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Growth failure v0.204 KDM6A Zornitza Stark Gene: kdm6a has been classified as Green List (High Evidence).
Growth failure v0.204 KDM6A Zornitza Stark Phenotypes for gene: KDM6A were changed from Kabuki to Kabuki syndrome 2, MIM# 300867
Growth failure v0.203 KDM6A Zornitza Stark Publications for gene: KDM6A were set to
Growth failure v0.202 KDM6A Zornitza Stark Classified gene: KDM6A as Green List (high evidence)
Growth failure v0.202 KDM6A Zornitza Stark Gene: kdm6a has been classified as Green List (High Evidence).
Growth failure v0.201 KDM6A Zornitza Stark reviewed gene: KDM6A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22197486, 23076834, 24633898, 25972376; Phenotypes: Kabuki syndrome 2, MIM# 300867; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Growth failure v0.201 MAPK1 Zornitza Stark Marked gene: MAPK1 as ready
Growth failure v0.201 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Growth failure v0.201 MAPK1 Zornitza Stark Classified gene: MAPK1 as Green List (high evidence)
Growth failure v0.201 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Growth failure v0.200 MAPK1 Zornitza Stark gene: MAPK1 was added
gene: MAPK1 was added to Growth failure in early childhood. Sources: Expert Review
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Noonan syndrome 13, MIM#619087
Mode of pathogenicity for gene: MAPK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

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

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

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

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).
Sources: Expert Review
Growth failure v0.199 RRAS2 Zornitza Stark Marked gene: RRAS2 as ready
Growth failure v0.199 RRAS2 Zornitza Stark Gene: rras2 has been classified as Green List (High Evidence).
Growth failure v0.199 RRAS2 Zornitza Stark Classified gene: RRAS2 as Green List (high evidence)
Growth failure v0.199 RRAS2 Zornitza Stark Gene: rras2 has been classified as Green List (High Evidence).
Growth failure v0.198 RRAS2 Zornitza Stark gene: RRAS2 was added
gene: RRAS2 was added to Growth failure in early childhood. Sources: Expert Review
Mode of inheritance for gene: RRAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAS2 were set to 31130282
Phenotypes for gene: RRAS2 were set to Noonan syndrome 12, MIM #618624
Mode of pathogenicity for gene: RRAS2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RRAS2 was set to GREEN
Added comment: Six unrelated families reported, GoF variants.
Sources: Expert Review
Mendeliome v0.8876 SHOX Zornitza Stark Marked gene: SHOX as ready
Mendeliome v0.8876 SHOX Zornitza Stark Gene: shox has been classified as Green List (High Evidence).
Mendeliome v0.8876 SHOX Zornitza Stark Phenotypes for gene: SHOX were changed from to Langer mesomelic dysplasia, MIM# 249700; Leri-Weill dyschondrosteosis, MIM# 127300
Mendeliome v0.8875 SHOX Zornitza Stark Mode of inheritance for gene: SHOX was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8874 SHOX Zornitza Stark Tag SV/CNV tag was added to gene: SHOX.
Mendeliome v0.8874 SHOX Zornitza Stark reviewed gene: SHOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Langer mesomelic dysplasia, MIM# 249700, Leri-Weill dyschondrosteosis, MIM# 127300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure v0.197 SHOX Zornitza Stark Marked gene: SHOX as ready
Growth failure v0.197 SHOX Zornitza Stark Gene: shox has been classified as Green List (High Evidence).
Growth failure v0.197 SHOX Zornitza Stark changed review comment from: Deletions common.; to: Deletions common. Pseudoautosomal region of X chromosome.
Growth failure v0.197 SHOX Zornitza Stark edited their review of gene: SHOX: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure v0.197 SHOX Zornitza Stark Phenotypes for gene: SHOX were changed from to Langer mesomelic dysplasia, MIM# 249700; Leri-Weill dyschondrosteosis, MIM# 127300
Growth failure v0.196 SHOX Zornitza Stark Classified gene: SHOX as Green List (high evidence)
Growth failure v0.196 SHOX Zornitza Stark Gene: shox has been classified as Green List (High Evidence).
Growth failure v0.195 SHOX Zornitza Stark Tag SV/CNV tag was added to gene: SHOX.
Growth failure v0.195 SHOX Zornitza Stark reviewed gene: SHOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Langer mesomelic dysplasia, MIM# 249700, Leri-Weill dyschondrosteosis, MIM# 127300; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Growth failure v0.195 CENPJ Zornitza Stark Marked gene: CENPJ as ready
Growth failure v0.195 CENPJ Zornitza Stark Gene: cenpj has been classified as Red List (Low Evidence).
Growth failure v0.195 CENPJ Zornitza Stark Phenotypes for gene: CENPJ were changed from seckel syndrome to Seckel syndrome 4, MIM# 613676
Growth failure v0.194 CENPJ Zornitza Stark Publications for gene: CENPJ were set to 20522431
Growth failure v0.193 CENPJ Zornitza Stark changed review comment from: Single family reported with Seckel phenotype and supportive mouse model. However, bi-allelic variants in this gene are typically associated with microcephaly.; to: Single family reported with Seckel phenotype and supportive mouse model. However, bi-allelic variants in this gene are typically associated with microcephaly without short stature.
Growth failure v0.193 CENPJ Zornitza Stark reviewed gene: CENPJ: Rating: RED; Mode of pathogenicity: None; Publications: 20522431, 23166506; Phenotypes: Seckel syndrome 4, MIM# 613676; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8874 ORC4 Zornitza Stark Marked gene: ORC4 as ready
Mendeliome v0.8874 ORC4 Zornitza Stark Gene: orc4 has been classified as Green List (High Evidence).
Mendeliome v0.8874 ORC4 Zornitza Stark Phenotypes for gene: ORC4 were changed from to Meier-Gorlin syndrome 2, MIM# 613800
Mendeliome v0.8873 ORC4 Zornitza Stark Publications for gene: ORC4 were set to
Mendeliome v0.8872 ORC4 Zornitza Stark Mode of inheritance for gene: ORC4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8871 ORC4 Zornitza Stark reviewed gene: ORC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 21358631, 23023959, 22333897; Phenotypes: Meier-Gorlin syndrome 2, MIM# 613800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.193 ORC4 Zornitza Stark Marked gene: ORC4 as ready
Growth failure v0.193 ORC4 Zornitza Stark Gene: orc4 has been classified as Green List (High Evidence).
Growth failure v0.193 ORC4 Zornitza Stark Phenotypes for gene: ORC4 were changed from Meier-Gorlin syndrome 2, 613800; micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia; Meier-Gorlin to Meier-Gorlin syndrome 2, MIM# 613800
Growth failure v0.192 ORC4 Zornitza Stark Publications for gene: ORC4 were set to 21358632
Growth failure v0.191 ORC4 Zornitza Stark Classified gene: ORC4 as Green List (high evidence)
Growth failure v0.191 ORC4 Zornitza Stark Gene: orc4 has been classified as Green List (High Evidence).
Growth failure v0.190 ORC4 Zornitza Stark reviewed gene: ORC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 21358631, 23023959, 22333897; Phenotypes: Meier-Gorlin syndrome 2, MIM# 613800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8871 ORC1 Zornitza Stark Marked gene: ORC1 as ready
Mendeliome v0.8871 ORC1 Zornitza Stark Gene: orc1 has been classified as Green List (High Evidence).
Mendeliome v0.8871 ORC1 Zornitza Stark Phenotypes for gene: ORC1 were changed from to Meier-Gorlin syndrome 1, MIM# 224690; MONDO:0009143
Mendeliome v0.8870 ORC1 Zornitza Stark Publications for gene: ORC1 were set to
Mendeliome v0.8869 ORC1 Zornitza Stark Mode of inheritance for gene: ORC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8868 ORC1 Zornitza Stark reviewed gene: ORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358633, 21358632, 21358631, 23023959; Phenotypes: Meier-Gorlin syndrome 1, MIM# 224690, MONDO:0009143; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.190 ORC1 Zornitza Stark Marked gene: ORC1 as ready
Growth failure v0.190 ORC1 Zornitza Stark Gene: orc1 has been classified as Green List (High Evidence).
Growth failure v0.190 ORC1 Zornitza Stark Phenotypes for gene: ORC1 were changed from Meier-Gorlin syndrome 1, 224690; microtia, beaked nose, patellar aplasia/hypoplasia, mammary hypoplasia, micrognathia; Meier-Gorlin to Meier-Gorlin syndrome 1, MIM# 224690; MONDO:0009143
Growth failure v0.189 ORC1 Zornitza Stark Publications for gene: ORC1 were set to 21358632
Growth failure v0.188 ORC1 Zornitza Stark Classified gene: ORC1 as Green List (high evidence)
Growth failure v0.188 ORC1 Zornitza Stark Gene: orc1 has been classified as Green List (High Evidence).
Growth failure v0.187 ORC1 Zornitza Stark reviewed gene: ORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358633, 21358632, 21358631, 23023959; Phenotypes: Meier-Gorlin syndrome 1, MIM# 224690, MONDO:0009143; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8868 ORC6 Zornitza Stark Marked gene: ORC6 as ready
Mendeliome v0.8868 ORC6 Zornitza Stark Gene: orc6 has been classified as Green List (High Evidence).
Mendeliome v0.8868 ORC6 Zornitza Stark Phenotypes for gene: ORC6 were changed from to Meier-Gorlin syndrome 3, MIM# 613803
Mendeliome v0.8867 ORC6 Zornitza Stark Publications for gene: ORC6 were set to
Mendeliome v0.8866 ORC6 Zornitza Stark Mode of inheritance for gene: ORC6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8865 ORC6 Zornitza Stark reviewed gene: ORC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 22333897, 25691413, 26139588; Phenotypes: Meier-Gorlin syndrome 3, MIM# 613803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.187 ORC6 Zornitza Stark Marked gene: ORC6 as ready
Growth failure v0.187 ORC6 Zornitza Stark Gene: orc6 has been classified as Green List (High Evidence).
Growth failure v0.187 ORC6 Zornitza Stark Phenotypes for gene: ORC6 were changed from Meier-Gorlin; micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia; Meier-Gorlin syndrome 3, 613803 to Meier-Gorlin syndrome 3, MIM# 613803
Growth failure v0.186 ORC6 Zornitza Stark Publications for gene: ORC6 were set to 21358632
Growth failure v0.185 ORC6 Zornitza Stark Classified gene: ORC6 as Green List (high evidence)
Growth failure v0.185 ORC6 Zornitza Stark Gene: orc6 has been classified as Green List (High Evidence).
Growth failure v0.184 ORC6 Zornitza Stark reviewed gene: ORC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 22333897, 25691413, 26139588; Phenotypes: Meier-Gorlin syndrome 3, MIM# 613803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.184 IGF1R Zornitza Stark Marked gene: IGF1R as ready
Growth failure v0.184 IGF1R Zornitza Stark Gene: igf1r has been classified as Green List (High Evidence).
Growth failure v0.184 IGF1R Zornitza Stark Phenotypes for gene: IGF1R were changed from 15q-Del; Insulin likegrowthfactorI,resistanceto,270450; Insulin-Like Growth Factor I Resistance to Insulin-like growth factor I, resistance to, MIM # 270450
Growth failure v0.183 IGF1R Zornitza Stark Publications for gene: IGF1R were set to
Intellectual disability syndromic and non-syndromic v0.4066 IGF1 Zornitza Stark Marked gene: IGF1 as ready
Intellectual disability syndromic and non-syndromic v0.4066 IGF1 Zornitza Stark Gene: igf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4066 IGF1 Zornitza Stark Phenotypes for gene: IGF1 were changed from to Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747
Intellectual disability syndromic and non-syndromic v0.4065 IGF1 Zornitza Stark Publications for gene: IGF1 were set to
Intellectual disability syndromic and non-syndromic v0.4064 IGF1 Zornitza Stark Mode of inheritance for gene: IGF1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4063 IGF1 Zornitza Stark reviewed gene: IGF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8857020, 15769976, 14684690, 31539878, 28768959, 34125705, 22832530; Phenotypes: Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8865 IGF1 Zornitza Stark Marked gene: IGF1 as ready
Mendeliome v0.8865 IGF1 Zornitza Stark Gene: igf1 has been classified as Green List (High Evidence).
Mendeliome v0.8865 IGF1 Zornitza Stark Phenotypes for gene: IGF1 were changed from to Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747
Mendeliome v0.8864 IGF1 Zornitza Stark Publications for gene: IGF1 were set to
Mendeliome v0.8863 IGF1 Zornitza Stark Mode of inheritance for gene: IGF1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8862 IGF1 Zornitza Stark reviewed gene: IGF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8857020, 15769976, 14684690, 31539878, 28768959, 34125705, 22832530; Phenotypes: Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure v0.182 IGF1 Zornitza Stark Publications for gene: IGF1 were set to 8857020; 15769976; 14684690; 31539878; 28768959; 34125705; 22832530
Growth failure v0.181 IGF1 Zornitza Stark Marked gene: IGF1 as ready
Growth failure v0.181 IGF1 Zornitza Stark Gene: igf1 has been classified as Green List (High Evidence).
Growth failure v0.181 IGF1 Zornitza Stark Phenotypes for gene: IGF1 were changed from Insulin-Like Growth Factor I Deficiency; Growth retardation with deafness and mental retardation due to IGF1 deficiency, 608747; IGF1 to Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747
Growth failure v0.180 IGF1 Zornitza Stark Publications for gene: IGF1 were set to
Growth failure v0.179 IGF1 Zornitza Stark Mode of inheritance for gene: IGF1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Imprinting disorders v0.3 IGF2 Zornitza Stark Marked gene: IGF2 as ready
Imprinting disorders v0.3 IGF2 Zornitza Stark Gene: igf2 has been classified as Green List (High Evidence).
Imprinting disorders v0.3 IGF2 Zornitza Stark Phenotypes for gene: IGF2 were changed from Affected tissue: all; Phenotypes resulting from gene over expression: Beckwith-Wiedemann Syndrome (proven effects of dosage alteration rather than gene muation). Phenotype resulting from under expression: Silver-Russell Syndrome to Affected tissue: all; Phenotypes resulting from gene over expression: Beckwith-Wiedemann Syndrome (proven effects of dosage alteration rather than gene muation). Phenotype resulting from under expression: Silver-Russell syndrome 3, MIM #616489
Imprinting disorders v0.2 IGF2 Zornitza Stark Publications for gene: IGF2 were set to http://igc.otago.ac.nz/home.html; PMID: 26154720; 30794780
Imprinting disorders v0.1 IGF2 Zornitza Stark reviewed gene: IGF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26154720, 31544945; Phenotypes: Silver-Russell syndrome 3, MIM #616489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.8862 IGF2 Zornitza Stark Mode of inheritance for gene: IGF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Mendeliome v0.8861 IGF2 Zornitza Stark changed review comment from: RSS phenotype.; to: Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay. Disruption of any gene in the HMGA2-PLAG1-IGF2 pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects.

