gene: IKBKG as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Gene: ikbkg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.221 IKBKG Zornitza Stark Tag technically challenging tag was added to gene: IKBKG.
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Marked gene: CYP19A1 as ready
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Gene: cyp19a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Classified gene: CYP19A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Gene: cyp19a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Marked gene: CYP17A1 as ready
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Gene: cyp17a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Classified gene: CYP17A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Gene: cyp17a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Marked gene: ANKRD31 as ready
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Gene: ankrd31 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Classified gene: ANKRD31 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Gene: ankrd31 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.218 ANKRD31 Zornitza Stark Phenotypes for gene: ANKRD31 were changed from Premature ovarian failure to Premature ovarian failure, MONDO:0019852, ANKRD31-related
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Marked gene: ACTL7A as ready
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Classified gene: ACTL7A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Marked gene: BCORL1 as ready
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Phenotypes for gene: BCORL1 were changed from Spermatogenic failure to Spermatogenic failure, MONDO:0004983, BCORL1-related
Infertility and Recurrent Pregnancy Loss v0.215 BCORL1 Zornitza Stark Classified gene: BCORL1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.215 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Marked gene: ANOS1 as ready
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Gene: anos1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Publications for gene: ANOS1 were set to
Infertility and Recurrent Pregnancy Loss v0.213 ANOS1 Zornitza Stark Classified gene: ANOS1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.213 ANOS1 Zornitza Stark Gene: anos1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Marked gene: ACTL9 as ready
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Classified gene: ACTL9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Marked gene: CHRNA1 as ready
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Gene: chrna1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Classified gene: CHRNA1 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Gene: chrna1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.210 CHRNA1 Zornitza Stark reviewed gene: CHRNA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Marked gene: C4BPA as ready
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Phenotypes for gene: C4BPA were changed from recurrent pregnancy loss susceptibility to recurrent pregnancy loss susceptibility MONDO:0000144, C4BPA-related
Infertility and Recurrent Pregnancy Loss v0.209 C4BPA Zornitza Stark Classified gene: C4BPA as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.209 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Marked gene: C14orf39 as ready
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Classified gene: C14orf39 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Marked gene: C17orf53 as ready
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Publications for gene: C17orf53 were set to 34707299, 38105698,36099812; 31467087
Infertility and Recurrent Pregnancy Loss v0.206 C17orf53 Zornitza Stark Classified gene: C17orf53 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.206 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.205 C17orf53 Zornitza Stark Tag new gene name tag was added to gene: C17orf53.
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Marked gene: CLPP as ready
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Classified gene: CLPP as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Marked gene: CLPB as ready
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Classified gene: CLPB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.203 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from Primary ovarian insufficiency to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Primary ovarian insufficiency
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Marked gene: CAPS as ready
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Phenotypes for gene: CAPS were changed from Recurrent pregnancy loss to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CAPS-related
Infertility and Recurrent Pregnancy Loss v0.201 CAPS Zornitza Stark Classified gene: CAPS as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.201 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Marked gene: FKBP4 as ready
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Phenotypes for gene: FKBP4 were changed from Recurrent pregnancy loss susceptibility to Recurrent pregnancy loss susceptibility, MONDO:0000144, FKBP4-related
Infertility and Recurrent Pregnancy Loss v0.199 FKBP4 Zornitza Stark Classified gene: FKBP4 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.199 FKBP4 Zornitza Stark Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.198 NOTCH2 Zornitza Stark Classified gene: NOTCH2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.198 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Marked gene: NOTCH2 as ready
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Gene: notch2 has been removed from the panel.
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Phenotypes for gene: NOTCH2 were changed from Primary ovarian insufficiency to Inherited primary ovarian failure, MONDO:0019852, NOTCH2-related
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Marked gene: BRCA2 as ready
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Gene: brca2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Classified gene: BRCA2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Gene: brca2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.195 BRCA2 Zornitza Stark reviewed gene: BRCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Marked gene: FANCM as ready
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Gene: fancm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Classified gene: FANCM as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Gene: fancm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Marked gene: BNC1 as ready
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Gene: bnc1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Classified gene: BNC1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Gene: bnc1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Marked gene: BLM as ready
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Classified gene: BLM as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Marked gene: DCAF17 as ready
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Gene: dcaf17 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Phenotypes for gene: DCAF17 were changed from Hypergonadotropic/ Hypogonadotropic Hypogonadism to Woodhouse-Sakati syndrome, MIM# 241080; Hypergonadotropic/ Hypogonadotropic Hypogonadism
Infertility and Recurrent Pregnancy Loss v0.191 DCAF17 Zornitza Stark Classified gene: DCAF17 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.191 DCAF17 Zornitza Stark Gene: dcaf17 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Marked gene: HSF2BP as ready
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Classified gene: HSF2BP as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Marked gene: KIAA1683 as ready
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Classified gene: KIAA1683 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Marked gene: KCNU1 as ready
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Publications for gene: KCNU1 were set to 34980136, 35551387; 20138882; 21427226; 25271166; 35551387
Infertility and Recurrent Pregnancy Loss v0.187 KCNU1 Zornitza Stark Classified gene: KCNU1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.187 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Marked gene: MSH5 as ready
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Gene: msh5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Classified gene: MSH5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Gene: msh5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Marked gene: PIEZO1 as ready
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Gene: piezo1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Classified gene: PIEZO1 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Gene: piezo1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.184 PIEZO1 Zornitza Stark reviewed gene: PIEZO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Marked gene: KIF14 as ready
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Gene: kif14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Phenotypes for gene: KIF14 were changed from to Meckel syndrome 12, MIM# 616258
Infertility and Recurrent Pregnancy Loss v0.183 KIF14 Zornitza Stark Classified gene: KIF14 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.183 KIF14 Zornitza Stark Gene: kif14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Marked gene: WT1 as ready
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Phenotypes for gene: WT1 were changed from Primary ovarian failure, MONDO:0005387 to Primary ovarian failure, MONDO:0005387, WT1-related
Infertility and Recurrent Pregnancy Loss v0.181 WT1 Zornitza Stark Classified gene: WT1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.181 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Phenotypes for gene: PMM2 were changed from Primary ovarian failure to Congenital disorder of glycosylation, type Ia, MIM #212065; Primary ovarian failure
Infertility and Recurrent Pregnancy Loss v0.179 PMM2 Zornitza Stark Classified gene: PMM2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.179 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Marked gene: POR as ready
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Classified gene: POR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Marked gene: RNF212B as ready
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Phenotypes for gene: RNF212B were changed from Female and male infertility with recurrent medically assisted reproduction (MAR) failures. to Infertility disorder, MONDO:0005047, RNF212B-related; Female and male infertility with recurrent medically assisted reproduction (MAR) failures.
Infertility and Recurrent Pregnancy Loss v0.176 RNF212B Zornitza Stark Classified gene: RNF212B as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.176 RNF212B Zornitza Stark Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Marked gene: SCN5A as ready
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Gene: scn5a has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Classified gene: SCN5A as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Gene: scn5a has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.174 SCN5A Zornitza Stark reviewed gene: SCN5A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Marked gene: SEMA3A as ready
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Classified gene: SEMA3A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Marked gene: SYCP2L as ready
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Classified gene: SYCP2L as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Marked gene: SYCE1 as ready
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Classified gene: SYCE1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Marked gene: TAC3 as ready
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Gene: tac3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Classified gene: TAC3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Gene: tac3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Marked gene: TP63 as ready
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Classified gene: TP63 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Marked gene: SYCP2 as ready
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Classified gene: SYCP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Marked gene: TLE6 as ready
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Classified gene: TLE6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Marked gene: TIMP2 as ready
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Phenotypes for gene: TIMP2 were changed from Recurrent pregnancy loss susceptibility, MONDO:0000144 to Recurrent pregnancy loss susceptibility, MONDO:0000144, TIMP2-related
Infertility and Recurrent Pregnancy Loss v0.166 TIMP2 Zornitza Stark Classified gene: TIMP2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.166 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Marked gene: REC114 as ready
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Classified gene: REC114 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Marked gene: SYCP3 as ready
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Classified gene: SYCP3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Marked gene: TACR3 as ready
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Gene: tacr3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Classified gene: TACR3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Gene: tacr3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Marked gene: TBPL2 as ready
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Phenotypes for gene: TBPL2 were changed from Oocyte maturation arrest to Inherited oocyte maturation defect, MONDO:0014769, TBPL2-related
Infertility and Recurrent Pregnancy Loss v0.161 TBPL2 Zornitza Stark Classified gene: TBPL2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.161 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Marked gene: LHB as ready
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Gene: lhb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Classified gene: LHB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Gene: lhb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Marked gene: GNRH1 as ready
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Gene: gnrh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Classified gene: GNRH1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Gene: gnrh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Marked gene: TRIP13 as ready
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Gene: trip13 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Classified gene: TRIP13 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Gene: trip13 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Marked gene: TTN as ready
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Gene: ttn has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Classified gene: TTN as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Gene: ttn has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.156 TTN Zornitza Stark reviewed gene: TTN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lethal congenital contracture syndrome, MONDO:0017436; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Marked gene: WDR11 as ready
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Classified gene: WDR11 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Marked gene: WEE2 as ready
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Gene: wee2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Classified gene: WEE2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Gene: wee2 has been classified as Green List (High Evidence).
Cerebral Palsy v1.390 MAPK8IP3 Chirag Patel changed review comment from: 18 individuals from 17 families reported with de novo heterozygous variants in MAPK8IP3 gene (recurrence in one family due to gonadal mosaicism). Variant types were nonsense, frameshift, and missense. Expression of the missense variants in zebrafish resulted in axonal abnormalities, suggesting defects in neural development.

Clinical features included: development delay, speech delay/minimal speech, intellectual disability (mild-severe), hypotonia, spasticity, ataxia. Less common features included: cortical visual impairment, scoliosis, short stature, microcephaly, dysmorphism. Brain imaging showed variable abnormalities: perisylvian polymicrogyria, cerebral atrophy, cerebellar atrophy, abnormal corpus callosum, white matter volume loss, and hypomyelination.; to: 18 individuals from 17 families reported with de novo heterozygous variants in MAPK8IP3 gene (recurrence in one family due to gonadal mosaicism). Variant types were nonsense, frameshift, and missense. Expression of the missense variants in zebrafish resulted in axonal abnormalities, suggesting defects in neural development.

Clinical features included: development delay, speech delay/minimal speech, intellectual disability (mild-severe), hypotonia, spasticity, ataxia. Less common features included: cortical visual impairment, scoliosis, short stature, microcephaly, dysmorphism. Brain imaging showed variable abnormalities: perisylvian polymicrogyria, cerebral atrophy, cerebellar atrophy, abnormal corpus callosum, white matter volume loss, and hypomyelination.
Cerebellar and Pontocerebellar Hypoplasia v1.82 MAPK8IP3 Chirag Patel Classified gene: MAPK8IP3 as Green List (high evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.82 MAPK8IP3 Chirag Patel Gene: mapk8ip3 has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.81 MAPK8IP3 Chirag Patel gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to PMID: 30945334, 30612693
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities; NEDBA MONDO:0032755
Review for gene: MAPK8IP3 was set to GREEN
Added comment: 18 individuals from 17 families reported with de novo heterozygous variants in MAPK8IP3 gene (recurrence in one family due to gonadal mosaicism). Variant types were nonsense, frameshift, and missense. Expression of the missense variants in zebrafish resulted in axonal abnormalities, suggesting defects in neural development.