Begemann et al. (2015) performed exome sequencing in 4 affected people with severe growth restriction in one family, and identified a heterozygous nonsense mutation in the IGF2 gene that segregated fully with the disorder. Affected individuals inherited the mutation from their healthy fathers, and it originated from the healthy paternal grandmother. Clinical features occurred only in those who inherited the variant allele through paternal transmission, consistent with maternal imprinting of IGF2.

Many other cases reported since with de novo mutations in IGF2 present on the paternal allele.
Mendeliome v0.8861 IGF2 Zornitza Stark edited their review of gene: IGF2: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Growth failure v0.178 IGF2 Zornitza Stark Marked gene: IGF2 as ready
Growth failure v0.178 IGF2 Zornitza Stark Gene: igf2 has been classified as Green List (High Evidence).
Growth failure v0.178 IGF2 Zornitza Stark Phenotypes for gene: IGF2 were changed from Pre- and post-natal growth failure; SRS; ?Growth restriction, severe, with distinctive facies, 616489; Silver-Russell phenptype; IUGR to Silver-Russell syndrome 3, MIM #616489
Growth failure v0.177 IGF2 Zornitza Stark Publications for gene: IGF2 were set to 26154720
Mendeliome v0.8861 OBSL1 Zornitza Stark Marked gene: OBSL1 as ready
Mendeliome v0.8861 OBSL1 Zornitza Stark Gene: obsl1 has been classified as Green List (High Evidence).
Mendeliome v0.8861 OBSL1 Zornitza Stark Phenotypes for gene: OBSL1 were changed from to 3-M syndrome 2, MIM #612921
Mendeliome v0.8860 OBSL1 Zornitza Stark Publications for gene: OBSL1 were set to
Mendeliome v0.8859 OBSL1 Zornitza Stark Mode of inheritance for gene: OBSL1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8858 OBSL1 Zornitza Stark reviewed gene: OBSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21737058, 19481195, 23018678, 19877176; Phenotypes: 3-M syndrome 2, MIM #612921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.176 OBSL1 Zornitza Stark Marked gene: OBSL1 as ready
Growth failure v0.176 OBSL1 Zornitza Stark Gene: obsl1 has been classified as Green List (High Evidence).
Growth failure v0.176 OBSL1 Zornitza Stark Phenotypes for gene: OBSL1 were changed from 3M; 3-M syndrome 2, 612921 to 3-M syndrome 2, MIM #612921
Growth failure v0.175 OBSL1 Zornitza Stark Publications for gene: OBSL1 were set to 21737058
Mendeliome v0.8858 PIK3R1 Zornitza Stark Marked gene: PIK3R1 as ready
Mendeliome v0.8858 PIK3R1 Zornitza Stark Gene: pik3r1 has been classified as Green List (High Evidence).
Mendeliome v0.8858 PIK3R1 Zornitza Stark Phenotypes for gene: PIK3R1 were changed from to SHORT syndrome, MIM # 269880; Immunodeficiency 36, MIM#616005
Mendeliome v0.8857 PIK3R1 Zornitza Stark Publications for gene: PIK3R1 were set to
Mendeliome v0.8856 PIK3R1 Zornitza Stark Mode of inheritance for gene: PIK3R1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8855 PIK3R1 Zornitza Stark reviewed gene: PIK3R1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23810378, 23810379, 23810382; Phenotypes: SHORT syndrome, MIM # 269880; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.174 PIK3R1 Zornitza Stark Marked gene: PIK3R1 as ready
Growth failure v0.174 PIK3R1 Zornitza Stark Gene: pik3r1 has been classified as Green List (High Evidence).
Growth failure v0.174 PIK3R1 Zornitza Stark Phenotypes for gene: PIK3R1 were changed from SHORT syndrome, 269880; SHORT to SHORT syndrome, OMIM # 269880
Growth failure v0.173 PIK3R1 Zornitza Stark Publications for gene: PIK3R1 were set to
Mendeliome v0.8855 PLAG1 Zornitza Stark Publications for gene: PLAG1 were set to 28796236; 29913240
Mendeliome v0.8854 PLAG1 Zornitza Stark Classified gene: PLAG1 as Green List (high evidence)
Mendeliome v0.8854 PLAG1 Zornitza Stark Gene: plag1 has been classified as Green List (High Evidence).
Mendeliome v0.8853 PLAG1 Zornitza Stark edited their review of gene: PLAG1: Added comment: Additional families reported, upgrade to Green.

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

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

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

Vado et al. (2020) reported 1 family with multiple affected people with Silver-Russell syndrome with a frameshift variant in the PLAG1 gene, which segregated with disease.; Changed rating: GREEN; Changed publications: 28796236, 29913240, 33291420, 32546215
Growth failure v0.172 PLAG1 Zornitza Stark Marked gene: PLAG1 as ready
Growth failure v0.172 PLAG1 Zornitza Stark Gene: plag1 has been classified as Green List (High Evidence).
Growth failure v0.172 PLAG1 Zornitza Stark Phenotypes for gene: PLAG1 were changed from SRS; Silver-Russell syndrome to Silver-Russell syndrome 4, MIM # 618907
Growth failure v0.171 PLAG1 Zornitza Stark Publications for gene: PLAG1 were set to 28796236
Growth failure v0.170 SRCAP Zornitza Stark Marked gene: SRCAP as ready
Growth failure v0.170 SRCAP Zornitza Stark Gene: srcap has been classified as Green List (High Evidence).
Growth failure v0.170 SRCAP Zornitza Stark Phenotypes for gene: SRCAP were changed from Floating-Harbor syndrome, 136140; Floating Harbor to Floating-Harbor syndrome, OMIM # 136140
Growth failure v0.169 SRCAP Zornitza Stark Publications for gene: SRCAP were set to
Growth failure v0.168 IGF1R Chirag Patel reviewed gene: IGF1R: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 14657428, 22130793, 23045302, 26252249, 17264177, 31586944; Phenotypes: Insulin-like growth factor I, resistance to, OMIM # 270450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure v0.168 IGF1 Chirag Patel reviewed gene: IGF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 8857020, 15769976, 14684690, 31539878, 28768959, 34125705, 22832530; Phenotypes: Growth retardation with deafness and mental retardation due to IGF1 deficiency, OMIM # 608747; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure v0.168 IGF2 Chirag Patel reviewed gene: IGF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26154720, 31544945; Phenotypes: Silver-Russell syndrome 3, OMIM #616489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Growth failure v0.168 OBSL1 Chirag Patel reviewed gene: OBSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19481195, 23018678, 19877176; Phenotypes: 3-M syndrome 2, OMIM #612921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.168 PIK3R1 Chirag Patel reviewed gene: PIK3R1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23810378, 23810379, 23810382; Phenotypes: SHORT syndrome, OMIM # 269880; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.168 PLAG1 Chirag Patel reviewed gene: PLAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28796236, 33291420, 32546215; Phenotypes: Silver-Russell syndrome 4,OMIM # 618907; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.168 SRCAP Chirag Patel reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22265015, 22965468, 22965468; Phenotypes: Floating-Harbor syndrome, OMIM # 136140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8853 PACRG Zornitza Stark Marked gene: PACRG as ready
Mendeliome v0.8853 PACRG Zornitza Stark Gene: pacrg has been classified as Red List (Low Evidence).
Mendeliome v0.8853 PACRG Zornitza Stark Publications for gene: PACRG were set to
Mendeliome v0.8852 PACRG Zornitza Stark Classified gene: PACRG as Red List (low evidence)
Mendeliome v0.8852 PACRG Zornitza Stark Gene: pacrg has been classified as Red List (Low Evidence).
Mendeliome v0.8851 PACRG Zornitza Stark reviewed gene: PACRG: Rating: RED; Mode of pathogenicity: None; Publications: 31116684, 31182890, 14737177, 27193298; Phenotypes: ; Mode of inheritance: None
Combined Immunodeficiency v0.345 ZBTB24 Zornitza Stark Marked gene: ZBTB24 as ready
Combined Immunodeficiency v0.345 ZBTB24 Zornitza Stark Gene: zbtb24 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.345 ZBTB24 Zornitza Stark Publications for gene: ZBTB24 were set to 21596365; 21906047; 27626380 32061411
Combined Immunodeficiency v0.344 ZBTB24 Zornitza Stark Phenotypes for gene: ZBTB24 were changed from to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM# 614069; Facial dysmorphic features; developmental delay; macroglossia; bacterial/opportunistic infections; malabsorption; cytopaenia; malignancies; multiradial configurations of chromosomes 1, 9, 16; Hypogammaglobulinaemia or agammaglobulinaemia; variable antibody deficiency
Combined Immunodeficiency v0.343 ZBTB24 Zornitza Stark Publications for gene: ZBTB24 were set to
Combined Immunodeficiency v0.342 ZBTB24 Zornitza Stark Mode of inheritance for gene: ZBTB24 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.92 WIPF1 Zornitza Stark Marked gene: WIPF1 as ready
Predominantly Antibody Deficiency v0.92 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
Predominantly Antibody Deficiency v0.92 WIPF1 Zornitza Stark Phenotypes for gene: WIPF1 were changed from to Wiskott-Aldrich syndrome 2 MIM# 614493; Reduced T cells; defective lymphocyte responses to anti-CD3; high IgE; Thrombocytopenia with or without small platelets; recurrent bacterial and viral Infections; eczema; bloody diarrhoea; gastrointestinal bleeding; WAS protein absent
Predominantly Antibody Deficiency v0.91 WIPF1 Zornitza Stark Publications for gene: WIPF1 were set to
Predominantly Antibody Deficiency v0.90 WIPF1 Zornitza Stark Mode of inheritance for gene: WIPF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.89 WIPF1 Zornitza Stark reviewed gene: WIPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22231303, 27742395, 11869681, 14757742; Phenotypes: Wiskott-Aldrich syndrome 2 MIM# 614493, Reduced T cells, defective lymphocyte responses to anti-CD3, high IgE, Thrombocytopenia with or without small platelets, recurrent bacterial and viral Infections, eczema, bloody diarrhoea, gastrointestinal bleeding, WAS protein absent; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8851 WIPF1 Zornitza Stark Marked gene: WIPF1 as ready
Mendeliome v0.8851 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
Mendeliome v0.8851 WIPF1 Zornitza Stark Phenotypes for gene: WIPF1 were changed from to Wiskott-Aldrich syndrome 2 MIM# 614493; Reduced T cells; defective lymphocyte responses to anti-CD3; high IgE; Thrombocytopenia with or without small platelets; recurrent bacterial and viral Infections; eczema; bloody diarrhoea; gastrointestinal bleeding; WAS protein absent
Mendeliome v0.8850 WIPF1 Zornitza Stark Publications for gene: WIPF1 were set to
Mendeliome v0.8849 WIPF1 Zornitza Stark Mode of inheritance for gene: WIPF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4063 TCN2 Zornitza Stark Marked gene: TCN2 as ready
Intellectual disability syndromic and non-syndromic v0.4063 TCN2 Zornitza Stark Gene: tcn2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4063 TCN2 Zornitza Stark Phenotypes for gene: TCN2 were changed from to Transcobalamin II deficiency, 275350
Intellectual disability syndromic and non-syndromic v0.4062 TCN2 Zornitza Stark Publications for gene: TCN2 were set to
Intellectual disability syndromic and non-syndromic v0.4061 TCN2 Zornitza Stark Mode of inheritance for gene: TCN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8848 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.