Clinical features included: development delay, speech delay/minimal speech, intellectual disability (mild-severe), hypotonia, spasticity, ataxia. Less common features included: cortical visual impairment, scoliosis, short stature, microcephaly, dysmorphism. Brain imaging showed variable abnormalities: perisylvian polymicrogyria, cerebral atrophy, cerebellar atrophy, abnormal corpus callosum, white matter volume loss, and hypomyelination.
Sources: Literature
Cerebral Palsy v1.390 MAPK8IP3 Chirag Patel Classified gene: MAPK8IP3 as Green List (high evidence)
Cerebral Palsy v1.390 MAPK8IP3 Chirag Patel Gene: mapk8ip3 has been classified as Green List (High Evidence).
Cerebral Palsy v1.389 MAPK8IP3 Chirag Patel reviewed gene: MAPK8IP3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30945334, 30612693; Phenotypes: Neurodevelopmental disorder with or without variable brain abnormalities, NEDBA MONDO:0032755; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Differences of Sex Development v1.11 DAAM2 Leah Frajman reviewed gene: DAAM2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36972684; Phenotypes: Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related; 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
Hypertrophic cardiomyopathy_HCM v1.4 TRIM63 Zornitza Stark Phenotypes for gene: TRIM63 were changed from Hypertrophic cardiomyopathy, MONDO:0005045 to Cardiomyopathy, familial hypertrophic, 31, MIM# 621270
Hypertrophic cardiomyopathy_HCM v1.3 TRIM63 Zornitza Stark reviewed gene: TRIM63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, familial hypertrophic, 31, MIM# 621270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia - complex v0.282 PDE1B Zornitza Stark Marked gene: PDE1B as ready
Dystonia - complex v0.282 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Dystonia - complex v0.282 PDE1B Zornitza Stark Classified gene: PDE1B as Green List (high evidence)
Dystonia - complex v0.282 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Dystonia - complex v0.281 PDE1B Zornitza Stark gene: PDE1B was added
gene: PDE1B was added to Dystonia - complex. 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 Complex neurodevelopmental disorder with motor features, MONDO:0100516, PDE1B-related
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
Ataxia v1.43 PDE1B Zornitza Stark Marked gene: PDE1B as ready
Ataxia v1.43 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Ataxia v1.43 PDE1B Zornitza Stark Classified gene: PDE1B as Green List (high evidence)
Ataxia v1.43 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Ataxia v1.42 PDE1B Zornitza Stark gene: PDE1B was added
gene: PDE1B was added to Ataxia - paediatric. 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 Complex neurodevelopmental disorder with motor features, MONDO:0100516, PDE1B-related
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
Intellectual disability syndromic and non-syndromic v1.199 PDE1B Zornitza Stark Marked gene: PDE1B as ready
Intellectual disability syndromic and non-syndromic v1.199 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.199 PDE1B Zornitza Stark Classified gene: PDE1B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.199 PDE1B Zornitza Stark Gene: pde1b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.198 PDE1B Zornitza Stark gene: PDE1B was added
gene: PDE1B was added to Intellectual disability syndromic and non-syndromic. 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 Complex neurodevelopmental disorder with motor features, MONDO:0100516, PDE1B-related
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 v1.2731 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
Infertility and Recurrent Pregnancy Loss v0.154 ATG4D Zornitza Stark Publications for gene: ATG4D were set to
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark edited their review of gene: ATG4D: Changed publications: 33988247; Changed phenotypes: Spermatogenic failure 101, MIM# 621269
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Gene: atg4d has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Classified gene: ATG4D as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Gene: atg4d has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.152 ATG4D Zornitza Stark gene: ATG4D was added
gene: ATG4D was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATG4D were set to Spermatogenic failure 101, MIM# 621269
Review for gene: ATG4D was set to AMBER
Added comment: 4 individuals from 3 unrelated families, all variants are missense, limited functional data.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.94 SECISBP2 Zornitza Stark Marked gene: SECISBP2 as ready
Aortopathy_Connective Tissue Disorders v1.94 SECISBP2 Zornitza Stark Gene: secisbp2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.94 SECISBP2 Zornitza Stark Classified gene: SECISBP2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.94 SECISBP2 Zornitza Stark Gene: secisbp2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.93 SECISBP2 Zornitza Stark gene: SECISBP2 was added
gene: SECISBP2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: SECISBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SECISBP2 were set to 38042913
Phenotypes for gene: SECISBP2 were set to Thyroid hormone metabolism, abnormal, 1 MIM#609698; Selenoprotein deficiency
Review for gene: SECISBP2 was set to GREEN
Added comment: PMID:38042913 reported the identification of four unrelated individuals with biallelic SECISBP2 variants and showed early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. In addition, zebrafish and mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively showed similar aortopathy. Additional features present in probands, condition is more appropriately termed 'selenoprotein deficiency' rather than focusing on the thyroid disease.
Sources: Literature
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
Aortopathy_Connective Tissue Disorders v1.92 PMEPA1 Zornitza Stark Mode of pathogenicity for gene: PMEPA1 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Aortopathy_Connective Tissue Disorders v1.91 PMEPA1 Zornitza Stark Classified gene: PMEPA1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.91 PMEPA1 Zornitza Stark Gene: pmepa1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.90 PMEPA1 Zornitza Stark edited their review of gene: PMEPA1: Changed rating: GREEN
Aortopathy_Connective Tissue Disorders v1.90 ASPH Zornitza Stark Marked gene: ASPH as ready
Aortopathy_Connective Tissue Disorders v1.90 ASPH Zornitza Stark Gene: asph has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.90 ASPH Zornitza Stark Classified gene: ASPH as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.90 ASPH Zornitza Stark Gene: asph has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.89 ASPH Zornitza Stark gene: ASPH was added
gene: ASPH was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: ASPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASPH were set to 35918038
Phenotypes for gene: ASPH were set to Traboulsi syndrome, MIM #601552
Review for gene: ASPH was set to GREEN
Added comment: PMID: 35918038 reports 7 individuals from 6 families (patients 2 and 3 related) with homozygous or compound het variants in ASPH. All presented initially with ocular phenotypes and had characteristic facial features seen in Traboulsi syndrome, but 5 individuals from 4 families were additionally found to have aortic dilatation as part of their clinical characteristics.
Sources: Expert list
Muscular dystrophy and myopathy_Paediatric v1.96 CASQ1 Lauren Rogers reviewed gene: CASQ1: Rating: AMBER; Mode of pathogenicity: None; Publications: 38982518, 29039140; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates 616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Congenital anomalies of the kidney and urinary tract (CAKUT) Nonsyndromic v0.122 LIFR Ava Stevenson reviewed gene: LIFR: Rating: AMBER; 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: 28334964, 38025229, 36417404; Phenotypes: Congenital anomaly of kidney and urinary tract (MONDO:0019719), LIFR-related, AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Neuropathy_CMT - isolated v1.58 ITPR3 Zornitza Stark Phenotypes for gene: ITPR3 were changed from Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111 to Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111; Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254
Hereditary Neuropathy_CMT - isolated v1.57 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to 32949214; 24627108
Hereditary Neuropathy_CMT - isolated v1.56 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, 39270020, 39560673; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111, Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254
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
Combined Immunodeficiency v1.124 ITPR3 Zornitza Stark Phenotypes for gene: ITPR3 were changed from Combined immunodeficiency, MONDO:0015131, ITPR3-related to Combined immunodeficiency, MONDO:0015131, ITPR3-related; Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254
Combined Immunodeficiency v1.123 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to PMID: 36302985
Combined Immunodeficiency v1.122 ITPR3 Zornitza Stark Mode of inheritance for gene: ITPR3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Combined Immunodeficiency v1.121 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Added comment: More than 10 individuals reported with heterozygous variant and combined immunodeficiency +/- ectodermal features and neuropathy.; Changed publications: 36302985, 39270020, 39560673; Changed phenotypes: Combined immunodeficiency, MONDO:0015131, ITPR3-related, Immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, MIM# 621254; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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
Vitreoretinopathy v1.7 LRP6 Zornitza Stark Marked gene: LRP6 as ready
Vitreoretinopathy v1.7 LRP6 Zornitza Stark Gene: lrp6 has been classified as Amber List (Moderate Evidence).
Vitreoretinopathy v1.7 LRP6 Zornitza Stark Classified gene: LRP6 as Amber List (moderate evidence)
Vitreoretinopathy v1.7 LRP6 Zornitza Stark Gene: lrp6 has been classified as Amber List (Moderate Evidence).
Vitreoretinopathy v1.6 LRP6 Zornitza Stark gene: LRP6 was added
gene: LRP6 was added to Vitreoretinopathy. Sources: Literature
Mode of inheritance for gene: LRP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRP6 were set to 34896607
Phenotypes for gene: LRP6 were set to Exudative vitreoretinopathy 8, MIM# 621268
Review for gene: LRP6 was set to AMBER
Added comment: 8 individuals from 3 unrelated families reported, all with missense variants. Insufficient segregation evidence in two of the families. Supportive mouse model.
Sources: Literature
Mitochondrial disease v0.986 FASTKD5 Zornitza Stark Marked gene: FASTKD5 as ready
Mitochondrial disease v0.986 FASTKD5 Zornitza Stark Gene: fastkd5 has been classified as Green List (High Evidence).
Mitochondrial disease v0.986 FASTKD5 Zornitza Stark Phenotypes for gene: FASTKD5 were changed from Leigh syndrome MONDO:0009723 to Leigh syndrome MONDO:0009723, FASTKD5-related
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
Intellectual disability syndromic and non-syndromic v1.197 FASTKD5 Zornitza Stark Marked gene: FASTKD5 as ready
Intellectual disability syndromic and non-syndromic v1.197 FASTKD5 Zornitza Stark Gene: fastkd5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.197 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
Arthrogryposis v0.422 DST Zornitza Stark Marked gene: DST as ready
Arthrogryposis v0.422 DST Zornitza Stark Gene: dst has been classified as Green List (High Evidence).
Arthrogryposis v0.422 DST Zornitza Stark Phenotypes for gene: DST were changed from congenital myopathy MONDO:0019952 to congenital myopathy MONDO:0019952, DST-related
Muscular dystrophy and myopathy_Paediatric v1.96 DST Zornitza Stark Marked gene: DST as ready
Muscular dystrophy and myopathy_Paediatric v1.96 DST Zornitza Stark Gene: dst has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.96 DST Zornitza Stark Phenotypes for gene: DST were changed from congenital myopathy MONDO:0019952 to congenital myopathy MONDO:0019952, DST-related
Muscular dystrophy and myopathy_Paediatric v1.95 DST Chirag Patel Classified gene: DST as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.95 DST Chirag Patel Gene: dst has been classified as Green List (High Evidence).
Arthrogryposis v0.421 DST Chirag Patel Classified gene: DST as Green List (high evidence)
Arthrogryposis v0.421 DST Chirag Patel Gene: dst has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.94 DST Chirag Patel gene: DST was added
gene: DST was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to PMID: 40497796
Phenotypes for gene: DST were set to congenital myopathy MONDO:0019952
Review for gene: DST was set to GREEN
Added comment: Dystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST are associated with Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e).

PMID 40497796 reports 19 affected individuals from 14 unrelated families with severe congenital myopathy characterized by arthrogryposis, hypotonia, myopathy, and motor delay. 3/19 resulted in TOP, 9/14 needed CPAP ventilation, 7/14 had dilated cardiomyopathy, 7/16 died under 3 years of life. 3 patients are now over 25 years with normal cognition and ambulation. Muscle biopsies in 4 patients (aged 1 month to 3 years) showed mild/non-specific myopathic changes, mild/focal myofibrillar disruption, and non-specific undulating nuclear membranes.

WES/WGS identified 9 different LOF variants in biallelic state located in exons 40-41 and specific to isoform DST-b. 18/19 individuals had homozygous variants, 1/19 individuals had compound heterozygous variants, 8/9 variants were in exon 40, 1/9 variants were in exon 41.

RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue, and cultured fibroblasts, but not in brain matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform.
Therefore, biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy.

Additionally, 2 homozygous LOF variants (outside of exons 40-41) affecting both DST-a and DST-b isoforms were found in 4 patients from 2 unrelated families with severe arthrogryposis and death in utero or shortly after birth. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome.
Sources: Literature
Arthrogryposis v0.420 DST Chirag Patel gene: DST was added
gene: DST was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to PMID: 40497796
Phenotypes for gene: DST were set to congenital myopathy MONDO:0019952
Review for gene: DST was set to GREEN
Added comment: Dystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST are associated with Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e).

PMID 40497796 reports 19 affected individuals from 14 unrelated families with severe congenital myopathy characterized by arthrogryposis, hypotonia, myopathy, and motor delay. 3/19 resulted in TOP, 9/14 needed CPAP ventilation, 7/14 had dilated cardiomyopathy, 7/16 died under 3 years of life. 3 patients are now over 25 years with normal cognition and ambulation. Muscle biopsies in 4 patients (aged 1 month to 3 years) showed mild/non-specific myopathic changes, mild/focal myofibrillar disruption, and non-specific undulating nuclear membranes.

WES/WGS identified 9 different LOF variants in biallelic state located in exons 40-41 and specific to isoform DST-b. 18/19 individuals had homozygous variants, 1/19 individuals had compound heterozygous variants, 8/9 variants were in exon 40, 1/9 variants were in exon 41.

RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue, and cultured fibroblasts, but not in brain matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform.
Therefore, biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy.

Additionally, 2 homozygous LOF variants (outside of exons 40-41) affecting both DST-a and DST-b isoforms were found in 4 patients from 2 unrelated families with severe arthrogryposis and death in utero or shortly after birth. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome.
Sources: Literature
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
Intellectual disability syndromic and non-syndromic v1.196 FASTKD5 Chirag Patel Classified gene: FASTKD5 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.196 FASTKD5 Chirag Patel Gene: fastkd5 has been classified as Green List (High Evidence).
Mitochondrial disease v0.985 FASTKD5 Chirag Patel Classified gene: FASTKD5 as Green List (high evidence)
Mitochondrial disease v0.985 FASTKD5 Chirag Patel Gene: fastkd5 has been classified as Green List (High Evidence).
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).
Mitochondrial disease v0.984 FASTKD5 Chirag Patel gene: FASTKD5 was added
gene: FASTKD5 was added to Mitochondrial disease. 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
Intellectual disability syndromic and non-syndromic v1.195 FASTKD5 Chirag Patel gene: FASTKD5 was added
gene: FASTKD5 was added to Intellectual disability syndromic and non-syndromic. 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 v1.2718 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
Genetic Epilepsy v1.168 LRPPRC Chirag Patel Classified gene: LRPPRC as Green List (high evidence)
Genetic Epilepsy v1.168 LRPPRC Chirag Patel Gene: lrpprc has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.151 KCNU1 Jasmine Chew edited their review of gene: KCNU1: Changed publications: 34980136, 35551387, 20138882, 21427226, 25271166, 35551387
Infertility and Recurrent Pregnancy Loss v0.151 KCNU1 Jasmine Chew gene: KCNU1 was added
gene: KCNU1 was added to Infertility and Pregnancy Loss. Sources: Literature
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: Literature
Infertility and Recurrent Pregnancy Loss v0.151 KIAA1683 Jasmine Chew gene: KIAA1683 was added
gene: KIAA1683 was added to Infertility and Pregnancy Loss. Sources: Literature
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: Literature
Infertility and Recurrent Pregnancy Loss v0.151 ACTL9 Jasmine Chew gene: ACTL9 was added
gene: ACTL9 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ACTL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL9 were set to 33626338; 38963606
Phenotypes for gene: ACTL9 were set to Spermatogenic failure 53, MIM# 619258
Review for gene: ACTL9 was set to GREEN
Added comment: Literature in OMIM entry- PMID: 33626338 (3 unrelated Chinese men with infertility due to spermatogenic failure with 2 hom missense variants, supported by functional evidence)

Other papers:
i) PMID: 38963606 (2024)- novel homozygous p.Gly342Cys and p.Val380Leu sitting in the actin domain in two independent Chinese families. Spermatozoa with ACTL9 mutations showed decreased CASA parameters and a higher proportion of spermatozoa with abnormal morphology, exhibiting coiled flagella and a thickened midpiece. The spermatozoa were characterized by chaotic or irregular '9+2' structures and irregular mitochondrial sheath arrangements in the flagellum. There was no significant difference in ACTL9 expression between the HeLa cells transfected with the WT and mutant ACTL9 plasmids. Actl9 knock-in mice also showed abnormal CASA parameters and irregular '9+2' structures in flagella.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.151 ACTL7A Jasmine Chew changed review comment from: 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, confirming the pathogenicity of the variants.

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: Literature; to: 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: Literature
Infertility and Recurrent Pregnancy Loss v0.151 ACTL7A Jasmine Chew gene: ACTL7A was added
gene: ACTL7A was added to Infertility and Pregnancy Loss. Sources: Literature
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, confirming the pathogenicity of the variants.

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: Literature
Intellectual disability syndromic and non-syndromic v1.194 NDUFA4 Zornitza Stark Marked gene: NDUFA4 as ready
Intellectual disability syndromic and non-syndromic v1.194 NDUFA4 Zornitza Stark Gene: ndufa4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.194 NDUFA4 Zornitza Stark Classified gene: NDUFA4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.194 NDUFA4 Zornitza Stark Gene: ndufa4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.193 NDUFA4 Sarah Milton gene: NDUFA4 was added
gene: NDUFA4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NDUFA4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA4 were set to PMID: 39967265
Phenotypes for gene: NDUFA4 were set to Mitochondrial complex IV deficiency, nuclear type 21, MIM#619065
Review for gene: NDUFA4 was set to GREEN
Added comment: HGNC symbol now COXFA4

Around 10 patients reported in literature thus far with most having developmental delay. Association with hypertrophic cardiomyopathy reported in 3 siblings from a family in PMID: 39967265
Sources: Literature
Phagocyte Defects v1.35 MPO Bryony Thompson Marked gene: MPO as ready
Phagocyte Defects v1.35 MPO Bryony Thompson Gene: mpo has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.35 MPO Bryony Thompson Classified gene: MPO as Amber List (moderate evidence)
Phagocyte Defects v1.35 MPO Bryony Thompson Gene: mpo has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.34 MPO Bryony Thompson gene: MPO was added
gene: MPO was added to Phagocyte Defects. Sources: Other
Mode of inheritance for gene: MPO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPO were set to 7904599; 39087142; 29262241
Phenotypes for gene: MPO were set to myeloperoxidase deficiency MONDO:0009694
Review for gene: MPO was set to AMBER
Added comment: Most common inherited phagocyte defect leading to impaired microbial killing. The majority of cases are clinically asymptomatic except if diabetic.
Sources: Other
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
Intellectual disability syndromic and non-syndromic v1.193 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
Intellectual disability syndromic and non-syndromic v1.192 FEM1B Zornitza Stark edited their review of gene: FEM1B: Changed phenotypes: Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, MIM# 621263
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
Intellectual disability syndromic and non-syndromic v1.192 DOT1L Zornitza Stark Phenotypes for gene: DOT1L were changed from Neurodevelopmental disorder, MONDO:0700092, DOT1L-related to Nil-Deshwan neurodevelopmental syndrome, MIM# 621265
Intellectual disability syndromic and non-syndromic v1.191 DOT1L Zornitza Stark edited their review of gene: DOT1L: Changed phenotypes: Nil-Deshwan neurodevelopmental syndrome, MIM# 621265
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
Red cell disorders v1.31 RPL17 Zornitza Stark Marked gene: RPL17 as ready
Red cell disorders v1.31 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Red cell disorders v1.31 RPL17 Zornitza Stark Classified gene: RPL17 as Green List (high evidence)
Red cell disorders v1.31 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Red cell disorders v1.30 RPL17 Zornitza Stark gene: RPL17 was added
gene: RPL17 was added to Red cell disorders. 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 anaemia 22, MIM# 621262
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.
Sources: Literature
Bone Marrow Failure v1.121 RPL17 Zornitza Stark Marked gene: RPL17 as ready
Bone Marrow Failure v1.121 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Bone Marrow Failure v1.121 RPL17 Zornitza Stark Classified gene: RPL17 as Green List (high evidence)
Bone Marrow Failure v1.121 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Bone Marrow Failure v1.120 RPL17 Zornitza Stark gene: RPL17 was added
gene: RPL17 was added to Bone Marrow Failure. 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 anaemia 22, MIM# 621262
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.
Sources: Literature
Diamond Blackfan anaemia v1.11 RPL17 Zornitza Stark Marked gene: RPL17 as ready
Diamond Blackfan anaemia v1.11 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Diamond Blackfan anaemia v1.11 RPL17 Zornitza Stark Classified gene: RPL17 as Green List (high evidence)
Diamond Blackfan anaemia v1.11 RPL17 Zornitza Stark Gene: rpl17 has been classified as Green List (High Evidence).
Diamond Blackfan anaemia v1.10 RPL17 Zornitza Stark gene: RPL17 was added
gene: RPL17 was added to Diamond Blackfan anaemia. 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 anaemia 22, MIM# 621262
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.
Sources: Literature
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
Mitochondrial disease v0.983 GATB Bryony Thompson Phenotypes for gene: GATB were changed from Mitochondrial cardiomyopathy to inborn mitochondrial metabolism disorder MONDO:0004069
Mitochondrial disease v0.982 GATB Bryony Thompson Publications for gene: GATB were set to 30283131; 38703036
Mitochondrial disease v0.981 GATB Bryony Thompson Publications for gene: GATB were set to 30283131
Mitochondrial disease v0.981 GATB Bryony Thompson Classified gene: GATB as Amber List (moderate evidence)
Mitochondrial disease v0.981 GATB Bryony Thompson Gene: gatb has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.980 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 v1.2710 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
Genetic Epilepsy v1.167 LONP1 Zornitza Stark Marked gene: LONP1 as ready
Genetic Epilepsy v1.167 LONP1 Zornitza Stark Gene: lonp1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.167 LONP1 Zornitza Stark Classified gene: LONP1 as Green List (high evidence)
Genetic Epilepsy v1.167 LONP1 Zornitza Stark Gene: lonp1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.166 LONP1 Zornitza Stark gene: LONP1 was added
gene: LONP1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: LONP1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LONP1 were set to 31636596; 36353900; 31923470
Phenotypes for gene: LONP1 were set to CODAS syndrome, MIM#600373; mitochondrial disease (MONDO:0044970), LONP1-related
Review for gene: LONP1 was set to GREEN
Added comment: Seizures rarely reported with bi-allelic disease.

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.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.191 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
Intellectual disability syndromic and non-syndromic v1.190 LONP1 Zornitza Stark Publications for gene: LONP1 were set to 31636596
Intellectual disability syndromic and non-syndromic v1.189 LONP1 Zornitza Stark Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v1.188 LONP1 Zornitza Stark edited their review of gene: LONP1: Added comment: 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.; Changed publications: 31636596, 36353900 31923470; Changed phenotypes: CODAS syndrome, MIM#600373, mitochondrial disease (MONDO:0044970), LONP1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disease v0.980 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
Mitochondrial disease v0.979 LONP1 Zornitza Stark Publications for gene: LONP1 were set to 31636596
Mitochondrial disease v0.978 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 v1.2701 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
Mitochondrial disease v0.977 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 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
Congenital Myasthenia v1.13 CHD8 Zornitza Stark Marked gene: CHD8 as ready
Congenital Myasthenia v1.13 CHD8 Zornitza Stark Gene: chd8 has been classified as Red List (Low Evidence).
Congenital Myasthenia v1.13 CHD8 Zornitza Stark Classified gene: CHD8 as Red List (low evidence)
Congenital Myasthenia v1.13 CHD8 Zornitza Stark Gene: chd8 has been classified as Red List (Low Evidence).
Congenital Myasthenia v1.12 CHD8 Zornitza Stark reviewed gene: CHD8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2698 BHLHA9 Zornitza Stark Tag SV/CNV tag was added to gene: BHLHA9.
Cardiomyopathy_Paediatric v0.200 NEXN Zornitza Stark Marked gene: NEXN as ready
Cardiomyopathy_Paediatric v0.200 NEXN Zornitza Stark Gene: nexn has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.200 NEXN Zornitza Stark Phenotypes for gene: NEXN were changed from Cardiomyopathy, familial hypertrophic, 20,; Cardiomyopathy, dilated, 1CC to Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261; Cardiomyopathy, familial hypertrophic, 20,; Cardiomyopathy, dilated, 1CC
Cardiomyopathy_Paediatric v0.199 NEXN Zornitza Stark Mode of inheritance for gene: NEXN 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 v1.2698 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
Hydrops fetalis v0.328 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
Hydrops fetalis v0.327 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
Dilated Cardiomyopathy v1.42 NEXN Zornitza Stark Mode of inheritance for gene: NEXN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated Cardiomyopathy v1.41 NEXN Zornitza Stark edited their review of gene: NEXN: Changed publications: 19881492, 28416588, 25163546, 27532257, 24503780, 29540472; Changed phenotypes: Cardiomyopathy, dilated, 1CC, MIM# 613122; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated Cardiomyopathy v1.41 NEXN Zornitza Stark Phenotypes for gene: NEXN were changed from Cardiomyopathy, dilated, 1CC, MIM# 613122; Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261 to Cardiomyopathy, dilated, 1CC, MIM# 613122
Dilated Cardiomyopathy v1.40 NEXN Zornitza Stark Deleted their comment
Dilated Cardiomyopathy v1.40 NEXN Zornitza Stark Phenotypes for gene: NEXN were changed from Cardiomyopathy, dilated, 1CC, MIM# 613122 to Cardiomyopathy, dilated, 1CC, MIM# 613122; Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261
Dilated Cardiomyopathy v1.39 NEXN Zornitza Stark Mode of inheritance for gene: NEXN was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dilated Cardiomyopathy v1.38 NEXN Zornitza Stark edited their review of gene: NEXN: Added comment: 7 families reported with DCM and bi-allelic variants, several of the presentations were severe perinatal.; Changed publications: 19881492, 28416588, 25163546, 27532257, 24503780, 29540472, 26659360, 33949776, 39183344, 38059363, 35166435; Changed phenotypes: Cardiomyopathy, dilated, 1CC, MIM# 613122, Cardiomyopathy, dilated, 2M, autosomal recessive, MIM# 621261; Changed mode of inheritance: BOTH monoallelic and 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
Congenital Myasthenia v1.12 CHD8 Sangavi Sivagnanasundram gene: CHD8 was added
gene: CHD8 was added to Congenital Myasthenia. Sources: Literature
Mode of inheritance for gene: CHD8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD8 were set to 20301347; 32267004; 36835142
Phenotypes for gene: CHD8 were set to Complex neurodevelopmental disorder MONDO:0100038
Review for gene: CHD8 was set to AMBER
Added comment: Report of myasthenic phenotype in at least one confirmed family as per Gene Reviews. Additional pro

PMID: 32267004
14 female twins first children of healthy non consanguineous German parents
Presented with a range of neonatal complications including respiratory distress, cardiorespiratory instability, jaundice, ptosis and muscle weakness.
Arg578Cys - present in gnomAD but only a singleton