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

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

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

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

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

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.4060 TCN2 Zornitza Stark reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19373259, 32841161, 33023511, 30124850; Phenotypes: Transcobalamin II deficiency, 275350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8848 TCN2 Zornitza Stark Marked gene: TCN2 as ready
Mendeliome v0.8848 TCN2 Zornitza Stark Gene: tcn2 has been classified as Green List (High Evidence).
Mendeliome v0.8848 TCN2 Zornitza Stark Publications for gene: TCN2 were set to 19373259
Mendeliome v0.8847 TCN2 Zornitza Stark edited their review of gene: TCN2: Changed publications: 19373259, 32841161, 33023511, 30124850
Mendeliome v0.8847 TCN2 Zornitza Stark changed review comment from: Well established gene-disease association.
Sources: Expert list; to: Well established gene-disease association.

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

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

Individuals usually present within the first year of life with failure to thrive, diarrhoea, anaemia, pallor and agammaglobulinaemia.
Sources: Expert list
Mendeliome v0.8847 TCN2 Zornitza Stark Phenotypes for gene: TCN2 were changed from to Transcobalamin II deficiency, 275350
Mendeliome v0.8846 TCN2 Zornitza Stark Publications for gene: TCN2 were set to
Mendeliome v0.8845 TCN2 Zornitza Stark Mode of inheritance for gene: TCN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Vasculitis v0.35 TAP2 Zornitza Stark Marked gene: TAP2 as ready
Vasculitis v0.35 TAP2 Zornitza Stark Gene: tap2 has been classified as Green List (High Evidence).
Vasculitis v0.35 TAP2 Zornitza Stark Classified gene: TAP2 as Green List (high evidence)
Vasculitis v0.35 TAP2 Zornitza Stark Gene: tap2 has been classified as Green List (High Evidence).
Vasculitis v0.34 TAP2 Zornitza Stark gene: TAP2 was added
gene: TAP2 was added to Vasculitis. Sources: Expert Review
Mode of inheritance for gene: TAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAP2 were set to 7517574; 9232449; 10560675; 27861817
Phenotypes for gene: TAP2 were set to Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis
Review for gene: TAP2 was set to GREEN
Added comment: 5 individuals from 4 unrelated families reported with TAP2 variants resulting in BLS type 1; two mouse models

Homozygous missense variants resulting in premature stop codons were identified.