PMID: 36835142
Other LoF variants have been reported in other pubs. Personal communication between authors state that muscle hypotonia and muscle weakness was observed in affected individuals with ID with autism and macrocephaly
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.188 PIGU Zornitza Stark Classified gene: PIGU as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.188 PIGU Zornitza Stark Gene: pigu has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.187 PIGU Zornitza Stark reviewed gene: PIGU: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 21, OMIM #618590; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.165 PIGU Zornitza Stark Classified gene: PIGU as Amber List (moderate evidence)
Genetic Epilepsy v1.165 PIGU Zornitza Stark Gene: pigu has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.164 PIGU Zornitza Stark edited their review of gene: PIGU: Added comment: Downgraded due to LIMITED assessment by ClinGen: only 2 variants across 5 families.; Changed rating: AMBER
Congenital Disorders of Glycosylation v1.67 PIGU Zornitza Stark Classified gene: PIGU as Amber List (moderate evidence)
Congenital Disorders of Glycosylation v1.67 PIGU Zornitza Stark Gene: pigu has been classified as Amber List (Moderate Evidence).
Congenital Disorders of Glycosylation v1.66 PIGU Zornitza Stark edited their review of gene: PIGU: Added comment: LIMITED by ClinGen, only 2 variants across the 5 families.; Changed rating: AMBER
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
Severe Combined Immunodeficiency v1.10 POLD3 Zornitza Stark Classified gene: POLD3 as Amber List (moderate evidence)
Severe Combined Immunodeficiency v1.10 POLD3 Zornitza Stark Gene: pold3 has been classified as Amber List (Moderate Evidence).
Severe Combined Immunodeficiency v1.9 POLD3 Zornitza Stark edited their review of gene: POLD3: Added comment: Downgraded from MODERATE to LIMITED by ClinGen expert review.; 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).
Bleeding and Platelet Disorders v1.56 NFE2 Zornitza Stark Marked gene: NFE2 as ready
Bleeding and Platelet Disorders v1.56 NFE2 Zornitza Stark Gene: nfe2 has been classified as Red List (Low Evidence).
Bleeding and Platelet Disorders v1.56 NFE2 Zornitza Stark gene: NFE2 was added
gene: NFE2 was added to Bleeding and Platelet Disorders. 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, NFE2-related
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 v1.2695 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).
Intellectual disability syndromic and non-syndromic v1.187 FAAH2 Zornitza Stark commented on gene: FAAH2: DISPUTED by ClinGen
Intellectual disability syndromic and non-syndromic v1.187 FAAH2 Zornitza Stark Tag disputed tag was added to gene: FAAH2.
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
Fetal anomalies v1.378 FAAP100 Zornitza Stark Phenotypes for gene: FAAP100 were changed from Fanconi anaemia, MONDO:0019391, FAAP100-related to Fanconi anaemia, complementation group X, MIM# 621258
Fetal anomalies v1.377 FAAP100 Zornitza Stark edited their review of gene: FAAP100: Changed phenotypes: Fanconi anaemia, complementation group X, MIM# 621258
Radial Ray Abnormalities v1.19 FAAP100 Zornitza Stark Phenotypes for gene: FAAP100 were changed from Fanconi anaemia, MONDO:0019391, FAAP100-related to Fanconi anaemia, complementation group X, MIM# 621258
Radial Ray Abnormalities v1.18 FAAP100 Zornitza Stark edited their review of gene: FAAP100: Changed phenotypes: Fanconi anaemia, complementation group X, MIM# 621258
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
Bone Marrow Failure v1.119 FAAP100 Zornitza Stark Phenotypes for gene: FAAP100 were changed from Fanconi anaemia, MONDO:0019391, FAAP100-related to Fanconi anemia, complementation group X, MIM# 621258
Bone Marrow Failure v1.118 FAAP100 Zornitza Stark edited their review of gene: FAAP100: Changed phenotypes: Fanconi anemia, complementation group X, MIM# 621258
Intellectual disability syndromic and non-syndromic v1.187 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
Intellectual disability syndromic and non-syndromic v1.186 TMEM63B Zornitza Stark edited their review of gene: TMEM63B: Changed phenotypes: Developmental and epileptic encephalopathy 118, MIM# 621250
Genetic Epilepsy v1.164 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
Genetic Epilepsy v1.163 TMEM63B Zornitza Stark edited their review of gene: TMEM63B: Changed phenotypes: Developmental and epileptic encephalopathy 118, MIM# 621250
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
Intellectual disability syndromic and non-syndromic v1.186 LGI1 Krithika Murali Classified gene: LGI1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.186 LGI1 Krithika Murali Gene: lgi1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.185 LGI1 Krithika Murali Marked gene: LGI1 as ready
Intellectual disability syndromic and non-syndromic v1.185 LGI1 Krithika Murali Gene: lgi1 has been classified as Red List (Low Evidence).
Muscular dystrophy and myopathy_Paediatric v1.93 LGI1 Krithika Murali Classified gene: LGI1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.93 LGI1 Krithika Murali Gene: lgi1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.92 LGI1 Krithika Murali Marked gene: LGI1 as ready
Muscular dystrophy and myopathy_Paediatric v1.92 LGI1 Krithika Murali Gene: lgi1 has been classified as Red List (Low Evidence).
Muscular dystrophy and myopathy_Paediatric v1.92 LGI1 Krithika Murali gene: LGI1 was added
gene: LGI1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: LGI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI1 were set to PMID:40455867
Phenotypes for gene: LGI1 were set to Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related
Review for gene: LGI1 was set to GREEN
Added comment: PMID: 40455867 report patients with biallelic variants in 6 individuals from 4 consanguineous families with a more severe DEE phenotype. All indivduals had seizures, global dev delay/ID and generalised hypotonia. Four out of five exhibited spasticity.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.185 LGI1 Krithika Murali gene: LGI1 was added
gene: LGI1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LGI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI1 were set to PMID:40455867
Phenotypes for gene: LGI1 were set to Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related
Review for gene: LGI1 was set to GREEN
Added comment: PMID: 40455867 report patients with biallelic variants in 6 individuals from 4 consanguineous families with a more severe DEE phenotype. All indivduals had seizures, global dev delay/ID and generalised hypotonia. Four out of five exhibited spasticity.
Sources: Literature
Genetic Epilepsy v1.163 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
Genetic Epilepsy v1.162 LGI1 Krithika Murali Publications for gene: LGI1 were set to 18711109; 12205652; 15079010; 22496201; PMID:40455867
Genetic Epilepsy v1.161 LGI1 Krithika Murali Publications for gene: LGI1 were set to 18711109; 12205652; 15079010; 22496201
Genetic Epilepsy v1.161 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
Genetic Epilepsy v1.160 LGI1 Krithika Murali reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:40455867; Phenotypes: Developmental and epileptic encephalopathy MONDO:0100062, LGI1-related, Epilepsy, familial temporal lobe, 1, MIM# 6000512; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
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
Genetic Epilepsy v1.160 ELFN1 Krithika Murali Classified gene: ELFN1 as Green List (high evidence)
Genetic Epilepsy v1.160 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.159 ELFN1 Krithika Murali Marked gene: ELFN1 as ready
Genetic Epilepsy v1.159 ELFN1 Krithika Murali Gene: elfn1 has been classified as Red List (Low Evidence).
Muscular dystrophy and myopathy_Paediatric v1.91 ELFN1 Krithika Murali Classified gene: ELFN1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.91 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.90 ELFN1 Krithika Murali Classified gene: ELFN1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.90 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.89 ELFN1 Krithika Murali Marked gene: ELFN1 as ready
Muscular dystrophy and myopathy_Paediatric v1.89 ELFN1 Krithika Murali Gene: elfn1 has been classified as Red List (Low Evidence).
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).
Autism v0.209 ELFN1 Krithika Murali Classified gene: ELFN1 as Green List (high evidence)
Autism v0.209 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Autism v0.208 ELFN1 Krithika Murali Marked gene: ELFN1 as ready
Autism v0.208 ELFN1 Krithika Murali Gene: elfn1 has been classified as Red List (Low Evidence).
Ataxia v1.41 ELFN1 Krithika Murali Marked gene: ELFN1 as ready
Ataxia v1.41 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Ataxia v1.41 ELFN1 Krithika Murali Classified gene: ELFN1 as Green List (high evidence)
Ataxia v1.41 ELFN1 Krithika Murali Gene: elfn1 has been classified as Green List (High Evidence).
Ataxia v1.40 ELFN1 Krithika Murali gene: ELFN1 was added
gene: ELFN1 was added to Ataxia - paediatric. 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
Muscular dystrophy and myopathy_Paediatric v1.89 ELFN1 Krithika Murali gene: ELFN1 was added
gene: ELFN1 was added to Muscular dystrophy and myopathy_Paediatric. 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
Genetic Epilepsy v1.159 ELFN1 Krithika Murali gene: ELFN1 was added
gene: ELFN1 was added to Genetic Epilepsy. 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
Autism v0.208 ELFN1 Krithika Murali gene: ELFN1 was added
gene: ELFN1 was added to Autism. 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 v1.2687 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).
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Marked gene: TEX14 as ready
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Classified gene: TEX14 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.150 TEX14 Bryony Thompson gene: TEX14 was added
gene: TEX14 was added to Infertility and Pregnancy Loss. 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 v1.2686 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
Intellectual disability syndromic and non-syndromic v1.184 WDR91 Bryony Thompson Marked gene: WDR91 as ready
Intellectual disability syndromic and non-syndromic v1.184 WDR91 Bryony Thompson Gene: wdr91 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.184 WDR91 Bryony Thompson Classified gene: WDR91 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.184 WDR91 Bryony Thompson Gene: wdr91 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.183 WDR91 Bryony Thompson gene: WDR91 was added
gene: WDR91 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR91 were set to 32732226; 38041506; 34791078; 40550703; 28860274; 34028500; ClinVar: SCV000965687.1
Phenotypes for gene: WDR91 were set to Complex neurodevelopmental disorder MONDO:0100038
Review for gene: WDR91 was set to GREEN
Added comment: Homozygous LoF variants were identified in at least 5 families with a mainly neurodevelopmental disorder phenotype. Also, supporting mouse models
1. Brain malformation
2. Severe developmental delay, microcephaly, severe microlissencephaly, agenesis of corpus callosum, epilepsy, spastic tetraparesis, laryngomalacia, bicuspid aortic valve, congenital hip dislocation, growth retardation, dysmorphisms
3. Severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment
4. Hygroma, macrocephaly, abnormal ears, unilateral simian crease, hydrocephaly, cerebellar hypoplasia, interventricular
communication
5. Neurodevelopmental disorder with brain malformations and multiple congenital anomalies
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
Fetal anomalies v1.377 WDR91 Bryony Thompson Phenotypes for gene: WDR91 were changed from Hydrocephaly; Hygroma to Complex neurodevelopmental disorder MONDO:0100038
Fetal anomalies v1.376 WDR91 Bryony Thompson Publications for gene: WDR91 were set to 32732226; 34028500; 28860274
Fetal anomalies v1.375 WDR91 Bryony Thompson Classified gene: WDR91 as Green List (high evidence)
Fetal anomalies v1.375 WDR91 Bryony Thompson Gene: wdr91 has been classified as Green List (High Evidence).
Fetal anomalies v1.374 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 v1.2683 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).
Congenital Heart Defect v0.449 MIB1 Zornitza Stark Classified gene: MIB1 as Red List (low evidence)
Congenital Heart Defect v0.449 MIB1 Zornitza Stark Gene: mib1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.374 MIB1 Zornitza Stark Classified gene: MIB1 as Red List (low evidence)
Fetal anomalies v1.374 MIB1 Zornitza Stark Gene: mib1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.182 ADD1 Zornitza Stark Classified gene: ADD1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.182 ADD1 Zornitza Stark Gene: add1 has been classified as Amber List (Moderate Evidence).
Callosome v0.546 ADD1 Zornitza Stark Classified gene: ADD1 as Amber List (moderate evidence)
Callosome v0.546 ADD1 Zornitza Stark Gene: add1 has been classified as Amber List (Moderate 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).
Fetal anomalies v1.373 ADD1 Zornitza Stark Classified gene: ADD1 as Amber List (moderate evidence)
Fetal anomalies v1.373 ADD1 Zornitza Stark Gene: add1 has been classified as Amber List (Moderate Evidence).
Amyloidosis v1.1 APOC2 Zornitza Stark Marked gene: APOC2 as ready
Amyloidosis v1.1 APOC2 Zornitza Stark Gene: apoc2 has been classified as Amber List (Moderate Evidence).
Amyloidosis v1.1 APOC2 Zornitza Stark Classified gene: APOC2 as Amber List (moderate evidence)
Amyloidosis v1.1 APOC2 Zornitza Stark Gene: apoc2 has been classified as Amber List (Moderate Evidence).
Frontonasal dysplasia v1.2 CDH11 Zornitza Stark Marked gene: CDH11 as ready
Frontonasal dysplasia v1.2 CDH11 Zornitza Stark Gene: cdh11 has been classified as Green List (High Evidence).
Frontonasal dysplasia v1.2 CDH11 Zornitza Stark Classified gene: CDH11 as Green List (high evidence)
Frontonasal dysplasia v1.2 CDH11 Zornitza Stark Gene: cdh11 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.158 ADAM23 Zornitza Stark Marked gene: ADAM23 as ready
Genetic Epilepsy v1.158 ADAM23 Zornitza Stark Gene: adam23 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v1.158 ADAM23 Zornitza Stark Classified gene: ADAM23 as Amber List (moderate evidence)
Genetic Epilepsy v1.158 ADAM23 Zornitza Stark Gene: adam23 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).
Intellectual disability syndromic and non-syndromic v1.181 ADAM23 Zornitza Stark Marked gene: ADAM23 as ready
Intellectual disability syndromic and non-syndromic v1.181 ADAM23 Zornitza Stark Gene: adam23 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.181 ADAM23 Zornitza Stark Classified gene: ADAM23 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.181 ADAM23 Zornitza Stark Gene: adam23 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.19 SIDT2 Zornitza Stark Marked gene: SIDT2 as ready
Lysosomal Storage Disorder v1.19 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.19 SIDT2 Zornitza Stark Classified gene: SIDT2 as Amber List (moderate evidence)
Lysosomal Storage Disorder v1.19 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.18 SIDT2 Zornitza Stark gene: SIDT2 was added
gene: SIDT2 was added to Lysosomal Storage Disorder. Sources: Literature
Mode of inheritance for gene: SIDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIDT2 were set to 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. Supportive mouse model
Sources: Literature
Regression v0.582 SIDT2 Zornitza Stark Marked gene: SIDT2 as ready
Regression v0.582 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Regression v0.582 SIDT2 Zornitza Stark Classified gene: SIDT2 as Amber List (moderate evidence)
Regression v0.582 SIDT2 Zornitza Stark Gene: sidt2 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).
Ataxia v1.39 SIDT2 Zornitza Stark Marked gene: SIDT2 as ready
Ataxia v1.39 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Ataxia v1.39 SIDT2 Zornitza Stark Classified gene: SIDT2 as Amber List (moderate evidence)
Ataxia v1.39 SIDT2 Zornitza Stark Gene: sidt2 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v1.19 SREK1 Zornitza Stark Marked gene: SREK1 as ready
Severe early-onset obesity v1.19 SREK1 Zornitza Stark Gene: srek1 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v1.19 SREK1 Zornitza Stark Classified gene: SREK1 as Amber List (moderate evidence)
Severe early-onset obesity v1.19 SREK1 Zornitza Stark Gene: srek1 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v1.18 SREK1 Zornitza Stark gene: SREK1 was added
gene: SREK1 was added to Severe early-onset obesity. 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 for now as variants homozygous missense with limited other supporting data.
Sources: Literature
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).
Intellectual disability syndromic and non-syndromic v1.180 SREK1 Zornitza Stark Marked gene: SREK1 as ready
Intellectual disability syndromic and non-syndromic v1.180 SREK1 Zornitza Stark Gene: srek1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.180 SREK1 Zornitza Stark Classified gene: SREK1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.180 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).
Intellectual disability syndromic and non-syndromic v1.179 NSUN3 Zornitza Stark Marked gene: NSUN3 as ready
Intellectual disability syndromic and non-syndromic v1.179 NSUN3 Zornitza Stark Gene: nsun3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.179 NSUN3 Zornitza Stark Classified gene: NSUN3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.179 NSUN3 Zornitza Stark Gene: nsun3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.178 NSUN3 Zornitza Stark gene: NSUN3 was added
gene: NSUN3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NSUN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSUN3 were set to 27356879; 32488845; 40465263
Phenotypes for gene: NSUN3 were set to Combined oxidative phosphorylation deficiency 48, MIM# 619012
Review for gene: NSUN3 was set to GREEN
Added comment: Six families reported. DD/ID can be part of the phenotype.
Sources: Literature
Mitochondrial disease v0.977 NSUN3 Zornitza Stark Publications for gene: NSUN3 were set to 27356879; 32488845
Mitochondrial disease v0.976 NSUN3 Zornitza Stark Classified gene: NSUN3 as Green List (high evidence)
Mitochondrial disease v0.976 NSUN3 Zornitza Stark Gene: nsun3 has been classified as Green List (High Evidence).
Microcephaly v1.318 METTL5 Zornitza Stark Marked gene: METTL5 as ready
Microcephaly v1.318 METTL5 Zornitza Stark Gene: mettl5 has been classified as Green List (High Evidence).
Microcephaly v1.318 METTL5 Zornitza Stark Classified gene: METTL5 as Green List (high evidence)
Microcephaly v1.318 METTL5 Zornitza Stark Gene: mettl5 has been classified as Green List (High Evidence).
Microcephaly v1.317 METTL5 Zornitza Stark gene: METTL5 was added
gene: METTL5 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL5 were set to 31564433; 40500307; 29302074
Phenotypes for gene: METTL5 were set to Intellectual developmental disorder, autosomal recessive 72, MIM# 618665
Review for gene: METTL5 was set to GREEN
Added comment: Fourth family reported. Microcephaly is part of the phenotype.
Sources: Literature
Monogenic Diabetes v0.142 POC5 Zornitza Stark Marked gene: POC5 as ready
Monogenic Diabetes v0.142 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Monogenic Diabetes v0.142 POC5 Zornitza Stark Classified gene: POC5 as Green List (high evidence)
Monogenic Diabetes v0.142 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Monogenic Diabetes v0.141 POC5 Zornitza Stark gene: POC5 was added
gene: POC5 was added to Monogenic Diabetes. Sources: Literature
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 40590205; 29272404
Phenotypes for gene: POC5 were set to Ciliopathy, MONDO:0005308, POC5-related
Review for gene: POC5 was set to GREEN
Added comment: Twelve families reported with bi-allelic variants in this gene and rod-cone dystrophy, diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. Single individual previously reported in 2018 with isolated RP.
Sources: Literature
Lipodystrophy_Lipoatrophy v1.22 POC5 Zornitza Stark Marked gene: POC5 as ready
Lipodystrophy_Lipoatrophy v1.22 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Lipodystrophy_Lipoatrophy v1.22 POC5 Zornitza Stark Classified gene: POC5 as Green List (high evidence)
Lipodystrophy_Lipoatrophy v1.22 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Lipodystrophy_Lipoatrophy v1.21 POC5 Zornitza Stark gene: POC5 was added
gene: POC5 was added to Lipodystrophy_Lipoatrophy. Sources: Literature
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 40590205; 29272404
Phenotypes for gene: POC5 were set to Ciliopathy, MONDO:0005308, POC5-related
Review for gene: POC5 was set to GREEN
Added comment: Twelve families reported with bi-allelic variants in this gene and rod-cone dystrophy, diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. Single individual previously reported in 2018 with isolated RP.
Sources: Literature
Retinitis pigmentosa v0.173 POC5 Zornitza Stark Marked gene: POC5 as ready
Retinitis pigmentosa v0.173 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Retinitis pigmentosa v0.173 POC5 Zornitza Stark Classified gene: POC5 as Green List (high evidence)
Retinitis pigmentosa v0.173 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Retinitis pigmentosa v0.172 POC5 Zornitza Stark gene: POC5 was added
gene: POC5 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 40590205; 29272404
Phenotypes for gene: POC5 were set to Ciliopathy, MONDO:0005308, POC5-related
Review for gene: POC5 was set to GREEN
Added comment: Twelve families reported with bi-allelic variants in this gene and rod-cone dystrophy, diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. Single individual previously reported in 2018 with isolated RP.
Sources: Literature
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
Ciliopathies v1.74 POC5 Zornitza Stark Marked gene: POC5 as ready
Ciliopathies v1.74 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Ciliopathies v1.74 POC5 Zornitza Stark Classified gene: POC5 as Green List (high evidence)
Ciliopathies v1.74 POC5 Zornitza Stark Gene: poc5 has been classified as Green List (High Evidence).
Ciliopathies v1.73 POC5 Zornitza Stark gene: POC5 was added
gene: POC5 was added to Ciliopathies. Sources: Literature
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 40590205; 29272404
Phenotypes for gene: POC5 were set to Ciliopathy, MONDO:0005308, POC5-related
Review for gene: POC5 was set to GREEN
Added comment: Twelve families reported with bi-allelic variants in this gene and rod-cone dystrophy, diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. Single individual previously reported in 2018 with isolated RP.
Sources: Literature
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
Ciliopathies v1.72 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
Ciliopathies v1.71 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
Retinitis pigmentosa v0.171 RDH8 Zornitza Stark Marked gene: RDH8 as ready
Retinitis pigmentosa v0.171 RDH8 Zornitza Stark Gene: rdh8 has been classified as Red List (Low Evidence).
Retinitis pigmentosa v0.171 RDH8 Zornitza Stark gene: RDH8 was added
gene: RDH8 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. 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).
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Marked gene: CFAP221 as ready
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Classified gene: CFAP221 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.148 CFAP221 Zornitza Stark gene: CFAP221 was added
gene: CFAP221 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CFAP221 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP221 were set to 31636325; 39362668; 40250778; 38960684; 40272718
Phenotypes for gene: CFAP221 were set to Ciliary dyskinesia, primary, 55, MIM# 279000
Review for gene: CFAP221 was set to GREEN
Added comment: Six affected families reported, male infertility is a feature.
Sources: Literature
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
Ciliary Dyskinesia v1.52 CFAP221 Zornitza Stark Phenotypes for gene: CFAP221 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 55, MIM# 279000
Ciliary Dyskinesia v1.51 CFAP221 Zornitza Stark Publications for gene: CFAP221 were set to PMID: 31636325
Ciliary Dyskinesia v1.50 CFAP221 Zornitza Stark Classified gene: CFAP221 as Green List (high evidence)
Ciliary Dyskinesia v1.50 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.49 CFAP221 Zornitza Stark reviewed gene: CFAP221: Rating: GREEN; Mode of pathogenicity: None; Publications: 39362668, 40250778, 38960684, 40272718; Phenotypes: Ciliary dyskinesia, primary, 55, MIM# 279000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disease v0.975 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 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
Intellectual disability syndromic and non-syndromic v1.177 SREK1 Sangavi Sivagnanasundram gene: SREK1 was added
gene: SREK1 was added to Intellectual disability syndromic and non-syndromic. 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. ID/DD is a feature in the 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 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
Ataxia v1.38 SIDT2 Sarah Milton gene: SIDT2 was added
gene: SIDT2 was added to Ataxia - paediatric. 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
Regression v0.581 SIDT2 Sarah Milton gene: SIDT2 was added
gene: SIDT2 was added to Regression. 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 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
Intellectual disability syndromic and non-syndromic v1.177 SMARCC1 Lilian Downie Marked gene: SMARCC1 as ready
Intellectual disability syndromic and non-syndromic v1.177 SMARCC1 Lilian Downie Added comment: Comment when marking as ready: 6/13 developmental delay
many inherited variants - known reduced penetrance
Intellectual disability syndromic and non-syndromic v1.177 SMARCC1 Lilian Downie Gene: smarcc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.177 SMARCC1 Lilian Downie Classified gene: SMARCC1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.177 SMARCC1 Lilian Downie Gene: smarcc1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.448 SMARCC1 Lilian Downie Marked gene: SMARCC1 as ready
Congenital Heart Defect v0.448 SMARCC1 Lilian Downie Gene: smarcc1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.448 SMARCC1 Lilian Downie Classified gene: SMARCC1 as Green List (high evidence)
Congenital Heart Defect v0.448 SMARCC1 Lilian Downie Gene: smarcc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.176 ADAM23 Sarah Milton gene: ADAM23 was added
gene: ADAM23 was added to Intellectual disability syndromic and non-syndromic. 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 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 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
Genetic Epilepsy v1.157 ADAM23 Sarah Milton gene: ADAM23 was added
gene: ADAM23 was added to Genetic Epilepsy. 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 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
Frontonasal dysplasia v1.1 CDH11 Sangavi Sivagnanasundram gene: CDH11 was added
gene: CDH11 was added to Frontonasal dysplasia. Sources: Expert Review
Mode of inheritance for gene: CDH11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH11 were set to 33811546
Phenotypes for gene: CDH11 were set to Teebi hypertelorism syndrome, MONDO:0030639
Review for gene: CDH11 was set to GREEN
Added comment: Affected individuals present with craniofacial features.

Review from Mendeliome - Li et al (2021) report 19 subjects from 9 families with Teebi hypertelorism syndrome (hypertelorism, prominent forehead, short nose, broad/depressed nasal root, cardiac and umbilical defects). Patients had heterozygous missense variants affected residues in the extracellular region of CDH11. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, they showed 5 variants significantly reduced the cell-substrate trans adhesion activity and changed cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Some clinical features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. 37% of Teebi cohort had ID. All variants were missense.
Sources: Expert Review
Amyloidosis v1.0 APOC2 Sangavi Sivagnanasundram gene: APOC2 was added
gene: APOC2 was added to Amyloidosis. Sources: Literature
Mode of inheritance for gene: APOC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOC2 were set to 39547356; 27297947; 27840752; 30686043; 30197986
Phenotypes for gene: APOC2 were set to APOC2-related amyloidosis, MONDO:0019065
Review for gene: APOC2 was set to AMBER
Added comment: Two missense variants appear to be the only two reported heterozygous variants in multiple affected individuals with amyloidosis (PMID: 39547356). Unclear whether these variants are common pathogenic variants. Further functional evidence is required to upgrade the gene to Green.

PMID: 27297947 (reports the same individual in PMID: 27840752)
61F with history hypertension and hypothyroidism and recent diagnosis of renal amyloidosis confirmed via biopsy
Heterozygous missense variant (E69V - absent in gnomAD v4.1) identified on sequencing which was identified in unaffected son
Proteomic analysis identified 7 other elderly probands with renal amyloidosis, aggregation of Apolipoprotein-CII amyloid deposits (genetic testing wasn't conducted on them)

PMID: 30686043
80M (from Greece)with deteriorated renal function. Biopsy of abdominal fat stained with Congo red was positive for amyloid.
Heterozygous p.Lys41Thr was identified in proband and unaffected son. The variant is present in gnomADv4.1 - NFE FAF - 0.1020%

PMID: 30197986
5 unrelated patients with AApoCII p.Lys41Thr amyloidosis. Affected individuals presented with a range of symptoms including proteinuria and increased serum creatinine.
All 5 individuals were >60yrs supporting late age of onset.
Sources: Literature
Ectodermal Dysplasia v0.95 MBTPS1 Zornitza Stark Marked gene: MBTPS1 as ready
Ectodermal Dysplasia v0.95 MBTPS1 Zornitza Stark Gene: mbtps1 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.95 MBTPS1 Zornitza Stark Classified gene: MBTPS1 as Amber List (moderate evidence)
Ectodermal Dysplasia v0.95 MBTPS1 Zornitza Stark Gene: mbtps1 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.94 MBTPS1 Zornitza Stark gene: MBTPS1 was added
gene: MBTPS1 was added to Ectodermal Dysplasia. Sources: Expert list
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to 35362222
Phenotypes for gene: MBTPS1 were set to CAOP syndrome, MIM# 621252
Review for gene: MBTPS1 was set to AMBER
Added comment: Two unrelated individuals with compound heterozygous variants in this gene and early-onset lens cataract, generalized non-scarring alopecia, oral mucosal disorder, and severe psoriasiform skin lesions affecting the scalp, facial, inguinal region, buttocks and lower extremities. Some supportive functional data.
Sources: Expert list
Fetal anomalies v1.372 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
Intellectual disability syndromic and non-syndromic v1.176 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
Callosome v0.545 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 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
Congenital Heart Defect v0.447 SMARCC1 Lucy Spencer gene: SMARCC1 was added
gene: SMARCC1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SMARCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMARCC1 were set to 38128548
Phenotypes for gene: SMARCC1 were set to SMARCC1-associated developmental dysgenesis syndrome (MONDO:0700123)
Review for gene: SMARCC1 was set to GREEN
Added comment: Phenotype expansion since original literature. Clingen: "SMARCC1-associated developmental dysgenesis syndrome is characterized by developmental delay, cerebral ventriculomegaly, aqueductal stenosis, and other associated structural brain and cardiac defects."

PMID: 38128548 : 9/10 patients had cardiac defects including atrial septal defect, ventricular septal defect, double outlet right ventricle and cardiac hypoplasia.
Sources: Literature
Intellectual disability syndromic and non-syndromic v1.176 SMARCC1 Gemma Edwards gene: SMARCC1 was added
gene: SMARCC1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SMARCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCC1 were set to 29983323; 37285932
Phenotypes for gene: SMARCC1 were set to SMARCC1-associated developmental dysgenesis syndrome (MONDO:0700123)
Review for gene: SMARCC1 was set to GREEN
Added comment: Phenotype expansion since original literature. ClinGen - "SMARCC1-associated developmental dysgenesis syndrome is characterized by developmental delay, cerebral ventriculomegaly, aqueductal stenosis, and other associated structural brain and cardiac defects". See cases in PMIDs 29983323, 37285932.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.88 ABCC6 Bryony Thompson Classified gene: ABCC6 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.88 ABCC6 Bryony Thompson Gene: abcc6 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.87 ABCC6 Bryony Thompson reviewed gene: ABCC6: Rating: AMBER; Mode of pathogenicity: None; Publications: 23968982, 20301292; Phenotypes: autosomal recessive inherited pseudoxanthoma elasticum MONDO:0009925; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.372 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
Congenital Heart Defect v0.447 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 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
Dilated Cardiomyopathy v1.38 C10orf71 Zornitza Stark Phenotypes for gene: C10orf71 were changed from dilated cardiomyopathy MONDO:0005021 to Cardiomyopathy, dilated, 1QQ, MIM# 621251
Dilated Cardiomyopathy v1.37 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
Autoinflammatory Disorders v2.12 CD274 Zornitza Stark Marked gene: CD274 as ready
Autoinflammatory Disorders v2.12 CD274 Zornitza Stark Gene: cd274 has been classified as Amber List (Moderate Evidence).
Autoinflammatory Disorders v2.12 CD274 Zornitza Stark Classified gene: CD274 as Amber List (moderate evidence)
Autoinflammatory Disorders v2.12 CD274 Zornitza Stark Gene: cd274 has been classified as Amber List (Moderate Evidence).
Autoinflammatory Disorders v2.11 CD274 Zornitza Stark gene: CD274 was added
gene: CD274 was added to Autoinflammatory Disorders. Sources: Literature
Mode of inheritance for gene: CD274 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD274 were set to 38634869
Phenotypes for gene: CD274 were set to Autoimmune disease, multisystem, infantile-onset, 5, MIM# 621235
Review for gene: CD274 was set to AMBER
Added comment: Two siblings, born to second-degree consanguineous parents of Moroccan descent, both developed neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk, respectively). One sibling was subsequently diagnosed with asthma at the age of 5 mo, auto-immune hypothyroidism at the age of 3 years, and growth hormone (GH) deficiency at the age of 10 years. He also had mild intellectual disability with delayed language development. By contrast, his sister had no clinical manifestations other than T1D.

Homozygous for splicing variant. This is the ligand of PD1, deficiency of which is also linked to immune dysregulation. Functional data.
Sources: Literature
Disorders of immune dysregulation v1.16 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
Disorders of immune dysregulation v1.15 CD274 Zornitza Stark edited their review of gene: CD274: Changed phenotypes: Autoimmune disease, multisystem, infantile-onset, 5, MIM# 621235
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
Genomic newborn screening: ICoNS v0.4 ALDH7A1 Katrina Stone changed review comment from: Summary: classic presentation neonatal onset seizures which respond to pyridoxine but are not well controlled with antiepileptics. Later onset of seizures has been reported.
Despite seizure control most patients have developmental delay/Intellectual disability

Confirmatory test: alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma (elevated)
Pipecolic acid
Δ1-piperideine-6-carboxylate (Δ1-P6C)

Intervention: Pyridoxine for seizure control.
From consensus guideline: To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy

Additional information
Incidence: 1:65 000 to 1:250 000 live births
Onset of seizures can be outside the neonatal period

Consensus guideline: PMID: 33200442
Sources: Other; to: Well established gene disease association
ClinGen: strong actionability in paediatric patients

Summary: classic presentation neonatal onset seizures which respond to pyridoxine but are not well controlled with antiepileptics. Later onset of seizures has been reported.
Despite seizure control most patients have developmental delay/Intellectual disability

Non genetic confirmatory tests: alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma (elevated)
Pipecolic acid
Δ1-piperideine-6-carboxylate (Δ1-P6C)

Intervention: Pyridoxine for seizure control.
From consensus guideline: To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy

Additional information
Incidence: 1:65 000 to 1:250 000 live births
Onset of seizures can be outside the neonatal period

Consensus guideline: PMID: 33200442

Included in:

Sources: Other
Genomic newborn screening: ICoNS v0.4 ALDH7A1 Katrina Stone gene: ALDH7A1 was added
gene: ALDH7A1 was added to Genomic newborn screening: ICoNS. Sources: Other
Mode of inheritance for gene: ALDH7A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH7A1 were set to PMID: 20301659; 33200442
Phenotypes for gene: ALDH7A1 were set to Epilepsy, early-onset, 4, vitamin B6-dependent
Penetrance for gene: ALDH7A1 were set to Complete
Review for gene: ALDH7A1 was set to GREEN
Added comment: Summary: classic presentation neonatal onset seizures which respond to pyridoxine but are not well controlled with antiepileptics. Later onset of seizures has been reported.
Despite seizure control most patients have developmental delay/Intellectual disability

Confirmatory test: alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma (elevated)
Pipecolic acid
Δ1-piperideine-6-carboxylate (Δ1-P6C)

Intervention: Pyridoxine for seizure control.
From consensus guideline: To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy

Additional information
Incidence: 1:65 000 to 1:250 000 live births
Onset of seizures can be outside the neonatal period

Consensus guideline: PMID: 33200442
Sources: Other
Infertility and Recurrent Pregnancy Loss v0.147 GALT Zornitza Stark Classified gene: GALT as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.147 GALT Zornitza Stark Gene: galt has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Marked gene: RNF216 as ready
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Gene: rnf216 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Classified gene: RNF216 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Gene: rnf216 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Marked gene: PABPC1L as ready
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Classified gene: PABPC1L as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Marked gene: CCDC155 as ready
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Gene: ccdc155 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Classified gene: CCDC155 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Gene: ccdc155 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.143 CCDC155 Zornitza Stark Tag new gene name tag was added to gene: CCDC155.
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Marked gene: TWNK as ready
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Gene: twnk has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Classified gene: TWNK as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Gene: twnk has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Marked gene: FGF8 as ready
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Gene: fgf8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Classified gene: FGF8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Gene: fgf8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.141 STIL Zornitza Stark Marked gene: STIL as ready
Infertility and Recurrent Pregnancy Loss v0.141 STIL Zornitza Stark Gene: stil has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.141 STIL Zornitza Stark Phenotypes for gene: STIL were changed from Recurrent pregnancy loss susceptibility, MONDO:0000144; Primary microcephaly 7, autosomal recessive, MIM# 612703 to Primary microcephaly 7, autosomal recessive, MIM# 612703
Infertility and Recurrent Pregnancy Loss v0.140 STIL Zornitza Stark Classified gene: STIL as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.140 STIL Zornitza Stark Gene: stil has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.139 STIL Zornitza Stark reviewed gene: STIL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.139 KIF14 Zornitza Stark reviewed gene: KIF14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Marked gene: KISS1R as ready
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Gene: kiss1r has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Classified gene: KISS1R as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Gene: kiss1r has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.138 CDC25A Zornitza Stark Marked gene: CDC25A as ready
Infertility and Recurrent Pregnancy Loss v0.138 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.138 CDC25A Zornitza Stark Phenotypes for gene: CDC25A were changed from Spermatogenic failure to Spermatogenic failure, MONDO:0004983, CDC25A-related
Infertility and Recurrent Pregnancy Loss v0.137 CDC25A Zornitza Stark Classified gene: CDC25A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.137 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Marked gene: GNRHR as ready
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Gene: gnrhr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Classified gene: GNRHR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Gene: gnrhr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.135 PREPL Zornitza Stark Marked gene: PREPL as ready
Infertility and Recurrent Pregnancy Loss v0.135 PREPL Zornitza Stark Gene: prepl has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.135 PREPL Zornitza Stark Phenotypes for gene: PREPL were changed from Hypergonadotropic hypogonadism to Myasthenic syndrome, congenital, 22, MIM# 616224; Hypergonadotropic hypogonadism
Infertility and Recurrent Pregnancy Loss v0.134 PREPL Zornitza Stark Classified gene: PREPL as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.134 PREPL Zornitza Stark Gene: prepl has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Marked gene: SPEF2 as ready
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Gene: spef2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Classified gene: SPEF2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Gene: spef2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Marked gene: PDCD2 as ready
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Classified gene: PDCD2 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Red List (Low Evidence).
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
Fetal anomalies v1.372 PDCD2 Zornitza Stark Marked gene: PDCD2 as ready
Fetal anomalies v1.372 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.372 PDCD2 Zornitza Stark Classified gene: PDCD2 as Amber List (moderate evidence)
Fetal anomalies v1.372 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.371 PDCD2 Zornitza Stark gene: PDCD2 was added
gene: PDCD2 was added to Fetal anomalies. 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
Hydrops fetalis v0.327 PDCD2 Zornitza Stark Marked gene: PDCD2 as ready
Hydrops fetalis v0.327 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Hydrops fetalis v0.327 PDCD2 Zornitza Stark Classified gene: PDCD2 as Amber List (moderate evidence)
Hydrops fetalis v0.327 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Amber List (Moderate Evidence).
Hydrops fetalis v0.326 PDCD2 Zornitza Stark gene: PDCD2 was added
gene: PDCD2 was added to Hydrops fetalis. 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
Infertility and Recurrent Pregnancy Loss v0.131 PDCD2 Zornitza Stark reviewed gene: PDCD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.131 RXFP2 Zornitza Stark Marked gene: RXFP2 as ready
Infertility and Recurrent Pregnancy Loss v0.131 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.131 RXFP2 Zornitza Stark Phenotypes for gene: RXFP2 were changed from to Spermatogenic failure, MONDO:0004983, RXFP2-related
Infertility and Recurrent Pregnancy Loss v0.130 RXFP2 Zornitza Stark Classified gene: RXFP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.130 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Marked gene: ERCC6 as ready
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Gene: ercc6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Classified gene: ERCC6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Gene: ercc6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.128 HARS2 Zornitza Stark Marked gene: HARS2 as ready
Infertility and Recurrent Pregnancy Loss v0.128 HARS2 Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.128 HARS2 Zornitza Stark Publications for gene: HARS2 were set to 31449985,21464306, 34406847
Infertility and Recurrent Pregnancy Loss v0.127 HARS2 Zornitza Stark Classified gene: HARS2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.127 HARS2 Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Marked gene: FOXL2 as ready
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Gene: foxl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Classified gene: FOXL2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Gene: foxl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.125 FOXL2 Zornitza Stark reviewed gene: FOXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure 3, #MIM 608996; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Marked gene: PNPLA6 as ready
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Gene: pnpla6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Classified gene: PNPLA6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Gene: pnpla6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.124 OOEP Zornitza Stark Marked gene: OOEP as ready
Infertility and Recurrent Pregnancy Loss v0.124 OOEP Zornitza Stark Gene: ooep has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.124 OOEP Zornitza Stark Phenotypes for gene: OOEP were changed from Recurrent preimplantation embryonic arrest to Recurrent preimplantation embryonic arrest; Female infertility due to oocyte meiotic arrest, MONDO:0044626
Infertility and Recurrent Pregnancy Loss v0.123 OOEP Zornitza Stark Classified gene: OOEP as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.123 OOEP Zornitza Stark Gene: ooep has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Marked gene: PROK2 as ready
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Gene: prok2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Classified gene: PROK2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Gene: prok2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Marked gene: NUP107 as ready
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Gene: nup107 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Classified gene: NUP107 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Gene: nup107 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Marked gene: POLR3A as ready
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Gene: polr3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Classified gene: POLR3A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Gene: polr3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Marked gene: DAP3 as ready
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Classified gene: DAP3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Marked gene: LHX8 as ready
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Classified gene: LHX8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Marked gene: MCM9 as ready
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Gene: mcm9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Classified gene: MCM9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Gene: mcm9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Marked gene: NBN as ready
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Gene: nbn has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Classified gene: NBN as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Gene: nbn has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Marked gene: NR0B1 as ready
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Classified gene: NR0B1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Marked gene: NLRP2 as ready
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Gene: nlrp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Classified gene: NLRP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Gene: nlrp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Marked gene: NR5A1 as ready
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Gene: nr5a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Classified gene: NR5A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Gene: nr5a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Marked gene: MRPS22 as ready
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Gene: mrps22 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Classified gene: MRPS22 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Gene: mrps22 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.111 MRPS22 Zornitza Stark reviewed gene: MRPS22: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Ovarian dysgenesis 7, MIM# 618117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Marked gene: FGFR1 as ready
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Gene: fgfr1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Classified gene: FGFR1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Gene: fgfr1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Marked gene: EIF2B5 as ready
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Gene: eif2b5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Classified gene: EIF2B5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Gene: eif2b5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Marked gene: MEIOB as ready
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Gene: meiob has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Classified gene: MEIOB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Gene: meiob has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Marked gene: EIF2B4 as ready
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Gene: eif2b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Classified gene: EIF2B4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Gene: eif2b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Marked gene: EIF2B2 as ready
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Gene: eif2b2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Classified gene: EIF2B2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Gene: eif2b2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Marked gene: GGPS1 as ready
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Gene: ggps1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Classified gene: GGPS1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Gene: ggps1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.105 C11orf80 Zornitza Stark Marked gene: C11orf80 as ready
Infertility and Recurrent Pregnancy Loss v0.105 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.105 C11orf80 Zornitza Stark Publications for gene: C11orf80 were set to
Infertility and Recurrent Pregnancy Loss v0.104 C11orf80 Zornitza Stark Classified gene: C11orf80 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.104 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.103 C11orf80 Zornitza Stark Tag new gene name tag was added to gene: C11orf80.
Early-onset Dementia v1.43 SQSTM1 Zornitza Stark Publications for gene: SQSTM1 were set to 22084127; 22972638
Early-onset Dementia v1.42 SQSTM1 Zornitza Stark Classified gene: SQSTM1 as Green List (high evidence)
Early-onset Dementia v1.42 SQSTM1 Zornitza Stark Gene: sqstm1 has been classified as Green List (High Evidence).
Pulmonary Arterial Hypertension v1.42 SOX17 Zornitza Stark Phenotypes for gene: SOX17 were changed from Heritable pulmonary arterial hypertension, MONDO:0017148, SOX17-related to Pulmonary hypertension, primary, 7, MIM# 621248
Pulmonary Arterial Hypertension v1.41 SOX17 Zornitza Stark edited their review of gene: SOX17: Changed phenotypes: Pulmonary hypertension, primary, 7, MIM# 621248
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
Early-onset Dementia v1.41 SQSTM1 Chris Ciotta reviewed gene: SQSTM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27554286, 31362587, 28490746, 31859009, 23942205; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (MIM#616437); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.103 CAPS Jasmine Chew changed review comment from: PMID: 30339840- Homozygous del 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: Literature; to: 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: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CAPS Jasmine Chew gene: CAPS was added
gene: CAPS was added to Infertility and Pregnancy Loss. Sources: Literature
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
Review for gene: CAPS was set to AMBER
Added comment: PMID: 30339840- Homozygous del 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: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MTHFR Jasmine Chew gene: MTHFR was added
gene: MTHFR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MTHFR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTHFR were set to 37260775; 39534907; 38322638
Phenotypes for gene: MTHFR were set to Recurrent pregnancy loss susceptibility
Review for gene: MTHFR was set to AMBER
Added comment: PMID: 37260775- RPL5 couple was found to be carriers for mutation in the MTHFR gene. It is already known that women with a MTHFR variant have a higher risk for pregnancy-related issues such as miscarriages, preeclampsia, or a baby born with birth defects, such as spina bifida. The theory behind the connection between the MTHFR mutation and pregnancy loss is that tiny blood clots are formed because of homocysteinemia, which blocks the flow of nutrition to the placenta, essentially starving the fetus and triggering a spontaneous abortion (Dell’dera et al., 2018- PMID: 29435277).