Individuals typically presented with recurrent respiratory bacterial infections and reduced CD8+ cells with granulomatous lesions and/or skin vasculitis.
Sources: Expert Review
Mendeliome v0.8844 TAP2 Zornitza Stark Marked gene: TAP2 as ready
Mendeliome v0.8844 TAP2 Zornitza Stark Gene: tap2 has been classified as Green List (High Evidence).
Mendeliome v0.8844 TAP2 Zornitza Stark Phenotypes for gene: TAP2 were changed from to Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis
Mendeliome v0.8843 TAP2 Zornitza Stark Publications for gene: TAP2 were set to
Mendeliome v0.8842 TAP2 Zornitza Stark Mode of inheritance for gene: TAP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8841 TAP1 Zornitza Stark Marked gene: TAP1 as ready
Mendeliome v0.8841 TAP1 Zornitza Stark Gene: tap1 has been classified as Green List (High Evidence).
Mendeliome v0.8841 TAP1 Zornitza Stark Phenotypes for gene: TAP1 were changed from to Bare lymphocyte syndrome, type I MIM#604571; Low CD8; absent MHC I on lymphocytes; vasculitis; pyoderma gangrenosum; skin lesions; recurrent respiratory tract infections; bronchiectasis
Mendeliome v0.8840 TAP1 Zornitza Stark Publications for gene: TAP1 were set to
Mendeliome v0.8839 TAP1 Zornitza Stark Mode of inheritance for gene: TAP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8838 PGRMC1 Bryony Thompson Phenotypes for gene: PGRMC1 were changed from Premature ovarian failure to Premature ovarian failure; Isolated paediatric cataract
Mendeliome v0.8837 PGRMC1 Bryony Thompson Tag SV/CNV tag was added to gene: PGRMC1.
Mendeliome v0.8837 PGRMC1 Bryony Thompson Publications for gene: PGRMC1 were set to 25246111; 18782852
Mendeliome v0.8836 WIPF1 Danielle Ariti reviewed gene: WIPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22231303, 27742395, 11869681, 14757742; Phenotypes: Wiskott-Aldrich syndrome 2 MIM# 614493, Reduced T cells, defective lymphocyte responses to anti-CD3, high IgE, Thrombocytopenia with or without small platelets, recurrent bacterial and viral Infections, eczema, bloody diarrhoea, gastrointestinal bleeding, WAS protein absent; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8836 PGRMC1 Bryony Thompson Classified gene: PGRMC1 as Amber List (moderate evidence)
Mendeliome v0.8836 PGRMC1 Bryony Thompson Gene: pgrmc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8835 PGRMC1 Bryony Thompson reviewed gene: PGRMC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33867527, 23783460; Phenotypes: Isolated paediatric cataract; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cataract v0.286 PGRMC1 Bryony Thompson Marked gene: PGRMC1 as ready
Cataract v0.286 PGRMC1 Bryony Thompson Gene: pgrmc1 has been classified as Amber List (Moderate Evidence).
Cataract v0.286 PGRMC1 Bryony Thompson changed review comment from: A single large family with X-linked isolated paediatric cataract segregating a large 127 kb deletion truncating PGRMC1. A supporting knockout zebrafish model with cataract. Also, two unrelated probands with non-syndromic ID and cataract with a large deletion encompassing PGRMC1 and SLC25A5.
Sources: Literature; to: A single large family with X-linked isolated paediatric cataract in males segregating a large 127 kb deletion truncating PGRMC1. A supporting knockout zebrafish model with cataract. Also, two unrelated male probands with non-syndromic ID and cataract with a large deletion encompassing PGRMC1 and SLC25A5.
Sources: Literature
Cataract v0.286 PGRMC1 Bryony Thompson Classified gene: PGRMC1 as Amber List (moderate evidence)
Cataract v0.286 PGRMC1 Bryony Thompson Gene: pgrmc1 has been classified as Amber List (Moderate Evidence).
Cataract v0.285 PGRMC1 Bryony Thompson gene: PGRMC1 was added
gene: PGRMC1 was added to Cataract. Sources: Literature
SV/CNV tags were added to gene: PGRMC1.
Mode of inheritance for gene: PGRMC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PGRMC1 were set to 33867527; 23783460
Phenotypes for gene: PGRMC1 were set to Isolated paediatric cataract
Review for gene: PGRMC1 was set to AMBER
Added comment: A single large family with X-linked isolated paediatric cataract segregating a large 127 kb deletion truncating PGRMC1. A supporting knockout zebrafish model with cataract. Also, two unrelated probands with non-syndromic ID and cataract with a large deletion encompassing PGRMC1 and SLC25A5.
Sources: Literature
Combined Immunodeficiency v0.341 WIPF1 Zornitza Stark Marked gene: WIPF1 as ready
Combined Immunodeficiency v0.341 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.341 WIPF1 Zornitza Stark Phenotypes for gene: WIPF1 were changed from to Wiskott-Aldrich syndrome 2 MIM# 614493; Reduced T cells; defective lymphocyte responses to anti-CD3; high IgE; Thrombocytopenia with or without small platelets; recurrent bacterial and viral Infections; eczema; bloody diarrhoea; gastrointestinal bleeding; WAS protein absent
Combined Immunodeficiency v0.340 WIPF1 Zornitza Stark Publications for gene: WIPF1 were set to
Combined Immunodeficiency v0.339 WIPF1 Zornitza Stark Mode of inheritance for gene: WIPF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.338 TCN2 Zornitza Stark Marked gene: TCN2 as ready
Combined Immunodeficiency v0.338 TCN2 Zornitza Stark Gene: tcn2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.338 TCN2 Zornitza Stark Phenotypes for gene: TCN2 were changed from to Transcobalamin II deficiency MIM# 275350; Decreased Ig levels; Megaloblastic anaemia; pancytopaenia; if untreated (B12) for prolonged periods results in intellectual disability; failure to thrive; diarrhoea; hypogammaglobulinaemia; pallor; hypotonia; respiratory infection
Growth failure v0.168 TRIM37 Chirag Patel reviewed gene: TRIM37: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 10888877, 12754710, 15108285, 14757854, 27044324; Phenotypes: Mulibrey nanism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.337 TCN2 Zornitza Stark Publications for gene: TCN2 were set to
Combined Immunodeficiency v0.336 TCN2 Zornitza Stark Mode of inheritance for gene: TCN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.335 TAP2 Zornitza Stark Marked gene: TAP2 as ready
Combined Immunodeficiency v0.335 TAP2 Zornitza Stark Gene: tap2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.335 TAP2 Zornitza Stark Phenotypes for gene: TAP2 were changed from to Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis
Mendeliome v0.8835 TAP2 Danielle Ariti reviewed gene: TAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7517574, 9232449, 10560675, 27861817; Phenotypes: Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571, Low CD8, absent MHC I on lymphocytes, Vasculitis, pyoderma gangrenosum, recurrent bacterial/viral respiratory infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.334 TAP2 Zornitza Stark Publications for gene: TAP2 were set to
Combined Immunodeficiency v0.333 TAP2 Zornitza Stark Mode of inheritance for gene: TAP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8835 TAP1 Danielle Ariti reviewed gene: TAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28161407, 10074494, 1473153; Phenotypes: Bare lymphocyte syndrome, type I MIM#604571, Low CD8, absent MHC I on lymphocytes, vasculitis, pyoderma gangrenosum, skin lesions, recurrent respiratory tract infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.332 TAP1 Zornitza Stark Marked gene: TAP1 as ready
Combined Immunodeficiency v0.332 TAP1 Zornitza Stark Gene: tap1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.332 TAP1 Zornitza Stark Phenotypes for gene: TAP1 were changed from to Bare lymphocyte syndrome, type I MIM#604571; Low CD8; absent MHC I on lymphocytes; vasculitis; pyoderma gangrenosum; skin lesions; recurrent respiratory tract infections; bronchiectasis
Combined Immunodeficiency v0.331 TAP1 Zornitza Stark Publications for gene: TAP1 were set to 28161407; 10074494; 1473153
Combined Immunodeficiency v0.330 TAP1 Zornitza Stark Publications for gene: TAP1 were set to
Combined Immunodeficiency v0.330 TAP1 Zornitza Stark Mode of inheritance for gene: TAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.329 TAP1 Zornitza Stark Mode of inheritance for gene: TAP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.328 ZBTB24 Danielle Ariti reviewed gene: ZBTB24: Rating: GREEN; Mode of pathogenicity: None; Publications: 21596365, 21906047, 27626380 32061411; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM# 614069, Facial dysmorphic features, developmental delay, macroglossia, bacterial/opportunistic infections, malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia or agammaglobulinaemia, variable antibody deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.328 WIPF1 Danielle Ariti reviewed gene: WIPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22231303, 27742395, 11869681, 14757742; Phenotypes: Wiskott-Aldrich syndrome 2 MIM# 614493, Reduced T cells, defective lymphocyte responses to anti-CD3, high IgE, Thrombocytopenia with or without small platelets, recurrent bacterial and viral Infections, eczema, bloody diarrhoea, gastrointestinal bleeding, WAS protein absent; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.328 WIPF1 Danielle Ariti Deleted their review
Combined Immunodeficiency v0.328 WIPF1 Danielle Ariti reviewed gene: WIPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22231303, 27742395, 11869681, 14757742; Phenotypes: Wiskott-Aldrich syndrome 2 MIM# 614493, Reduced T cells, defective lymphocyte responses to anti-CD3, high IgE, Thrombocytopenia with or without small platelets, recurrent bacterial and viral Infections, eczema, bloody diarrhoea, WAS protein absent; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8835 ALS2 Teresa Zhao gene: ALS2 was added
gene: ALS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALS2 were set to PMID: 30128655; 33409823
Phenotypes for gene: ALS2 were set to Infantile onset ascending spastic paralysis (MIM#607225); Juvenile amyotrophic lateral sclerosis 2 (MIM#205100); Juvenile primary lateral sclerosis (MIM#606353)
Review for gene: ALS2 was set to GREEN
Added comment: >50 variants reported in multiple individuals with Infantile onset ascending spastic paralysis, mostly originated from the Middle East and Mediterranean countries.
Sources: Literature
Combined Immunodeficiency v0.328 TCN2 Danielle Ariti reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32841161, 33023511, 30124850; Phenotypes: Transcobalamin II deficiency MIM# 275350, Decreased Ig levels, Megaloblastic anaemia, pancytopaenia, if untreated (B12) for prolonged periods results in intellectual disability, failure to thrive, diarrhoea, hypogammaglobulinaemia, pallor, hypotonia, respiratory infection; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.328 TAP2 Danielle Ariti reviewed gene: TAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7517574, 9232449, 10560675, 27861817; Phenotypes: Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571, Low CD8, absent MHC I on lymphocytes, Vasculitis, pyoderma gangrenosum, recurrent bacterial/viral respiratory infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Repeat Disorders v0.63 HMNMYO Bryony Thompson Marked STR: HMNMYO as ready
Repeat Disorders v0.63 HMNMYO Bryony Thompson Str: hmnmyo has been classified as Green List (High Evidence).
Repeat Disorders v0.63 HMNMYO Bryony Thompson Classified STR: HMNMYO as Green List (high evidence)
Repeat Disorders v0.63 HMNMYO Bryony Thompson Str: hmnmyo has been classified as Green List (High Evidence).
Repeat Disorders v0.62 HMNMYO Bryony Thompson STR: HMNMYO was added
STR: HMNMYO was added to Repeat Disorders. Sources: Literature
Mode of inheritance for STR: HMNMYO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: HMNMYO were set to 33559681; 33459760
Phenotypes for STR: HMNMYO were set to Neuropathy, hereditary motor, with myopathic features MIM#619216
Review for STR: HMNMYO was set to GREEN
STR: HMNMYO was marked as clinically relevant
Added comment: NM_022834.5(VWA1):c.62_71GCGCGGAGCG[X]
10-bp repeat expansion leading to a loss of function allele, was observed in 14/15 families and was homozygous in 10/15 with a recessive hereditary motor neuropathy.
Normal: 2 repeats
Pathogenic: >=3 repeats (currently only 3 repeats reported)
Sources: Literature
Combined Immunodeficiency v0.328 TAP1 Danielle Ariti reviewed gene: TAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28161407, 10074494, 1473153; Phenotypes: Bare lymphocyte syndrome, type I MIM#604571, Low CD8, absent MHC I on lymphocytes, vasculitis, pyoderma gangrenosum, skin lesions, recurrent respiratory tract infections, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v0.103 RNF220 Zornitza Stark Marked gene: RNF220 as ready
Cardiomyopathy_Paediatric v0.103 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.103 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Cardiomyopathy_Paediatric v0.103 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.102 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Cardiomyopathy_Paediatric. Sources: Literature
founder tags were added to gene: RNF220.
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Deafness_IsolatedAndComplex v1.89 RNF220 Zornitza Stark Marked gene: RNF220 as ready
Deafness_IsolatedAndComplex v1.89 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.89 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.89 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.88 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Deafness_IsolatedAndComplex. Sources: Literature
founder tags were added to gene: RNF220.
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Ataxia v0.291 RNF220 Zornitza Stark Marked gene: RNF220 as ready
Ataxia v0.291 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Ataxia v0.291 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Ataxia v0.291 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Ataxia v0.290 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Ataxia - paediatric. Sources: Literature
founder tags were added to gene: RNF220.
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Leukodystrophy v0.230 RNF220 Zornitza Stark Marked gene: RNF220 as ready
Leukodystrophy v0.230 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Leukodystrophy v0.230 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Leukodystrophy v0.230 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Mendeliome v0.8835 RNF220 Zornitza Stark Tag founder tag was added to gene: RNF220.
Leukodystrophy v0.229 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Leukodystrophy - paediatric. Sources: Literature
founder tags were added to gene: RNF220.
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Mendeliome v0.8835 RNF220 Zornitza Stark Marked gene: RNF220 as ready
Mendeliome v0.8835 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Mendeliome v0.8835 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Mendeliome v0.8835 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Mendeliome v0.8834 RNF220 Zornitza Stark gene: RNF220 was added
gene: RNF220 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Marked gene: RNF220 as ready
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Classified gene: RNF220 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4060 RNF220 Zornitza Stark Gene: rnf220 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4059 RNF220 Konstantinos Varvagiannis changed review comment from: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.

There is currently no associated phenotype in OMIM or G2P. SysID includes RNF220 among the current primary ID genes.
Sources: Literature, Other; to: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.

There is currently no associated phenotype in OMIM or G2P. SysID includes RNF220 among the current primary ID genes.

Consider inclusion in panels for leukodystrophies, childhood onset ataxia, sensorineural hearing loss, corpus callosum anomalies, cardiomyopathies, hepatopathies, etc in all cases with green rating.

Sources: Literature, Other
Intellectual disability syndromic and non-syndromic v0.4059 RNF220 Konstantinos Varvagiannis gene: RNF220 was added
gene: RNF220 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature,Other
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Penetrance for gene: RNF220 were set to Complete
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc :
*RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS)
*The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions.
*Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome.
*Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2).
*RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1.
*Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt.
*Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies.

There is currently no associated phenotype in OMIM or G2P. SysID includes RNF220 among the current primary ID genes.
Sources: Literature, Other
Growth failure v0.167 KMT2D Zornitza Stark changed review comment from: Association with Kabuki syndrome: failure to thrive in infancy and short stature are key features.

Note new association between missense variants located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism.
~10 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability.; to: Association with Kabuki syndrome: failure to thrive in infancy and short stature are key features.

Note new association between missense variants located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism.
~10 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. Extreme short stature reported.
Growth failure v0.167 KMT2D Zornitza Stark Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920 to Kabuki syndrome 1, MIM# 147920; KMT2D-associated neurodevelopmental syndrome
Growth failure v0.166 KMT2D Zornitza Stark Publications for gene: KMT2D were set to 21882399
Growth failure v0.165 KMT2D Zornitza Stark changed review comment from: Failure to thrive in infancy and short stature are key features.; to: Association with Kabuki syndrome: failure to thrive in infancy and short stature are key features.

Note new association between missense variants located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism.
~10 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability.
Growth failure v0.165 KMT2D Zornitza Stark edited their review of gene: KMT2D: Changed publications: 31949313, 32083401, 21882399; Changed phenotypes: Kabuki syndrome 1, MIM# 147920, KMT2D-associated neurodevelopmental syndrome
Growth failure v0.165 KMT2D Zornitza Stark Publications for gene: KMT2D were set to
Growth failure v0.164 KMT2D Zornitza Stark edited their review of gene: KMT2D: Changed publications: 21882399
Growth failure v0.164 KMT2D Zornitza Stark Marked gene: KMT2D as ready
Growth failure v0.164 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Growth failure v0.164 KMT2D Zornitza Stark Phenotypes for gene: KMT2D were changed from Kabuki to Kabuki syndrome 1, MIM# 147920
Growth failure v0.163 KMT2D Zornitza Stark Classified gene: KMT2D as Green List (high evidence)
Growth failure v0.163 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Growth failure v0.162 KMT2D Zornitza Stark reviewed gene: KMT2D: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Kabuki syndrome 1, MIM# 147920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.162 CDT1 Zornitza Stark Marked gene: CDT1 as ready
Growth failure v0.162 CDT1 Zornitza Stark Gene: cdt1 has been classified as Green List (High Evidence).
Growth failure v0.162 CDT1 Zornitza Stark Phenotypes for gene: CDT1 were changed from Meier-Gorlin syndrome 4, 613804; micrognathia, microtia, patellar hypoplasia/aplasia, mammary hypoplasia; Meier-Gorlin to Meier-Gorlin syndrome 4, MIM# 613804; MONDO:0013431
Growth failure v0.161 CDT1 Zornitza Stark Publications for gene: CDT1 were set to 21358632
Growth failure v0.160 CDT1 Zornitza Stark Classified gene: CDT1 as Green List (high evidence)
Growth failure v0.160 CDT1 Zornitza Stark Gene: cdt1 has been classified as Green List (High Evidence).
Growth failure v0.159 CDT1 Zornitza Stark reviewed gene: CDT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21358632, 21358631, 33338304, 22333897; Phenotypes: Meier-Gorlin syndrome 4, MIM# 613804, MONDO:0013431; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.159 CHD7 Zornitza Stark Marked gene: CHD7 as ready
Growth failure v0.159 CHD7 Zornitza Stark Gene: chd7 has been classified as Green List (High Evidence).
Growth failure v0.159 CHD7 Zornitza Stark Phenotypes for gene: CHD7 were changed from CHARGE syndrome, 214800; CHARGE syndrome - ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation to CHARGE syndrome, MIM# 214800
Growth failure v0.158 CHD7 Zornitza Stark Classified gene: CHD7 as Green List (high evidence)
Growth failure v0.158 CHD7 Zornitza Stark Gene: chd7 has been classified as Green List (High Evidence).
Growth failure v0.157 CHD7 Zornitza Stark reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: CHARGE syndrome, MIM# 214800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.157 ATRIP Zornitza Stark Marked gene: ATRIP as ready
Growth failure v0.157 ATRIP Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence).
Growth failure v0.157 ATRIP Zornitza Stark Phenotypes for gene: ATRIP were changed from microcephaly, micrognathia, small ear lobes, dental crowding to Seckel-like syndrome
Growth failure v0.156 ATRIP Zornitza Stark reviewed gene: ATRIP: Rating: RED; Mode of pathogenicity: None; Publications: 23144622; Phenotypes: Seckel syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.156 PLK4 Zornitza Stark Marked gene: PLK4 as ready
Growth failure v0.156 PLK4 Zornitza Stark Gene: plk4 has been classified as Green List (High Evidence).
Growth failure v0.156 PLK4 Zornitza Stark Phenotypes for gene: PLK4 were changed from microcephaly and chorioretinopathy 2, MONDO:0014516; Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171 to Microcephaly and chorioretinopathy 2, MONDO:0014516; Microcephaly and chorioretinopathy, autosomal recessive, 2, #MIM:616171
Growth failure v0.155 PLK4 Zornitza Stark Classified gene: PLK4 as Green List (high evidence)
Growth failure v0.155 PLK4 Zornitza Stark Gene: plk4 has been classified as Green List (High Evidence).
Growth failure v0.154 PLK4 Zornitza Stark reviewed gene: PLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25344692, 25320347, 27650967; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.154 Zornitza Stark Panel types changed to Rare Disease
Growth failure v0.153 RNPC3 Zornitza Stark Marked gene: RNPC3 as ready
Growth failure v0.153 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Growth failure v0.153 RNPC3 Zornitza Stark Phenotypes for gene: RNPC3 were changed from ?Growth hormone deficiency, isolated, type V, 618160; isolated growth hormone deficiency to Growth hormone deficiency
Growth failure v0.152 RNPC3 Zornitza Stark reviewed gene: RNPC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29866761, 32462814; Phenotypes: Growth hormone deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.152 RAP1B Zornitza Stark edited their review of gene: RAP1B: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.152 RAP1B Zornitza Stark Marked gene: RAP1B as ready
Growth failure v0.152 RAP1B Zornitza Stark Gene: rap1b has been classified as Amber List (Moderate Evidence).
Growth failure v0.152 RAP1B Zornitza Stark Phenotypes for gene: RAP1B were changed from short stature; Syndromic intellectual disability to Syndromic intellectual disability; short stature
Growth failure v0.151 RAP1B Zornitza Stark reviewed gene: RAP1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 32627184, 26280580; Phenotypes: Syndromic intellectual disability, short stature; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.151 CDC6 Zornitza Stark Marked gene: CDC6 as ready
Growth failure v0.151 CDC6 Zornitza Stark Gene: cdc6 has been classified as Red List (Low Evidence).
Growth failure v0.151 CDC6 Zornitza Stark Phenotypes for gene: CDC6 were changed from patellar hypoplasia/aplasia, microtia, meier-gorlin syndrome, mammary hypoplasia; ?Meier-Gorlin syndrome 5, 613805 to Meier-Gorlin syndrome 5 (MIM#613805)
Growth failure v0.150 CDC6 Zornitza Stark reviewed gene: CDC6: Rating: RED; Mode of pathogenicity: None; Publications: 21358632; Phenotypes: Meier-Gorlin syndrome 5 (MIM#613805); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.149 HDAC8 Zornitza Stark Marked gene: HDAC8 as ready
Growth failure v0.149 HDAC8 Zornitza Stark Gene: hdac8 has been classified as Green List (High Evidence).
Growth failure v0.149 HDAC8 Zornitza Stark Phenotypes for gene: HDAC8 were changed from Cornelia De Lange to Cornelia de Lange syndrome 5, MIM# 300882
Growth failure v0.148 HDAC8 Zornitza Stark Publications for gene: HDAC8 were set to
Growth failure v0.147 HDAC8 Zornitza Stark Classified gene: HDAC8 as Green List (high evidence)
Growth failure v0.147 HDAC8 Zornitza Stark Gene: hdac8 has been classified as Green List (High Evidence).
Growth failure v0.146 HDAC8 Zornitza Stark reviewed gene: HDAC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 30614194, 24403048; Phenotypes: Cornelia de Lange syndrome 5, MIM# 300882; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Growth failure v0.146 NLRP2 Zornitza Stark edited their review of gene: NLRP2: Changed publications: 30877238, 33090377, 29574422, 26323243, 19300480
Growth failure v0.146 NLRP2 Zornitza Stark Marked gene: NLRP2 as ready
Growth failure v0.146 NLRP2 Zornitza Stark Gene: nlrp2 has been classified as Amber List (Moderate Evidence).
Growth failure v0.146 NLRP2 Zornitza Stark Mode of inheritance for gene: NLRP2 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to Other
Growth failure v0.145 NLRP2 Zornitza Stark reviewed gene: NLRP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29574422; Phenotypes: IUGR; Mode of inheritance: Other
Growth failure v0.145 NHLRC2 Zornitza Stark Marked gene: NHLRC2 as ready
Growth failure v0.145 NHLRC2 Zornitza Stark Gene: nhlrc2 has been classified as Green List (High Evidence).
Growth failure v0.145 NHLRC2 Zornitza Stark Phenotypes for gene: NHLRC2 were changed from FINCA syndrome OMIM:618278 to Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome MIM#618278
Growth failure v0.144 NHLRC2 Zornitza Stark Classified gene: NHLRC2 as Green List (high evidence)
Growth failure v0.144 NHLRC2 Zornitza Stark Gene: nhlrc2 has been classified as Green List (High Evidence).
Growth failure v0.143 NHLRC2 Zornitza Stark reviewed gene: NHLRC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29423877, 32435055; Phenotypes: Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome MIM#618278; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.143 NBAS Zornitza Stark Marked gene: NBAS as ready
Growth failure v0.143 NBAS Zornitza Stark Gene: nbas has been classified as Green List (High Evidence).
Mendeliome v0.8833 NBAS Zornitza Stark Marked gene: NBAS as ready
Mendeliome v0.8833 NBAS Zornitza Stark Gene: nbas has been classified as Green List (High Evidence).
Mendeliome v0.8833 NBAS Zornitza Stark Phenotypes for gene: NBAS were changed from to Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800; Infantile liver failure syndrome 2, MIM# 616483
Mendeliome v0.8832 NBAS Zornitza Stark Publications for gene: NBAS were set to
Mendeliome v0.8831 NBAS Zornitza Stark Mode of inheritance for gene: NBAS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8830 NBAS Zornitza Stark reviewed gene: NBAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31761904; Phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, Infantile liver failure syndrome 2, MIM# 616483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.143 NBAS Zornitza Stark Marked gene: NBAS as ready
Growth failure v0.143 NBAS Zornitza Stark Gene: nbas has been classified as Green List (High Evidence).
Growth failure v0.143 NBAS Zornitza Stark Phenotypes for gene: NBAS were changed from Short stature, optic nerve atrophy, and Pelger-Huet anomaly, 614800 to Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800
Growth failure v0.142 NBAS Zornitza Stark Publications for gene: NBAS were set to 31761904
Growth failure v0.141 NBAS Zornitza Stark changed review comment from: Founder mutation in Yakut population but also reported in other ethnicities. Short stature is a feature.

Note bi-allelic variants in this gene also cause infantile liver failure syndrome, MIM#616483.; to: Founder mutation in Yakut population but also reported in other ethnicities. Short stature is a feature.