ii) PMID: 39534907- The MTHFR C677T variant showed strong associations with unexplained RPL, particularly the CT genotype (OR: 6.07, 95% CI: 3.00-12.93; p < 0.001) and TT genotype (OR: 14.62, 95% CI: 2.85-114.77; p = 0.003) in Vietnamese population.

iii) PMID: 38322638- 6.2% of couples with a history of RPL had MTHFR C677T in an Iranian population

Note: MTHFR is a thrombophilic marker and DNA methylation- PMID: 34745108).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FKBP4 Jasmine Chew gene: FKBP4 was added
gene: FKBP4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FKBP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FKBP4 were set to 31504499
Phenotypes for gene: FKBP4 were set to Recurrent pregnancy loss susceptibility
Review for gene: FKBP4 was set to AMBER
Added comment: i) PMID: 31504499- Four heterozygous missense variants (Ala16Glu, Asn125Ser, Gln381Leu, Arg399Gln) at conserved residues within two functional domains of FKBP52 identified in four different Asian patients with RPL. The variants were predicted to have damaging effects to structure-function properties and were shown to abrogate PPIase activity in a cell-based assay.
- Although FKBP4 heterozygous null animals were all fertile and without reproductive failures, both male and female homozygous mice were reported to be infertile, highlighting the importance of FKBP52 in reproduction. Interestingly, male null mice were found to produce viable spermatozoa but had defects in reproductive tissues consistent with androgen insensitivity. Female null mice were anatomically normal, but infertility was found to be a consequence of either implantation failure or pregnancy loss following implantation, which was associated with impaired progesterone function.
- There remains a possibility that this apparent population bias might suggest an Asian specific cause of RPL.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C4BPA Jasmine Chew changed review comment from: PMID: 23508668- Five unrelated female with history of recurrent RPL (<10 weeks) carrying het missnese variants (See table 3- G423E, R120H, I126T, P4Q). l. 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. However, they observed that 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: Literature; to: 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: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C4BPA Jasmine Chew gene: C4BPA was added
gene: C4BPA was added to Infertility and Pregnancy Loss. Sources: Literature
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
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). l. 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. However, they observed that 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: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DAP3 Jasmine Chew gene: DAP3 was added
gene: DAP3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Perrault syndrome 7, MIM# 621101
Review for gene: DAP3 was set to GREEN
Added comment: PMID: 39701103- biallelic variants in 3 unrelated patients. Proteomic analysis in patient fibroblasts showed reduced DAP3 expression, reduced expression of respiratory chain complexes I, III, and IV, and decreased expression of proteins encompassing the small mitoribosomal subunit complex. Patient fibroblasts transduced with wildtype DAP3 demonstrated partial rescue of mitoribosomal MRPS7 (611974) and MRPS9 (611975) protein levels.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPB Jasmine Chew gene: CLPB was added
gene: CLPB was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CLPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPB were set to 36074910
Phenotypes for gene: CLPB were set to Primary ovarian insufficiency
Review for gene: CLPB was set to GREEN
Added comment: PMID: 36074910- A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CCDC155 Jasmine Chew changed review comment from: Note- HGNC Approved Gene Symbol: KASH5 (MIM #618125)

Literature in OMIM- PMID: 29790874; 35674372; 36864840;35708642- multiple unrelated infertile females (diminished ovarian reserve, recurrent miscarriage) and males (NOA) with different biallelic variants

New paper:
i) PMID: 39545410- Compound heterozygous variants pArg519* and p.Leu535Gln in patient 439 (Jordanian), with 3 HMs and 2 miscarriages. The L535Q variant was previously reported in a homozygous state by Fakhro et al. in 2 infertile Qatari brothers with azoospermia (PMID: 29790874). In mice, both male and female null mutants of Kash5 are infertile (PMID: 24062341).
Sources: Literature; to: HGNC approved symbol- KASH5

Biallelic variants reported for POI- PMID: 35587281; 35674372; 35708642; 36864840

Biallelic variants reported for spermatogenic failure-PMID: 29790874; 35587281; 35674372; 36864840

Biallelic variants reported for recurrent miscarriages- PMID:36864840- The authors hypothesized that this reduced interaction with SUN1 might be sufficient to allow folliculogenesis and fertilization despite severe meiotic defects, and suggested that in addition to POF, KASH5 might represent a recurrent pregnancy loss-associated gene.

Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C17orf53 Jasmine Chew edited their review of gene: C17orf53: Changed publications: 34707299, 38105698, 36099812, 31467087
Infertility and Recurrent Pregnancy Loss v0.103 C17orf53 Jasmine Chew gene: C17orf53 was added
gene: C17orf53 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: C17orf53 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C17orf53 were set to 34707299, 38105698,36099812; 31467087
Phenotypes for gene: C17orf53 were set to Ovarian dysgenesis 11, MIM# 620897
Review for gene: C17orf53 was set to GREEN
Added comment: HGNC approved symbol- HROB

Biallelic variants reported for POI- PMID: 34707299, 38105698,36099812

PMID: 31467087- Knockout mice were infertile due to lack of germ cells. The sterile females had ovaries that lacked follicles, whereas the sterile males had mostly empty seminiferous tubules, suggesting a defect in sperm production. Concluded that these phenotypes were consistent with a prophase I meiotic arrest.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BLM Jasmine Chew gene: BLM was added
gene: BLM was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BLM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLM were set to 34794894; 29056561; 28846287
Phenotypes for gene: BLM were set to Bloom syndrome, MIM# 210900
Review for gene: BLM was set to GREEN
Added comment: PMID: 28846287 (Gene Review)- Women may be fertile but often have early menopause, and men tend to be infertile. Most men with BSyn assessed for infertility have had azoospermia or severe oligospermia.

PMID: 35671666, PMID: 24858046- BLM physically interacts with MUS81, an endonuclease involved in the restart of stalled replication forks and HR repair. Loss of Mus81 in Blm hypomorph mutant mice leads to infertility, and growth and developmental defects that are not observed in single mutants. Double mutant cells and mice were hypersensitive to Mitomycin C and γ-irradiation (IR) compared with controls and their repair of DNA double-strand breaks (DSBs) mediated by HR pathway was significantly defective, whereas their non-homologous-end-joining repair was elevated compared with controls.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew changed review comment from: Hemizygous variants reported for HH- PMID:40508017; 40262549; 40258767; 40101754
Sources: Literature; to: Hemizygous variants reported for HH- PMID:40508017; 40262549; 40258767; 40101754; 16882753
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew edited their review of gene: ANOS1: Changed publications: 40508017, 40262549, 40258767, 40101754, 16882753
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew edited their review of gene: ANOS1: Changed publications: 40508017, 40262549, 40258767, 40101754
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew gene: ANOS1 was added
gene: ANOS1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ANOS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: ANOS1 were set to Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), MIM# 308700
Review for gene: ANOS1 was set to GREEN
Added comment: Hemizygous variants reported for HH- PMID:40508017; 40262549; 40258767; 40101754
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 WDR11 Jasmine Chew edited their review of gene: WDR11: Changed publications: 20887964, 37988663, 36130823, 35722485, 32982993, 29263200
Infertility and Recurrent Pregnancy Loss v0.103 WDR11 Jasmine Chew gene: WDR11 was added
gene: WDR11 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: WDR11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR11 were set to 20887964, 37988663; 36130823; 35722485; 32982993; 29263200
Phenotypes for gene: WDR11 were set to Hypogonadotropic hypogonadism 14 with or without anosmia, MIM# 614858
Review for gene: WDR11 was set to GREEN
Added comment: Monoallelic variants reported for HH- PMID: 20887964, 37988663; 36130823; 35722485; 32982993

PMID: 29263200- Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TWNK Jasmine Chew gene: TWNK was added
gene: TWNK was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TWNK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TWNK were set to 28178980; 26970254; 25355836; 25355836; 32281099; 31852434; 31455392
Phenotypes for gene: TWNK were set to Perrault syndrome 5, MIM# 616138
Review for gene: TWNK was set to GREEN
Added comment: Ovarian dysgenesis is one of the phenotypes of Perrault syndrome.

FeRGI database- moderate evidence for POI (Perrault syndrome)- biallelic variants reported in multiple papers
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TP63 Jasmine Chew gene: TP63 was added
gene: TP63 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TP63 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TP63 were set to 30924587; 35801529; 36856110; 27798044
Phenotypes for gene: TP63 were set to Premature ovarian failure 21, MIM# 620311
Review for gene: TP63 was set to GREEN
Added comment: Monoallelic missense/LOF variants reported for POI- PMID: 30924587; 35801529;36856110
- PMID: 35801529;36856110- suggested that POF-related variants cause constitutive activation of the oocyte-specific TAp63-alpha isoform, increasing expression of downstream targets that can initiate the apoptotic pathway in oocytes.
- PMID:36856110- Heterozygous mutant females were infertile, whereas mutant males were fertile. Eexpression of mutant p63 lacking the TID resulted in rapid depletion of oocytes and loss of fertility, similar to the human POF phenotype.

PMID: 27798044- monoallelic variants for Mullerian duct anomalies
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 SYCP2L Jasmine Chew gene: SYCP2L was added
gene: SYCP2L was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SYCP2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCP2L were set to 32303603; 38521400
Phenotypes for gene: SYCP2L were set to Premature ovarian failure 24, MIM# 620840
Review for gene: SYCP2L was set to GREEN
Added comment: Biallelic LOF/missense variants reported for POI- PMID:32303603; 38521400
- Sycp2l-deficient female mice are subfertile (PMID: 26362258). The association of the genes that have key roles in meiosis and DNA repair with POI has been previously reported (PMID: 32381463;34707299).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TACR3 Jasmine Chew gene: TACR3 was added
gene: TACR3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TACR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TACR3 were set to 22031817; 20332248; 20194706; 20395662; 19755480; 28915117; 19079066
Phenotypes for gene: TACR3 were set to Hypogonadotropic hypogonadism 11 with or without anosmia, MIM# 614840
Review for gene: TACR3 was set to GREEN
Added comment: Biallelic variants reported for HH- PMID:22031817; 20332248; 20194706; 20395662; 19755480; 28915117; 19079066
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TAC3 Jasmine Chew gene: TAC3 was added
gene: TAC3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TAC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAC3 were set to 20332248; 20194706; 34403359; 19079066
Phenotypes for gene: TAC3 were set to Hypogonadotropic hypogonadism 10 with or without anosmia, MIM# 614839
Review for gene: TAC3 was set to GREEN
Added comment: Biallelic variants reported for HH- PMID:20332248; 20194706; 34403359; 19079066
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 SEMA3A Jasmine Chew gene: SEMA3A was added
gene: SEMA3A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SEMA3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3A were set to 22416012; 22927827; 32060892; 31200363; 33819414
Phenotypes for gene: SEMA3A were set to Hypogonadotropic hypogonadism 16 with or without anosmia, MIM# 614897
Review for gene: SEMA3A was set to GREEN
Added comment: Monoallelic variants reported for HH/infertility- PMID:22416012; 22927827; 32060892;31200363;33819414
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 RNF216 Jasmine Chew gene: RNF216 was added
gene: RNF216 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: RNF216 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF216 were set to 31200363; 25841028; 39444518; 38050071
Phenotypes for gene: RNF216 were set to Cerebellar ataxia and hypogonadotropic hypogonadism, MIM# 212840
Review for gene: RNF216 was set to GREEN
Added comment: Biallelic variants reported for HH phenotype-PMID:31200363;25841028;39444518

PMID:38050071 (review paper, 2024)- Over 90% of individuals presented with cognitive impairment and hypogonadotropic hypogonadism throughout the disease. Male individuals seemed to be more vulnerable than female individuals. Most male individuals suffered from poor pubertal development. .This phenomenon was consistent with the results of previous animal experiments, whereby targeted deletion of the RNF216 gene in mice resulted in disruption in spermatogenesis and male infertility, but RNF216 was not required for female fertility.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PROK2 Jasmine Chew gene: PROK2 was added
gene: PROK2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PROK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PROK2 were set to 23341491; 18559922; 17959774; 17054399; 31200363; 33819414
Phenotypes for gene: PROK2 were set to Hypogonadotropic hypogonadism 4 with or without anosmia, MIM# 610628
Review for gene: PROK2 was set to GREEN
Added comment: FeRGI database- strong evidence for hypogonadotropic hypogonadism- PMID:23341491;18559922; 17959774;17054399;31200363;33819414 - monoallelic and biallelic variants reported.

PMID:17959774- Prok2 -/- mice also showed hypogonadotropic hypogonadism.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PREPL Jasmine Chew changed review comment from: Hypergonadotropic hypogonadism is one of the phenotypes of prolyl endopeptidase-like (PREPL) deficiency.
Biallelic variants reported in patients with PREPL deficiency- PMID: 34794894;28726805;30924587;32218803
Sources: Literature; to: Hypergonadotropic hypogonadism/POI is one of the phenotypes of prolyl endopeptidase-like (PREPL) deficiency. Biallelic variants reported in patients with PREPL deficiency- PMID: 34794894;28726805;30924587;32218803.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PREPL Jasmine Chew gene: PREPL was added
gene: PREPL was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PREPL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PREPL were set to 34794894; 28726805; 30924587; 32218803
Phenotypes for gene: PREPL were set to Hypergonadotropic hypogonadism
Review for gene: PREPL was set to GREEN
Added comment: Hypergonadotropic hypogonadism is one of the phenotypes of prolyl endopeptidase-like (PREPL) deficiency.
Biallelic variants reported in patients with PREPL deficiency- PMID: 34794894;28726805;30924587;32218803
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POR Jasmine Chew gene: POR was added
gene: POR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POR were set to 32725309; 32242900
Phenotypes for gene: POR were set to Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM# 613571
Review for gene: POR was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:32725309, 32242900- biallelic variants reported for menstrual cycle disorders and female infertility. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POLR3A Jasmine Chew changed review comment from: FeRGI database- moderate evidence for hypogonadotropic hypogonadism- biallelic variants reported
Sources: Literature; to: FeRGI database- moderate evidence for hypogonadotropic hypogonadism- biallelic variants reported.
- PMID: 25339210 - delayed puberty or primary amenorrhea was present in 27/33 patients with POLR3A (81%).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POLR3A Jasmine Chew edited their review of gene: POLR3A: Changed publications: 23694757, 21855841, 30414627, 34611991, 25339210
Infertility and Recurrent Pregnancy Loss v0.103 POLR3A Jasmine Chew gene: POLR3A was added
gene: POLR3A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POLR3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3A were set to 23694757; 21855841; 30414627; 34611991
Phenotypes for gene: POLR3A were set to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694
Review for gene: POLR3A was set to GREEN
Added comment: FeRGI database- moderate evidence for hypogonadotropic hypogonadism- biallelic variants reported
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PNPLA6 Jasmine Chew edited their review of gene: PNPLA6: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.103 PNPLA6 Jasmine Chew gene: PNPLA6 was added
gene: PNPLA6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PNPLA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA6 were set to 27866050; 24790214; 25267340; 25033069; 24355708; 33141049
Phenotypes for gene: PNPLA6 were set to Boucher-Neuhauser syndrome, MIM# 215470
Added comment: Hypogonadotropic hypogonadism is a feature of Boucher-Neuhauser syndrome, MIM# 215470.

FeRGI database- Strong evidence for hypogonadotropic hypogonadism- multiple papers reported biallelic variants
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158 - Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis- PMID: 26485283; 34707299; 29363275 (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158 - Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158 - Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158-Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew gene: NUP107 was added
gene: NUP107 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NUP107 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP107 were set to 26485283; 34707299; 29363275
Phenotypes for gene: NUP107 were set to Ovarian dysgenesis 6, MIM# 618078
Review for gene: NUP107 was set to GREEN
Added comment: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158-Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NOTCH2 Jasmine Chew gene: NOTCH2 was added
gene: NOTCH2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NOTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2 were set to 32312275; 30304577; 28505269; 28283672
Phenotypes for gene: NOTCH2 were set to Primary ovarian insufficiency
Review for gene: NOTCH2 was set to GREEN
Added comment: i) PMID: 32312275 -Heterozygous missense variant p.Asp1853His in both mother an daughter with POI. Cells expressing the D1853H NOTCH2 mutant had similar effect in activating the NOTCH signaling pathway downstream target genes. 106 protein-coding genes enriched for collagen degradation, NCAM1 interactions and HDACs deacetylate histones were differentially expressed between D1853H expressing cells and WT NOTCH2 expressing cells.

ii) PMID: 30304577, 28505269 - 4 unrelated women with POI with heterozygous missense variants (p.Ser1804Leu, p.Gln1811His, p.Leu2408His, p.Pro2359Ala) and 1 woman with POI suspected biallelic (p.Ala2316Val & p.Leu2408His). NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcriptional activity. Suggested that POI is associated with loss of function of NOTCH2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew changed review comment from: Premature ovarian failure/infertility has been observed.
Sources: Literature; to: Premature ovarian failure/infertility has been observed in individuals with biallelic variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew changed review comment from: Premature ovarian failure/infertility has been observed.
Sources: Literature; to: Premature ovarian failure/infertility has been observed.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew changed review comment from: Premature ovarian failure has been observed.
Sources: Literature; to: Premature ovarian failure/infertility has been observed.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew gene: NBN was added
gene: NBN was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NBN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NBN were set to 19105185; 29706645; 31729086; 34794894; 20444919
Phenotypes for gene: NBN were set to Nijmegen breakage syndrome, MIM# 251260
Review for gene: NBN was set to GREEN
Added comment: Premature ovarian failure has been observed.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MRPS22 Jasmine Chew gene: MRPS22 was added
gene: MRPS22 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MRPS22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS22 were set to 29566152; 31042289
Phenotypes for gene: MRPS22 were set to Ovarian dysgenesis 7, MIM# 618117
Review for gene: MRPS22 was set to GREEN
Added comment: PMID:29566152, 31042289- Two homozygous missense variants (p.Arg202His and p.Arg135Gln) reported in independent families with POI. Mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, Drosophila model with mRpS22 deficiency specifically in germ cells were infertile and agametic. Heterozygous MRPS22 knockout mice are fertile and show no overt abnormalities. Homozygous MRPS22 knockout results in embryonic lethality.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MCM9 Jasmine Chew changed review comment from: FeRGI database- definitive evidence for ovarian dysgenesis- PMID:25480036, 26771056, 31042289 (biallelic variants reported)
Sources: Literature; to: FeRGI database- definitive evidence for ovarian dysgenesis- PMID:27802094, 25480036, 26771056, 31042289, 32145932 (monoallelic and biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MCM9 Jasmine Chew edited their review of gene: MCM9: Changed publications: 27802094, 25480036, 26771056, 31042289, 32145932; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.103 MCM9 Jasmine Chew gene: MCM9 was added
gene: MCM9 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MCM9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM9 were set to 25480036; 26771056; 31042289
Phenotypes for gene: MCM9 were set to Ovarian dysgenesis 4, MIM# 616185
Review for gene: MCM9 was set to GREEN
Added comment: FeRGI database- definitive evidence for ovarian dysgenesis- PMID:25480036, 26771056, 31042289 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 LHX8 Jasmine Chew gene: LHX8 was added
gene: LHX8 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: LHX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LHX8 were set to 27603904; 34095689; 29329412; 36029299
Phenotypes for gene: LHX8 were set to Inherited premature ovarian failure, MONDO:0019852, LHX8-related
Review for gene: LHX8 was set to GREEN
Added comment: PMID:27603904; 34095689- reported POI patient with the same heterozygous missense p.Ala325Val variant.

PMID: 29329412 - Lhx8 knockout mouse model demonstrates that Lhx8-/- ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth. Lhx8-/- oocytes failed to repair DNA damage-which normally occurs when meiosis is initiated during embryonic development and DNA damage repair genes were downregulated throughout the oocyte short lifespan.

PMID: 36029299- 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families with infertility characterized by oocyte maturation arrest. All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 KISS1R Jasmine Chew gene: KISS1R was added
gene: KISS1R was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: KISS1R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KISS1R were set to 23349759; 22619348; 21193544; 17164310; 14573733; 27094476; 33819414
Phenotypes for gene: KISS1R were set to Hypogonadotropic hypogonadism 8 with or without anosmia, MIM# 614837
Review for gene: KISS1R was set to GREEN
Added comment: FeRGI database- Definitive evidence for hypogonadotropic hypogonadism- multiple papers reported biallelic variants.
- early miscarriages have been reported in couples with the male partner being a carrier of a KISS1R variant (PMID: 23349759)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 HSF2BP Jasmine Chew changed review comment from: Sources: Literature; to: PMID:32845237, 35174157- Three different homozygous missense variants (S167L, C128R, p.L186P) reported in three independent families.
- HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers.
- C128R and p.L186P variants impaired the nuclear location of HSF2BP and affected its DNA repair capacity.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 HSF2BP Jasmine Chew gene: HSF2BP was added
gene: HSF2BP was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237; 35174157
Phenotypes for gene: HSF2BP were set to Premature ovarian failure 19, OMIM#619245
Review for gene: HSF2BP was set to GREEN
Added comment: Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GGPS1 Jasmine Chew gene: GGPS1 was added
gene: GGPS1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32399598; 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, MMIM# 619518
Review for gene: GGPS1 was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:32399598, 32403198- biallelic variants reported. Also in mice, PMID: 32403198 found that homozygosity for the Y259C missense variant was embryonic lethal.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FGFR1 Jasmine Chew changed review comment from: FeRGI database- strong evidence for Hypogonadotropic hypogonadism- multiple literature reported monoallelic variants.
Sources: Literature; to: FeRGI database- strong evidence for Hypogonadotropic hypogonadism- multiple literature reported monoallelic missense/LOF variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FGFR1 Jasmine Chew edited their review of gene: FGFR1: Changed publications: 28008864, 26708526, 22035731, 21682876, 17154279, 16764984, 32485746; Changed phenotypes: Hypogonadotropic hypogonadism 2 with or without anosmia , MIM#147950
Infertility and Recurrent Pregnancy Loss v0.103 FGFR1 Jasmine Chew gene: FGFR1 was added
gene: FGFR1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FGFR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGFR1 were set to 28008864; 26708526; 17154279; 21682876; 16764984
Phenotypes for gene: FGFR1 were set to Hypogonadotropic hypogonadism 2 with or without anosmia , MIM#147950
Review for gene: FGFR1 was set to GREEN
Added comment: FeRGI database- strong evidence for Hypogonadotropic hypogonadism- multiple literature reported monoallelic variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FANCM Jasmine Chew gene: FANCM was added
gene: FANCM was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FANCM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCM were set to 33036707; 29231814; 30075111; 29895858; 38927643
Phenotypes for gene: FANCM were set to Premature ovarian failure 15, MIM# 618096; Spermatogenic failure 28, MIM# 618086
Review for gene: FANCM was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:33036707,29231814- biallelic variants reported

Evidence for Spermatogenic failure 28, MIM# 618086 (AR)- PMID: 30075111, 29895858, 38927643- biallelic variants in males with NOA/SCOS phenotypes
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ERCC6 Jasmine Chew gene: ERCC6 was added
gene: ERCC6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ERCC6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERCC6 were set to 26218421; 33109206; 33538981; 39277148; 35975393
Phenotypes for gene: ERCC6 were set to Premature ovarian failure 11, MIM# 616946
Review for gene: ERCC6 was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:26218421, 33109206, 33538981 (heterozygous variants reported)

New papers:
i) PMID: 39277148- Two different missense p.Val127Ile and p.Glu1408 Ala in 4 POI patients with RNA and protein expression absent/decreased in patients.

ii) PMID: 35975393- A novel het p.GLy815Asp in a POI patient and Swiss-Model revealed that the mutant amino acid formed multiple H-bonds with adjacent residues, which may lead to a dysfunction of ERCC6 protein.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DCAF17 Jasmine Chew changed review comment from: FeRGI db- Strong for POI (Woodhouse-Sakati syndrome, MIM#241080)- biallelic variants reported in multiple literature with hypogonadism as one of the phenotypes- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature; to: FeRGI db- Strong for POI (Woodhouse-Sakati syndrome, MIM#241080)- biallelic variants reported in multiple literature with hypogonadism as one of the phenotypes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DCAF17 Jasmine Chew changed review comment from: FeRGI db-Strong for POI (Woodhouse-Sakati syndrome)- biallelic variants reported in multiple literature- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature; to: FeRGI db- Strong for POI (Woodhouse-Sakati syndrome, MIM#241080)- biallelic variants reported in multiple literature with hypogonadism as one of the phenotypes- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DCAF17 Jasmine Chew gene: DCAF17 was added
gene: DCAF17 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DCAF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCAF17 were set to 33819414; 27240811; 20507343; 34630532; 31347785; 34590781; 29574468
Phenotypes for gene: DCAF17 were set to Hypergonadotropic/ Hypogonadotropic Hypogonadism
Review for gene: DCAF17 was set to GREEN
Added comment: FeRGI db-Strong for POI (Woodhouse-Sakati syndrome)- biallelic variants reported in multiple literature- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPP Jasmine Chew changed review comment from: FeRGI database- Strong evidence for POI (Perrault syndrome 3- premature ovarian failure (POF) secondary to ovarian dysgenesis)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature; to: FeRGI database- Strong evidence for POI (Perrault syndrome 3- POI secondary to ovarian dysgenesis)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPP Jasmine Chew changed review comment from: FeRGI database- Strong evidence for POI (Perrault syndrome 3)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature; to: FeRGI database- Strong evidence for POI (Perrault syndrome 3- premature ovarian failure (POF) secondary to ovarian dysgenesis)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPP Jasmine Chew gene: CLPP was added
gene: CLPP was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 27087618; 23541340; 32399598; 33538981
Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129
Review for gene: CLPP was set to GREEN
Added comment: FeRGI database- Strong evidence for POI (Perrault syndrome 3)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C14orf39 Jasmine Chew gene: C14orf39 was added
gene: C14orf39 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: C14orf39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf39 were set to 33508233; 34718620; 27796301
Phenotypes for gene: C14orf39 were set to Premature ovarian failure 18, MIM# 619203; Spermatogenic failure 52, MIM# 619202
Review for gene: C14orf39 was set to GREEN
Added comment: Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BRCA2 Jasmine Chew edited their review of gene: BRCA2: Changed publications: 32482800, 30207912, 30865812
Infertility and Recurrent Pregnancy Loss v0.103 BRCA2 Jasmine Chew gene: BRCA2 was added
gene: BRCA2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BRCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRCA2 were set to 32482800; 30207912
Phenotypes for gene: BRCA2 were set to Premature ovarian failure
Review for gene: BRCA2 was set to GREEN
Added comment: FeRGI database- limited evidence for POI/ovarian dysgenesis- PMID:32482800,30207912- biallelic variants reported
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BNC1 Jasmine Chew edited their review of gene: BNC1: Changed publications: 32962729, 30010909, 39595984, 39462784
Infertility and Recurrent Pregnancy Loss v0.103 BNC1 Jasmine Chew changed review comment from: FeRGI database- Moderate evidence for POI- PMID:32962729,30010909 (Reported monoallelic and biallelic variants)
Sources: Literature; to: FeRGI database- Moderate evidence for POI- PMID:32962729,30010909 (Reported monoallelic and biallelic variants)

New papers reported monoallelic variants in POI patients- PMID: 39595984, 39462784

Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BNC1 Jasmine Chew gene: BNC1 was added
gene: BNC1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BNC1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BNC1 were set to 32962729; 30010909
Phenotypes for gene: BNC1 were set to Premature ovarian failure 16, MIM# 618723
Review for gene: BNC1 was set to GREEN
Added comment: FeRGI database- Moderate evidence for POI- PMID:32962729,30010909 (Reported monoallelic and biallelic variants)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ANKRD31 Jasmine Chew gene: ANKRD31 was added
gene: ANKRD31 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ANKRD31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD31 were set to 34794894; 34257419; 31003867
Phenotypes for gene: ANKRD31 were set to Premature ovarian failure
Review for gene: ANKRD31 was set to GREEN
Added comment: i) PMID: 34794894, PMID: 34257419- Three unrelated cases with premature ovarian failure and loss of function variants (het p.Q329∗ and c.1565-2A>G). Both mutations weakened the interaction between ANKRD31 and REC114 and were unable to further stabilise and regulate the binding of downstream DSB-forming proteins to chromatin. Mice with knocked out Ankrd31 have been reported to result in an increase in the number of DSBs and the enabling of the default DSB site, which also results in decremental efficiency of the regulation of DSB formation and may be responsible for the loss of synapsis and the delay in DSB repair (PMID: 31000436).

ii) PMID: 31003867- Unrepaired DSBs and pairing failures-stochastic on autosomes, nearly absolute on X and Y-cause meiotic arrest and sterility in males. Ankrd31-deficient females have reduced oocyte reserves. This gene plays a role in DNA double strand breaks formation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POLR3B Jasmine Chew gene: POLR3B was added
gene: POLR3B was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POLR3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3B were set to 25339210; 27512013; 26113998; 22036171; 22036172; 32319736; 26113998
Phenotypes for gene: POLR3B were set to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 614381
Review for gene: POLR3B was set to GREEN
Added comment: Intolerome database- candidate gene for spontaneous miscarriage, FeRGI db- limited evidence for POI.