Note bi-allelic variants in this gene also cause infantile liver failure syndrome, MIM#616483. Clinical features are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH)
Growth failure v0.141 NBAS Zornitza Stark Classified gene: NBAS as Green List (high evidence)
Growth failure v0.141 NBAS Zornitza Stark Gene: nbas has been classified as Green List (High Evidence).
Growth failure v0.140 NBAS Zornitza Stark reviewed gene: NBAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 20577004, 26286438; Phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.140 MTX2 Zornitza Stark Marked gene: MTX2 as ready
Growth failure v0.140 MTX2 Zornitza Stark Gene: mtx2 has been classified as Green List (High Evidence).
Growth failure v0.140 MTX2 Zornitza Stark Classified gene: MTX2 as Green List (high evidence)
Growth failure v0.140 MTX2 Zornitza Stark Gene: mtx2 has been classified as Green List (High Evidence).
Growth failure v0.139 MTX2 Zornitza Stark reviewed gene: MTX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32917887; Phenotypes: Mandibuloacral dysplasia progeroid syndrome, MIM# 619127, Mandibuloacral dysplasia, lipodystrophy, arterial calcification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Repeat Disorders v0.61 SCA8 Bryony Thompson Marked STR: SCA8 as ready
Repeat Disorders v0.61 SCA8 Bryony Thompson Str: sca8 has been classified as Green List (High Evidence).
Repeat Disorders v0.61 SCA8 Bryony Thompson Classified STR: SCA8 as Green List (high evidence)
Repeat Disorders v0.61 SCA8 Bryony Thompson Str: sca8 has been classified as Green List (High Evidence).
Repeat Disorders v0.60 SCA8 Bryony Thompson STR: SCA8 was added
STR: SCA8 was added to Repeat Disorders. Sources: Expert list
Mode of inheritance for STR: SCA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA8 were set to 20301445
Phenotypes for STR: SCA8 were set to Spinocerebellar ataxia 8 MIM#608768
Review for STR: SCA8 was set to GREEN
STR: SCA8 was marked as clinically relevant
Added comment: NR_002717.2:n.1073CTA[X]1103CTG[X]
ATXN8 (CAG)n(TAG)n vs ATXN8OS on opposite strand (CTA)n(CTG)n
Both toxic RNA and toxic protein gain of function mechanisms likely contribute to disease mechanism
Normal alleles: 15-50 combined (CTA·TAG)n(CTG·CAG)n repeats
Alleles of questionable significance: 50-70 repeats.
Reduced penetrance allele size: found for (CTA·TAG)n(CTG·CAG)n repeats of all sizes
Higher penetrance allele size: ≥80 (CTA·TAG)n(CTG·CAG)n repeats most often seen in individuals with ataxia; however, repeat sizes ranging from 71 to more than 1300 repeats have been found both in individuals who develop ataxia and in those who do not.
Sources: Expert list
Repeat Disorders v0.59 FXPOI Bryony Thompson Marked STR: FXPOI as ready
Repeat Disorders v0.59 FXPOI Bryony Thompson Str: fxpoi has been classified as Green List (High Evidence).
Repeat Disorders v0.59 FXPOI Bryony Thompson Classified STR: FXPOI as Green List (high evidence)
Repeat Disorders v0.59 FXPOI Bryony Thompson Str: fxpoi has been classified as Green List (High Evidence).
Repeat Disorders v0.58 FXPOI Bryony Thompson STR: FXPOI was added
STR: FXPOI was added to Repeat Disorders. Sources: Expert list
Mode of inheritance for STR: FXPOI 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 STR: FXPOI were set to 20301558
Phenotypes for STR: FXPOI were set to Premature ovarian failure 1 MIM#311360
Review for STR: FXPOI was set to GREEN
STR: FXPOI was marked as clinically relevant
Added comment: HGVS nomenclature - NM_002024.5:c.-129_-127CGG[X]
RNA-mediated toxicity may result in the POI phenotype, whereas loss of function through methylation silencing of FMR1 is associated with the FXS phenotype.
Intermediate (grey zone, inconclusive, borderline): ~45 to ~54 repeats
Premutation - risk of FXPOI: ~55 to ~200 repeats
Full mutation - fragile X syndrome (FXS): >200 repeats
It is estimated that 21% of women who carry a premutation develop FXPOI. The association between repeat size of the premutation allele and FXPOI is nonlinear; women with 80-99 repeats are at greatest risk for FXPOI.
Sources: Expert list
Repeat Disorders v0.57 EPM1 Bryony Thompson Marked STR: EPM1 as ready
Repeat Disorders v0.57 EPM1 Bryony Thompson Str: epm1 has been classified as Green List (High Evidence).
Repeat Disorders v0.57 EPM1 Bryony Thompson Classified STR: EPM1 as Green List (high evidence)
Repeat Disorders v0.57 EPM1 Bryony Thompson Str: epm1 has been classified as Green List (High Evidence).
Repeat Disorders v0.56 EPM1 Bryony Thompson STR: EPM1 was added
STR: EPM1 was added to Repeat Disorders. Sources: Expert list
Mode of inheritance for STR: EPM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: EPM1 were set to 29325606; 20301321
Phenotypes for STR: EPM1 were set to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM#254800
Review for STR: EPM1 was set to GREEN
STR: EPM1 was marked as clinically relevant
Added comment: NM_000100​.4:c.-179CCCCGCCCCGCG[X]
Loss of function, other disease-associated variants can cause loss of function too. Ataxia age of onset usually occurs a couple of years after PME.
Normal: 2-3 dodecamer repeats
Uncertain significance: 12-17 dodecamer repeats (unstable, but not clinically characterized)
Pathogenic (full penetrance): ≥30 dodecamer repeats
Sources: Expert list
Repeat Disorders v0.55 FRDA Bryony Thompson Marked STR: FRDA as ready
Repeat Disorders v0.55 FRDA Bryony Thompson Str: frda has been classified as Green List (High Evidence).
Repeat Disorders v0.55 FRDA Bryony Thompson Classified STR: FRDA as Green List (high evidence)
Repeat Disorders v0.55 FRDA Bryony Thompson Str: frda has been classified as Green List (High Evidence).
Repeat Disorders v0.54 FRDA Bryony Thompson STR: FRDA was added
STR: FRDA was added to Repeat Disorders. Sources: Expert list
Mode of inheritance for STR: FRDA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: FRDA were set to 20301458
Phenotypes for STR: FRDA were set to Friedreich ataxia MIM#229300
Review for STR: FRDA was set to GREEN
STR: FRDA was marked as clinically relevant
Added comment: NM_000144.4:c.165+1340GAA[X]
Loss of function is the mechanism of disease
Normal: 5-33 repeats
Mutable normal (premutation): 34-65 repeats
Borderline: 44-66 repeats
Full-penetrance: ≥66 repeats
Sources: Expert list
Repeat Disorders v0.53 FRAXE Bryony Thompson Marked STR: FRAXE as ready
Repeat Disorders v0.53 FRAXE Bryony Thompson Str: fraxe has been classified as Green List (High Evidence).
Repeat Disorders v0.53 FRAXE Bryony Thompson Classified STR: FRAXE as Green List (high evidence)
Repeat Disorders v0.53 FRAXE Bryony Thompson Str: fraxe has been classified as Green List (High Evidence).
Repeat Disorders v0.52 FRAXE Bryony Thompson STR: FRAXE was added
STR: FRAXE was added to Repeat Disorders. Sources: Expert list
Mode of inheritance for STR: FRAXE was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for STR: FRAXE were set to 8334699; 8673085; 11388762
Phenotypes for STR: FRAXE were set to Intellectual developmental disorder, X-linked 109 MIM#309548
Review for STR: FRAXE was set to GREEN
STR: FRAXE was marked as clinically relevant
Added comment: NM_001169122.1(AFF2):c.-460_-458GCC(6_25)
Loss of function through methylation silencing is the mechanism of disease
Normal - 5-44 repeats
Inconclusive - 45-54 repeats
Premutation - 55-200 repeats
Abnormal - >200 or >230 repeats
Sources: Expert list
Mendeliome v0.8830 ARF3 Zornitza Stark Marked gene: ARF3 as ready
Mendeliome v0.8830 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8830 ARF3 Zornitza Stark Classified gene: ARF3 as Amber List (moderate evidence)
Mendeliome v0.8830 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8829 ARF3 Zornitza Stark gene: ARF3 was added
gene: ARF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Review for gene: ARF3 was set to AMBER
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

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

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

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

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

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

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

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

Evidence to support the effect of each variant include:

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

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

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Marked gene: ARF3 as ready
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Classified gene: ARF3 as Amber List (moderate evidence)
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4059 ARF3 Zornitza Stark Classified gene: ARF3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4059 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4058 ARF3 Zornitza Stark reviewed gene: ARF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic Epilepsy v0.1169 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: ARF3 were set to unknown
Review for gene: ARF3 was set to AMBER
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

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

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

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

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

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

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

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

Evidence to support the effect of each variant include:

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

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

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4058 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: ARF3 were set to unknown
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

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

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

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

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

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

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

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

Evidence to support the effect of each variant include:

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

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

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Repeat Disorders v0.51 DM1 Bryony Thompson Marked STR: DM1 as ready
Repeat Disorders v0.51 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Repeat Disorders v0.51 DM1 Bryony Thompson Classified STR: DM1 as Green List (high evidence)
Repeat Disorders v0.51 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Repeat Disorders v0.50 DM1 Bryony Thompson STR: DM1 was added
STR: DM1 was added to Repeat Disorders. Sources: Expert list
Mode of inheritance for STR: DM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM1 were set to 20301344; 29325606
Phenotypes for STR: DM1 were set to Myotonic dystrophy 1 MIM#160900
Review for STR: DM1 was set to GREEN
STR: DM1 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_001081560.2:c.*224_*226CTG[X]
RNA toxic gain of function is mechanism of disease
Premutation: 35-49 repeats, no clinical signs
Mild: 50-~150 repeats, age of onset 20-70 yrs, clinical signs - cataracts, mild myotonia
Classic: ~100-~1,000 repeats, age of onset 10-30 yrs, clinical signs - weakness, myotonia, cataracts, balding, cardiac arrhythmia
Congenital: >1,000 repeats, age of onset birth-10 yrs , clinical signs - infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adults
Sources: Expert list
Repeat Disorders v0.49 FXS Bryony Thompson Marked STR: FXS as ready
Repeat Disorders v0.49 FXS Bryony Thompson Str: fxs has been classified as Green List (High Evidence).
Repeat Disorders v0.49 FXS Bryony Thompson Classified STR: FXS as Green List (high evidence)
Repeat Disorders v0.49 FXS Bryony Thompson Str: fxs has been classified as Green List (High Evidence).
Repeat Disorders v0.48 FXS Bryony Thompson STR: FXS was added
STR: FXS was added to Repeat Disorders. Sources: Expert list
Mode of inheritance for STR: FXS 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 STR: FXS were set to 33795824; 25227148
Phenotypes for STR: FXS were set to Fragile X syndrome MIM#300624
Review for STR: FXS was set to GREEN
STR: FXS was marked as clinically relevant
Added comment: HGVS nomenclature - NM_002024.5:c.-129_-127CGG[X]
Loss of function through methylation silencing of FMR1 is associated with the FXS phenotype. Intermediate (gray zone, inconclusive, borderline): ~45 to ~54 repeats
Premutation - risk of FXTAS: ~55 to ~200 repeats
Full mutation - fragile X syndrome (FXS): >200
Sources: Expert list
Growth failure v0.139 KDM3B Zornitza Stark Phenotypes for gene: KDM3B were changed from Intellectual disability; short stature to Diets-Jongmans syndrome, MIM# 618846; Intellectual disability; short stature; deafness
Growth failure v0.138 KDM3B Zornitza Stark edited their review of gene: KDM3B: Changed phenotypes: Diets-Jongmans syndrome, MIM# 618846, Intellectual disability, short stature, deafness
Growth failure v0.138 KDM3B Zornitza Stark Marked gene: KDM3B as ready
Growth failure v0.138 KDM3B Zornitza Stark Gene: kdm3b has been classified as Green List (High Evidence).
Growth failure v0.138 KDM3B Zornitza Stark Phenotypes for gene: KDM3B were changed from Behavioral abnormality; Seizures; Global developmental delay; Short stature; Intellectual disability to Intellectual disability; short stature
Growth failure v0.137 KDM3B Zornitza Stark Mode of inheritance for gene: KDM3B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.136 KDM3B Zornitza Stark Classified gene: KDM3B as Green List (high evidence)
Growth failure v0.136 KDM3B Zornitza Stark Gene: kdm3b has been classified as Green List (High Evidence).
Growth failure v0.135 KDM3B Zornitza Stark reviewed gene: KDM3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30929739; Phenotypes: Intellectual disability, short stature; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.135 INTS1 Zornitza Stark Marked gene: INTS1 as ready
Growth failure v0.135 INTS1 Zornitza Stark Gene: ints1 has been classified as Green List (High Evidence).
Growth failure v0.135 INTS1 Zornitza Stark Classified gene: INTS1 as Green List (high evidence)
Growth failure v0.135 INTS1 Zornitza Stark Gene: ints1 has been classified as Green List (High Evidence).
Growth failure v0.134 INTS1 Zornitza Stark reviewed gene: INTS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28542170, 30622326, 31428919; Phenotypes: Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, #MIM:618571, MONDO:0032817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.134 FOXP4 Zornitza Stark Marked gene: FOXP4 as ready
Growth failure v0.134 FOXP4 Zornitza Stark Gene: foxp4 has been classified as Green List (High Evidence).
Growth failure v0.134 FOXP4 Zornitza Stark Phenotypes for gene: FOXP4 were changed from Neurodevelopmental disorder; multiple congenital abnormalities to Neurodevelopmental disorder; multiple congenital abnormalities; short stature
Growth failure v0.133 FOXP4 Zornitza Stark Mode of inheritance for gene: FOXP4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.132 FOXP4 Zornitza Stark Classified gene: FOXP4 as Green List (high evidence)
Growth failure v0.132 FOXP4 Zornitza Stark Gene: foxp4 has been classified as Green List (High Evidence).
Growth failure v0.131 FOXP4 Zornitza Stark reviewed gene: FOXP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33110267; Phenotypes: Neurodevelopmental disorder, multiple congenital abnormalities, short stature; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.131 COG4 Zornitza Stark Marked gene: COG4 as ready
Growth failure v0.131 COG4 Zornitza Stark Gene: cog4 has been classified as Green List (High Evidence).
Growth failure v0.131 COG4 Zornitza Stark Phenotypes for gene: COG4 were changed from microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407; Saul-Wilson syndrome, OMIM:618150 to Saul-Wilson syndrome, OMIM:618150; Microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Growth failure v0.130 COG4 Zornitza Stark Classified gene: COG4 as Green List (high evidence)
Growth failure v0.130 COG4 Zornitza Stark Gene: cog4 has been classified as Green List (High Evidence).
Growth failure v0.129 COG4 Zornitza Stark edited their review of gene: COG4: Changed mode of pathogenicity: Other
Growth failure v0.129 COG4 Zornitza Stark changed review comment from: 14 individuals reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like). All have a recurrent de novo heterozygous missense variant (p.Gly516Arg).