Mouse evidence-
i) PMID: 31221184-Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis. Using proteomics in a human cell line, POLR3B R103H mutation severely impairs assembly of the Pol III complex. Their mouse model indicates that the Polr3b R103H variant is embryonically lethal at or before mid-gestation, similarly to Polr3a−/−null mice , which may lead to early developmental arrest.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PMM2 Jasmine Chew gene: PMM2 was added
gene: PMM2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMM2 were set to 31902100; 25497157; 33583911
Phenotypes for gene: PMM2 were set to Primary ovarian failure
Review for gene: PMM2 was set to GREEN
Added comment: FeRGI db- moderate evidence for Congenital disorder of glycosylation (POI)- PMID:31902100, 25497157, 33583911(reported biallelic variants)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 HARS2 Jasmine Chew edited their review of gene: HARS2: Changed publications: 31449985, 21464306, 34406847
Infertility and Recurrent Pregnancy Loss v0.103 HARS2 Jasmine Chew gene: HARS2 was added
gene: HARS2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: HARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HARS2 were set to 31449985,21464306, 34406847
Phenotypes for gene: HARS2 were set to Perrault syndrome 2, MIM# 614926
Review for gene: HARS2 was set to GREEN
Added comment: FeRGI database- strong evidence for Perrault syndrome (POI)- PMID:31449985,21464306, 34406847(reported biallelic variants)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GNRHR Jasmine Chew changed review comment from: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with recurrent pregnancy loss, recurrent implantation failure and primary infertility (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature; to: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with recurrent pregnancy loss, recurrent implantation failure and primary infertility (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GNRHR Jasmine Chew changed review comment from: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with RPL, RIF, PI (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature; to: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with recurrent pregnancy loss, recurrent implantation failure and primary infertility (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GNRHR Jasmine Chew gene: GNRHR was added
gene: GNRHR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GNRHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNRHR were set to 28348023; 9371856; 36385415
Phenotypes for gene: GNRHR were set to Hypogonadotropic hypogonadism 7 without anosmia, MIM#146110
Review for gene: GNRHR was set to GREEN
Added comment: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with RPL, RIF, PI (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GALT Jasmine Chew changed review comment from: Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with classic galactosaemia (CG) due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. (PMID: 39440457).

FeRGI database- moderate evidence for POI- PMID:19733849, 34433538, 31042289.

Other paper:
i) PMID: 34730073- a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure.
Sources: Literature; to: Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with classic galactosaemia (CG) due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. (PMID: 39440457).

FeRGI database- moderate evidence for POI- PMID:19733849, 34433538, 31042289 (Reported biallelic variants)

Other paper:
i) PMID: 34730073- a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GALT Jasmine Chew gene: GALT was added
gene: GALT was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GALT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALT were set to 39440457; 19733849; 34433538; 31042289; 34730073
Phenotypes for gene: GALT were set to Premature ovarian failure
Review for gene: GALT was set to GREEN
Added comment: Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with classic galactosaemia (CG) due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. (PMID: 39440457).

FeRGI database- moderate evidence for POI- PMID:19733849, 34433538, 31042289.

Other paper:
i) PMID: 34730073- a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B4 Jasmine Chew gene: EIF2B4 was added
gene: EIF2B4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: EIF2B4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2B4 were set to 11835386; 12707859; 14566705; 25600065; 26043506
Phenotypes for gene: EIF2B4 were set to Ovarioleukodystrophy, MIM# 620314
Review for gene: EIF2B4 was set to GREEN
Added comment: Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B5 Jasmine Chew edited their review of gene: EIF2B5: Changed publications: 12707859, 18005052, 33245593
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B5 Jasmine Chew edited their review of gene: EIF2B5: Changed publications: 12707859, 18005052, 33245593.
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B5 Jasmine Chew gene: EIF2B5 was added
gene: EIF2B5 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: EIF2B5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2B5 were set to PMID:12707859; 18005052; 33245593.
Phenotypes for gene: EIF2B5 were set to Ovarioleukodystrophy, MIM# 620315
Review for gene: EIF2B5 was set to GREEN
Added comment: FeRGI database- strong evidence for POI- biallelic variants reported in PMID:12707859, 18005052,33245593.
Sources: Literature
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
Intellectual disability syndromic and non-syndromic v1.176 IKZF2 Zornitza Stark Marked gene: IKZF2 as ready
Intellectual disability syndromic and non-syndromic v1.176 IKZF2 Zornitza Stark Gene: ikzf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.176 IKZF2 Zornitza Stark Classified gene: IKZF2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v1.176 IKZF2 Zornitza Stark Gene: ikzf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v1.175 IKZF2 Zornitza Stark gene: IKZF2 was added
gene: IKZF2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: IKZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKZF2 were set to 37316189
Phenotypes for gene: IKZF2 were set to Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, MIM# 621234
Review for gene: IKZF2 was set to AMBER
Added comment: PMID 37316189: two individuals with de novo variants and syndromic immunodysregulation, including craniofacial anomalies, hearing impairment, athelia, and developmental delay.

Note that variants in this gene are also associated with non-syndromic immune dysregulation and non-syndromic HL. Genotype-phenotype correlation unclear.
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
Disorders of immune dysregulation v1.15 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233 to Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233; Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, MIM# 621234
Disorders of immune dysregulation v1.14 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454; 34826259
Disorders of immune dysregulation v1.13 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: 37316189; Changed phenotypes: Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, MIM# 621234
Disorders of immune dysregulation v1.13 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation to Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233
Disorders of immune dysregulation v1.12 IKZF2 Zornitza Stark edited their review of gene: IKZF2: Changed phenotypes: Immunodysregulation with variable immunodeficiency and autoimmunity, MIM# 621233
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
Metal Metabolism Disorders v0.49 BMP6 Bryony Thompson Classified gene: BMP6 as Amber List (moderate evidence)
Metal Metabolism Disorders v0.49 BMP6 Bryony Thompson Added comment: Comment on list classification: limited classification by clingen
Metal Metabolism Disorders v0.49 BMP6 Bryony Thompson Gene: bmp6 has been classified as Amber List (Moderate Evidence).
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).
Genomic newborn screening: ICoNS v0.4 AK2 Lilian Downie gene: AK2 was added
gene: AK2 was added to Genomic newborn screening: ICoNS. Sources: Expert list
Mode of inheritance for gene: AK2 was set to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.370 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
Cardiomyopathy_Paediatric v0.198 LDB3 Zornitza Stark Phenotypes for gene: LDB3 were changed from Cardiomyopathy, dilated, 1C, with or without LVNC, MIM# 601493 to Cardiomyopathy, dilated, 1C, with or without LVNC, MIM# 601493; Cardiomyopathy, dilated, 2L, MIM# 621237
Cardiomyopathy_Paediatric v0.197 LDB3 Zornitza Stark edited their review of gene: LDB3: Added comment: 5 families with bi-allelic variants and severe, perinatal onset DCM.; Changed publications: 36253531; Changed phenotypes: Cardiomyopathy, dilated, 1C, with or without LVNC, MIM# 601493, Cardiomyopathy, dilated, 2L, MIM# 621237
Dilated Cardiomyopathy v1.37 LDB3 Zornitza Stark changed review comment from: 5 families reported with bi-allelic variants and severe, perinatal onset DCM.; to: 5 families reported with bi-allelic variants and severe, perinatal onset DCM. However, note scope of panel is adolescent/adult onset DCM, therefore retain Amber rating which relates to mono-allelic disease in the adult context.
Dilated Cardiomyopathy v1.37 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 v1.2659 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
Infertility and Recurrent Pregnancy Loss v0.103 NLRP14 Zornitza Stark Classified gene: NLRP14 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.103 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.102 MEI1 Zornitza Stark Marked gene: MEI1 as ready
Infertility and Recurrent Pregnancy Loss v0.102 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.102 MEI1 Zornitza Stark Publications for gene: MEI1 were set to 30388401
Infertility and Recurrent Pregnancy Loss v0.101 MEI1 Zornitza Stark Classified gene: MEI1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.101 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Marked gene: MAJIN as ready
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Classified gene: MAJIN as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and Metabolic Myopathy v1.25 ATP2A2 Zornitza Stark Phenotypes for gene: ATP2A2 were changed from Congenital myopathy, MONDO:0019952, ATP2A2-related; rhabdomyolysis to Congenital myopathy, MONDO:0019952, ATP2A2-related; {Rhabdomyolysis, susceptibility to, 2}, MIM# 621236
Rhabdomyolysis and Metabolic Myopathy v1.24 ATP2A2 Zornitza Stark edited their review of gene: ATP2A2: Changed phenotypes: Congenital myopathy, MONDO:0019952, ATP2A2-related, {Rhabdomyolysis, susceptibility to, 2}, MIM# 621236
Mendeliome v1.2656 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
Intellectual disability syndromic and non-syndromic v1.174 ANKS1B Zornitza Stark Classified gene: ANKS1B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.174 ANKS1B Zornitza Stark Gene: anks1b has been classified as Green List (High Evidence).
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.
Intellectual disability syndromic and non-syndromic v1.173 ANKS1B Lilian Downie Marked gene: ANKS1B as ready
Intellectual disability syndromic and non-syndromic v1.173 ANKS1B Lilian Downie Gene: anks1b has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v1.173 ANKS1B Lilian Downie gene: ANKS1B was added
gene: ANKS1B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
SV/CNV tags were added to gene: ANKS1B.
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 disorder MONDO:0700092 ANKS1B related
Review for gene: ANKS1B was set to GREEN
Added comment: 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.

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.
Sources: Literature
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.
Hereditary Neuropathy_CMT - isolated v1.56 PMP2 Sangavi Sivagnanasundram edited their review of gene: PMP2: Added comment: Classified as Moderate by CMT GCEP on 29/05/2025 - https://search.clinicalgenome.org/CCID:005836

Variants have been reported in 9 unrelated probands and was shown to segregate with disease in a large multigenerational family; Changed rating: GREEN; Changed publications: 37238449, 28747762, https://search.clinicalgenome.org/CCID:005836
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.
Regression v0.581 Bryony Thompson removed gene:NOTCH2NL from the panel
Mendeliome v1.2653 Bryony Thompson removed gene:NOTCH2NL from the panel
Repeat Disorders v0.264 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.59 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Hereditary Neuropathy - complex v1.28 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Leukodystrophy - adult onset v0.149 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Regression v0.580 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Mendeliome v1.2652 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Early-onset Parkinson disease v2.36 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Early-onset Dementia v1.41 NOTCH2NLC_NIID_GGC Bryony Thompson Gene: NOTCH2NL was changed to NOTCH2NLC.
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Marked gene: H6PD as ready
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Gene: h6pd has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Classified gene: H6PD as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Gene: h6pd has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Marked gene: FBXO43 as ready
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Classified gene: FBXO43 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Marked gene: LARS2 as ready
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Classified gene: LARS2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Classified gene: HSD17B4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.95 FOXD1 Zornitza Stark Marked gene: FOXD1 as ready
Infertility and Recurrent Pregnancy Loss v0.95 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.95 FOXD1 Zornitza Stark Phenotypes for gene: FOXD1 were changed from to Recurrent pregnancy loss and repeated implantation failure susceptibility
Infertility and Recurrent Pregnancy Loss v0.94 FOXD1 Zornitza Stark Classified gene: FOXD1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.94 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Marked gene: FIGLA as ready
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Gene: figla has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Classified gene: FIGLA as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Gene: figla has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Marked gene: ESR1 as ready
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Gene: esr1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Classified gene: ESR1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Gene: esr1 has been classified as Green List (High Evidence).
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
Infertility and Recurrent Pregnancy Loss v0.91 TUBA1C Zornitza Stark Marked gene: TUBA1C as ready
Infertility and Recurrent Pregnancy Loss v0.91 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.91 TUBA1C Zornitza Stark Phenotypes for gene: TUBA1C were changed from Oocyte/zygote/embryo maturation arrest to Oocyte/zygote/embryo maturation arrest 24, MIM# 621232
Infertility and Recurrent Pregnancy Loss v0.90 TUBA1C Zornitza Stark Classified gene: TUBA1C as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.90 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.89 TUBA1C Zornitza Stark reviewed gene: TUBA1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 24, MIM# 621232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
Infertility and Recurrent Pregnancy Loss v0.89 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Oocyte/zygote/embryo maturation arrest to Oocyte/zygote/embryo maturation arrest 23, MIM# 621231
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Marked gene: TUBA4A as ready
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Gene: tuba4a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Classified gene: TUBA4A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Gene: tuba4a has been classified as Green List (High Evidence).
Ataxia v1.38 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Hereditary ataxia MONDO:0100309, TUBA4A-related to Spastic ataxia 11, autosomal dominant, MIM# 621226
Ataxia v1.37 TUBA4A Zornitza Stark reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 11, autosomal dominant, MIM# 621226; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Muscular dystrophy and myopathy_Paediatric v1.88 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Congenital myopathy MONDO:0019952 to Congenital myopathy 26, MIM# 621225
Muscular dystrophy and myopathy_Paediatric v1.87 TUBA4A Zornitza Stark reviewed gene: TUBA4A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 26, MIM# 621225; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Hair disorders v0.75 HRURF Zornitza Stark Marked gene: HRURF as ready
Hair disorders v0.75 HRURF Zornitza Stark Gene: hrurf has been classified as Green List (High Evidence).
Hair disorders v0.75 HRURF Zornitza Stark Classified gene: HRURF as Green List (high evidence)
Hair disorders v0.75 HRURF Zornitza Stark Gene: hrurf has been classified as Green List (High Evidence).
Hair disorders v0.74 HRURF Zornitza Stark gene: HRURF was added
gene: HRURF was added to Hair disorders. 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
Intellectual disability syndromic and non-syndromic v1.172 KCNA6 Zornitza Stark Marked gene: KCNA6 as ready
Intellectual disability syndromic and non-syndromic v1.172 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.172 KCNA6 Zornitza Stark Classified gene: KCNA6 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v1.172 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v1.171 KCNA6 Zornitza Stark gene: KCNA6 was added
gene: KCNA6 was added to Intellectual disability syndromic and non-syndromic. 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
Genetic Epilepsy v1.157 KCNA6 Zornitza Stark Marked gene: KCNA6 as ready
Genetic Epilepsy v1.157 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.157 KCNA6 Zornitza Stark Classified gene: KCNA6 as Green List (high evidence)
Genetic Epilepsy v1.157 KCNA6 Zornitza Stark Gene: kcna6 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.156 KCNA6 Zornitza Stark gene: KCNA6 was added
gene: KCNA6 was added to Genetic Epilepsy. 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
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Marked gene: DNAAF4 as ready
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Gene: dnaaf4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Classified gene: DNAAF4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Gene: dnaaf4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Marked gene: CATSPER1 as ready
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Gene: catsper1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark edited their review of gene: CATSPER1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Classified gene: CATSPER1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Gene: catsper1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.85 CATSPER1 Zornitza Stark Tag SV/CNV tag was added to gene: CATSPER1.
Infertility and Recurrent Pregnancy Loss v0.85 CATSPER1 Zornitza Stark reviewed gene: CATSPER1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 7, MIM# 612997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.85 DNAAF1 Zornitza Stark Marked gene: DNAAF1 as ready