Please note bi-allelic variants cause CDG.; to: 14 individuals reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like). All have a recurrent de novo heterozygous missense variant (p.Gly516Arg). GoF suggested.

Please note bi-allelic variants cause CDG.
Growth failure v0.129 COG4 Zornitza Stark reviewed gene: COG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30290151; Phenotypes: Saul-Wilson syndrome, OMIM:618150, Microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.129 TRIP13 Zornitza Stark Marked gene: TRIP13 as ready
Growth failure v0.129 TRIP13 Zornitza Stark Gene: trip13 has been classified as Amber List (Moderate Evidence).
Growth failure v0.129 TRIP13 Zornitza Stark Classified gene: TRIP13 as Amber List (moderate evidence)
Growth failure v0.129 TRIP13 Zornitza Stark Gene: trip13 has been classified as Amber List (Moderate Evidence).
Growth failure v0.128 TRIP13 Zornitza Stark gene: TRIP13 was added
gene: TRIP13 was added to Growth failure in early childhood. Sources: Expert Review
Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIP13 were set to 28553959
Phenotypes for gene: TRIP13 were set to Mosaic variegated aneuploidy syndrome 3, MIM# 617598
Review for gene: TRIP13 was set to AMBER
Added comment: Autosomal recessive disorder resulting from errors in chromosome segregation. Most affected individuals develop early-onset Wilms tumor and show either aneuploidy or premature chromatid separation in cells. Some patients may have additional developmental features, such as microcephaly, growth retardation, or developmental delay.

6 unrelated families reported, but 5 shared the same homozygous stop variant, p.Arg354X, suggestive of founder effect.
Sources: Expert Review
Growth failure v0.127 BUB1B Zornitza Stark Marked gene: BUB1B as ready
Growth failure v0.127 BUB1B Zornitza Stark Gene: bub1b has been classified as Green List (High Evidence).
Growth failure v0.127 BUB1B Zornitza Stark Classified gene: BUB1B as Green List (high evidence)
Growth failure v0.127 BUB1B Zornitza Stark Gene: bub1b has been classified as Green List (High Evidence).
Growth failure v0.126 BUB1B Zornitza Stark gene: BUB1B was added
gene: BUB1B was added to Growth failure in early childhood. Sources: Expert Review
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1B were set to 18548531
Phenotypes for gene: BUB1B were set to Mosaic variegated aneuploidy syndrome 1, MIM#257300
Review for gene: BUB1B was set to GREEN
Added comment: Mosaic Variegated Aneuploidy Syndrome (MVA) is a rare autosomal recessive disorder characterized by mosaic aneuploidies involving multiple chromosomes and tissues. Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy.

More than 10 families reported.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4058 CEP57 Zornitza Stark Marked gene: CEP57 as ready
Intellectual disability syndromic and non-syndromic v0.4058 CEP57 Zornitza Stark Gene: cep57 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4058 CEP57 Zornitza Stark Phenotypes for gene: CEP57 were changed from to Mosaic variegated aneuploidy syndrome 2, #MIM 614114
Intellectual disability syndromic and non-syndromic v0.4057 CEP57 Zornitza Stark Publications for gene: CEP57 were set to
Intellectual disability syndromic and non-syndromic v0.4056 CEP57 Zornitza Stark Mode of inheritance for gene: CEP57 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4055 CEP57 Zornitza Stark reviewed gene: CEP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 24259107, 21552266, 32861809, 30147898; Phenotypes: Mosaic variegated aneuploidy syndrome 2, #MIM 614114; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8828 CEP57 Zornitza Stark Marked gene: CEP57 as ready
Mendeliome v0.8828 CEP57 Zornitza Stark Gene: cep57 has been classified as Green List (High Evidence).
Mendeliome v0.8828 CEP57 Zornitza Stark Phenotypes for gene: CEP57 were changed from to Mosaic variegated aneuploidy syndrome 2, #MIM 614114
Mendeliome v0.8827 CEP57 Zornitza Stark Publications for gene: CEP57 were set to
Mendeliome v0.8826 CEP57 Zornitza Stark Mode of inheritance for gene: CEP57 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8825 CEP57 Zornitza Stark reviewed gene: CEP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 24259107, 21552266, 32861809, 30147898; Phenotypes: Mosaic variegated aneuploidy syndrome 2, #MIM 614114; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.125 CEP57 Zornitza Stark edited their review of gene: CEP57: Changed publications: 24259107, 21552266, 32861809, 30147898
Growth failure v0.125 CEP57 Zornitza Stark Marked gene: CEP57 as ready
Growth failure v0.125 CEP57 Zornitza Stark Gene: cep57 has been classified as Green List (High Evidence).
Growth failure v0.125 CEP57 Zornitza Stark Classified gene: CEP57 as Green List (high evidence)
Growth failure v0.125 CEP57 Zornitza Stark Gene: cep57 has been classified as Green List (High Evidence).
Growth failure v0.124 CEP57 Zornitza Stark Phenotypes for gene: CEP57 were changed from Mosaic variegated aneuploidy syndrome 2, 614114 to Mosaic variegated aneuploidy syndrome 2, MIM#614114
Growth failure v0.123 CEP57 Zornitza Stark Publications for gene: CEP57 were set to 24259107; 21552266
Growth failure v0.122 CEP57 Zornitza Stark Deleted their comment
Growth failure v0.122 CEP57 Zornitza Stark edited their review of gene: CEP57: Added comment: Mosaic Variegated Aneuploidy Syndrome (MVA) is a rare autosomal recessive disorder characterized by mosaic aneuploidies involving multiple chromosomes and tissues. Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy.; Changed publications: 24259107, 21552266, 32861809
Growth failure v0.122 CEP57 Zornitza Stark reviewed gene: CEP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 24259107, 21552266; Phenotypes: Mosaic variegated aneuploidy syndrome 2, #MIM 614114; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.122 Zornitza Stark removed gene:CCDC186 from the panel
Growth failure v0.121 ANAPC1 Zornitza Stark Marked gene: ANAPC1 as ready
Growth failure v0.121 ANAPC1 Zornitza Stark Gene: anapc1 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.55 ANAPC1 Zornitza Stark Phenotypes for gene: ANAPC1 were changed from Rothmund-Thomson syndrome, type 1 MIM#618625 to Rothmund-Thomson syndrome, type 1 MIM#618625; MONDO:0016368
Ectodermal Dysplasia v0.54 ANAPC1 Zornitza Stark Tag deep intronic tag was added to gene: ANAPC1.
Ectodermal Dysplasia v0.54 ANAPC1 Zornitza Stark reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund Thomson syndrome type 1, #MIM:618625, MONDO:0016368; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.121 ANAPC1 Zornitza Stark Tag deep intronic tag was added to gene: ANAPC1.
Growth failure v0.121 ANAPC1 Zornitza Stark Classified gene: ANAPC1 as Green List (high evidence)
Growth failure v0.121 ANAPC1 Zornitza Stark Gene: anapc1 has been classified as Green List (High Evidence).
Growth failure v0.120 ANAPC1 Zornitza Stark reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome, type 1, MIM# 618625; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.120 FANCM Zornitza Stark Marked gene: FANCM as ready
Growth failure v0.120 FANCM Zornitza Stark Gene: fancm has been classified as Red List (Low Evidence).
Growth failure v0.120 FANCM Zornitza Stark Phenotypes for gene: FANCM were changed from Fanconi anemia, complementation group M, 614087; Fanconi anemia; Fanconi Anemia to Fanconi anaemia
Growth failure v0.119 SMC3 Zornitza Stark Marked gene: SMC3 as ready
Growth failure v0.119 SMC3 Zornitza Stark Gene: smc3 has been classified as Green List (High Evidence).
Growth failure v0.119 SMC3 Zornitza Stark Phenotypes for gene: SMC3 were changed from Cornelia De Lange to Cornelia de Lange syndrome 3, MIM# 610759
Growth failure v0.118 SMC3 Zornitza Stark Publications for gene: SMC3 were set to
Growth failure v0.117 SMC3 Zornitza Stark Classified gene: SMC3 as Green List (high evidence)
Growth failure v0.117 SMC3 Zornitza Stark Gene: smc3 has been classified as Green List (High Evidence).
Growth failure v0.116 SMC3 Zornitza Stark reviewed gene: SMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25125236, 25655089; Phenotypes: Cornelia de Lange syndrome 3, MIM# 610759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.116 SOX3 Zornitza Stark Marked gene: SOX3 as ready
Growth failure v0.116 SOX3 Zornitza Stark Gene: sox3 has been classified as Red List (Low Evidence).
Growth failure v0.116 SOX3 Zornitza Stark Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked, OMIM:312000; Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Panhypopituitarism, X-linked, MONDO:0010712; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252 to Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123; Panhypopituitarism, X-linked, MIM#312000
Growth failure v0.115 SOX3 Zornitza Stark Publications for gene: SOX3 were set to 15800844
Growth failure v0.114 SOX3 Zornitza Stark Mode of inheritance for gene: SOX3 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
Growth failure v0.113 SOX3 Zornitza Stark Tag SV/CNV tag was added to gene: SOX3.
Growth failure v0.113 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: RED; Mode of pathogenicity: None; Publications: 29175558, 30125608, 12428212, 15800844; Phenotypes: Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123, Panhypopituitarism, X-linked, MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Growth failure v0.113 SOX2 Zornitza Stark Marked gene: SOX2 as ready
Growth failure v0.113 SOX2 Zornitza Stark Gene: sox2 has been classified as Green List (High Evidence).
Growth failure v0.113 SOX2 Zornitza Stark Phenotypes for gene: SOX2 were changed from to Microphthalmia, syndromic 3, MIM# 206900
Growth failure v0.112 SOX2 Zornitza Stark Publications for gene: SOX2 were set to
Growth failure v0.111 SOX2 Zornitza Stark Classified gene: SOX2 as Green List (high evidence)
Growth failure v0.111 SOX2 Zornitza Stark Gene: sox2 has been classified as Green List (High Evidence).
Growth failure v0.110 SOX2 Zornitza Stark reviewed gene: SOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15812812, 16543359, 16932809,; Phenotypes: Microphthalmia, syndromic 3, MIM# 206900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.110 ERCC8 Zornitza Stark edited their review of gene: ERCC8: Changed phenotypes: Cockayne syndrome, type A, MIM# 216400, MONDO:0019569
Growth failure v0.110 ERCC8 Zornitza Stark Marked gene: ERCC8 as ready
Growth failure v0.110 ERCC8 Zornitza Stark Gene: ercc8 has been classified as Green List (High Evidence).
Growth failure v0.110 ERCC8 Zornitza Stark Phenotypes for gene: ERCC8 were changed from cockayne to Cockayne syndrome, type A, MIM# 216400; MONDO:0019569
Growth failure v0.109 ERCC8 Zornitza Stark Publications for gene: ERCC8 were set to
Growth failure v0.108 ERCC8 Zornitza Stark Classified gene: ERCC8 as Green List (high evidence)
Growth failure v0.108 ERCC8 Zornitza Stark Gene: ercc8 has been classified as Green List (High Evidence).
Growth failure v0.107 ERCC6 Zornitza Stark Marked gene: ERCC6 as ready
Growth failure v0.107 ERCC6 Zornitza Stark Gene: ercc6 has been classified as Green List (High Evidence).
Growth failure v0.107 ERCC6 Zornitza Stark Phenotypes for gene: ERCC6 were changed from Cockayne syndrome, type B, 133540 to Cerebrooculofacioskeletal syndrome 1, MIM# 214150; MONDO:0008955; Cockayne syndrome, type B, MIM# 133540; MONDO:0019570
Growth failure v0.106 ERCC6 Zornitza Stark changed review comment from: Well established gene-disease association, spectrum of severity.; to: Well established gene-disease association, spectrum of severity. Marked short stature is a feature.
Growth failure v0.106 ERCC6 Zornitza Stark edited their review of gene: ERCC6: Changed phenotypes: Cerebrooculofacioskeletal syndrome 1, MIM# 214150, MONDO:0008955, Cockayne syndrome, type B, MIM# 133540, MONDO:0019570
Growth failure v0.106 ERCC6 Zornitza Stark Classified gene: ERCC6 as Green List (high evidence)
Growth failure v0.106 ERCC6 Zornitza Stark Gene: ercc6 has been classified as Green List (High Evidence).
Growth failure v0.105 LIG4 Zornitza Stark Marked gene: LIG4 as ready
Growth failure v0.105 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Growth failure v0.105 LIG4 Zornitza Stark Phenotypes for gene: LIG4 were changed from microcephaly, growth retardation, immunodeficiency, developmental delay to LIG4 syndrome, MIM# 606593; microcephaly, growth retardation, immunodeficiency, developmental delay
Growth failure v0.104 LIG4 Zornitza Stark Publications for gene: LIG4 were set to 11779494, 16088910,
Growth failure v0.103 LIG4 Zornitza Stark Classified gene: LIG4 as Green List (high evidence)
Growth failure v0.103 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Growth failure v0.102 STAT5B Zornitza Stark Marked gene: STAT5B as ready
Growth failure v0.102 STAT5B Zornitza Stark Gene: stat5b has been classified as Green List (High Evidence).
Growth failure v0.102 STAT5B Zornitza Stark Phenotypes for gene: STAT5B were changed from to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, MIM# 245590; Growth hormone insensitivity with immune dysregulation 2, autosomal dominant, MIM# 618985
Growth failure v0.101 STAT5B Zornitza Stark Publications for gene: STAT5B were set to
Growth failure v0.100 STAT5B Zornitza Stark Classified gene: STAT5B as Green List (high evidence)
Growth failure v0.100 STAT5B Zornitza Stark Gene: stat5b has been classified as Green List (High Evidence).
Growth failure v0.99 STAT5B Zornitza Stark reviewed gene: STAT5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 13679528, 15827093, 16787985, 17389811, 29844444; Phenotypes: Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, MIM# 245590, Growth hormone insensitivity with immune dysregulation 2, autosomal dominant, MIM# 618985; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure v0.99 TBCE Zornitza Stark Marked gene: TBCE as ready
Growth failure v0.99 TBCE Zornitza Stark Gene: tbce has been classified as Green List (High Evidence).
Growth failure v0.99 TBCE Zornitza Stark Phenotypes for gene: TBCE were changed from to Kenny-Caffey syndrome, type 1, MIM# 244460; Hypoparathyroidism-retardation-dysmorphism syndrome, MIM# 241410, Sanjad-Sakati syndrome
Growth failure v0.98 TBCE Zornitza Stark Publications for gene: TBCE were set to
Growth failure v0.97 TBCE Zornitza Stark Classified gene: TBCE as Green List (high evidence)
Growth failure v0.97 TBCE Zornitza Stark Gene: tbce has been classified as Green List (High Evidence).
Growth failure v0.96 TBCE Zornitza Stark reviewed gene: TBCE: Rating: GREEN; Mode of pathogenicity: None; Publications: 12389028, 26029652, 33010201, 30638765; Phenotypes: Kenny-Caffey syndrome, type 1, MIM# 244460, Hypoparathyroidism-retardation-dysmorphism syndrome, MIM# 241410, Sanjad-Sakati syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8825 PLXNA2 Zornitza Stark Marked gene: PLXNA2 as ready
Mendeliome v0.8825 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8825 PLXNA2 Zornitza Stark Classified gene: PLXNA2 as Amber List (moderate evidence)
Mendeliome v0.8825 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8824 PLXNA2 Zornitza Stark gene: PLXNA2 was added
gene: PLXNA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNA2 were set to 34327814
Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Review for gene: PLXNA2 was set to AMBER
Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

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

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

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

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

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

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

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

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

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Marked gene: PLXNA2 as ready
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Classified gene: PLXNA2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4055 PLXNA2 Zornitza Stark Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Congenital Diarrhoea v1.7 SLC51A Zornitza Stark Marked gene: SLC51A as ready
Congenital Diarrhoea v1.7 SLC51A Zornitza Stark Gene: slc51a has been classified as Red List (Low Evidence).
Congenital Diarrhoea v1.7 SLC51A Zornitza Stark gene: SLC51A was added
gene: SLC51A was added to Congenital Diarrhoea. Sources: Literature
Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51A were set to 31863603
Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484
Review for gene: SLC51A was set to RED
Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated.
Sources: Literature
Mendeliome v0.8823 SLC51A Zornitza Stark Marked gene: SLC51A as ready
Mendeliome v0.8823 SLC51A Zornitza Stark Gene: slc51a has been classified as Red List (Low Evidence).
Mendeliome v0.8823 SLC51A Zornitza Stark gene: SLC51A was added
gene: SLC51A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51A were set to 31863603
Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484
Review for gene: SLC51A was set to RED
Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated.
Sources: Literature
Cholestasis v0.203 SLC51A Zornitza Stark Marked gene: SLC51A as ready
Cholestasis v0.203 SLC51A Zornitza Stark Gene: slc51a has been classified as Red List (Low Evidence).
Cholestasis v0.203 SLC51A Zornitza Stark gene: SLC51A was added
gene: SLC51A was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51A were set to 31863603
Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484
Review for gene: SLC51A was set to RED
Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4054 SUPT16H Zornitza Stark Phenotypes for gene: SUPT16H were changed from Intellectual disability; Abnormality of the corpus callosum to Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480; Intellectual disability; Abnormality of the corpus callosum
Intellectual disability syndromic and non-syndromic v0.4053 SUPT16H Zornitza Stark edited their review of gene: SUPT16H: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480, Intellectual disability, Abnormality of the corpus callosum
Callosome v0.310 SUPT16H Zornitza Stark Phenotypes for gene: SUPT16H were changed from Intellectual disability; Abnormality of the corpus callosum to Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480; Intellectual disability; Abnormality of the corpus callosum
Callosome v0.309 SUPT16H Zornitza Stark edited their review of gene: SUPT16H: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480, Intellectual disability, Abnormality of the corpus callosum
Mendeliome v0.8822 SUPT16H Zornitza Stark Phenotypes for gene: SUPT16H were changed from Intellectual disability; Abnormality of the corpus callosum to Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480; Intellectual disability; Abnormality of the corpus callosum
Mendeliome v0.8821 SUPT16H Zornitza Stark edited their review of gene: SUPT16H: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, MIM# 619480, Intellectual disability, Abnormality of the corpus callosum
Early-onset Parkinson disease v0.110 FMR1 Bryony Thompson Phenotypes for gene: FMR1 were changed from to Fragile X tremor/ataxia syndrome MIM#300623; Fragile X syndrome MIM#300624
Early-onset Parkinson disease v0.109 FMR1 Bryony Thompson Publications for gene: FMR1 were set to
Early-onset Parkinson disease v0.108 FMR1 Bryony Thompson Mode of inheritance for gene: FMR1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.4053 PLXNA2 Konstantinos Varvagiannis gene: PLXNA2 was added
gene: PLXNA2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature,Other
Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNA2 were set to 34327814
Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Penetrance for gene: PLXNA2 were set to Incomplete
Review for gene: PLXNA2 was set to AMBER
Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

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

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

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

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

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

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

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

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

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other
Growth failure v0.96 Zornitza Stark removed gene:THRB from the panel
Growth failure v0.95 Zornitza Stark removed gene:IGFBP3 from the panel
Growth failure v0.94 Zornitza Stark removed gene:IGFBP1 from the panel
Growth failure v0.93 MRAS Zornitza Stark Marked gene: MRAS as ready
Growth failure v0.93 MRAS Zornitza Stark Gene: mras has been classified as Green List (High Evidence).
Growth failure v0.93 MRAS Zornitza Stark Mode of pathogenicity for gene: MRAS was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Growth failure v0.92 MRAS Zornitza Stark Classified gene: MRAS as Green List (high evidence)
Growth failure v0.92 MRAS Zornitza Stark Gene: mras has been classified as Green List (High Evidence).
Growth failure v0.91 MRAS Zornitza Stark gene: MRAS was added
gene: MRAS was added to Growth failure in early childhood. Sources: Expert Review
Mode of inheritance for gene: MRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRAS were set to 28289718; 31173466; 31108500; 31173466
Phenotypes for gene: MRAS were set to Noonan syndrome 11, MIM#618499
Review for gene: MRAS was set to GREEN
Added comment: At least 6 unrelated individuals reported.
Sources: Expert Review
Pituitary hormone deficiency v0.13 BTK Zornitza Stark Marked gene: BTK as ready
Pituitary hormone deficiency v0.13 BTK Zornitza Stark Gene: btk has been classified as Green List (High Evidence).
Pituitary hormone deficiency v0.13 BTK Zornitza Stark reviewed gene: BTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8013627, 7849697, 9554752; Phenotypes: Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Growth failure v0.90 BTK Zornitza Stark Publications for gene: BTK were set to 8013627; 7849697
Growth failure v0.89 BTK Zornitza Stark changed review comment from: At least 3 families reported with GH deficiency plus agammaglobulinaemia.; to: At least 4 families reported with GH deficiency plus agammaglobulinaemia.
Growth failure v0.89 BTK Zornitza Stark edited their review of gene: BTK: Changed publications: 8013627, 7849697, 9554752
Growth failure v0.89 BTK Zornitza Stark Marked gene: BTK as ready
Growth failure v0.89 BTK Zornitza Stark Gene: btk has been classified as Green List (High Evidence).
Growth failure v0.89 BTK Zornitza Stark Phenotypes for gene: BTK were changed from to Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200
Growth failure v0.88 BTK Zornitza Stark Publications for gene: BTK were set to
Growth failure v0.87 BTK Zornitza Stark Mode of inheritance for gene: BTK was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Growth failure v0.86 BTK Zornitza Stark Classified gene: BTK as Green List (high evidence)
Growth failure v0.86 BTK Zornitza Stark Gene: btk has been classified as Green List (High Evidence).
Growth failure v0.85 BTK Zornitza Stark reviewed gene: BTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8013627, 7849697; Phenotypes: Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Predominantly Antibody Deficiency v0.89 BTK Zornitza Stark Marked gene: BTK as ready
Predominantly Antibody Deficiency v0.89 BTK Zornitza Stark Gene: btk has been classified as Green List (High Evidence).
Predominantly Antibody Deficiency v0.89 BTK Zornitza Stark Phenotypes for gene: BTK were changed from to Agammaglobulinaemia, X-linked 1, MIM# 300755; Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200
Predominantly Antibody Deficiency v0.88 BTK Zornitza Stark Publications for gene: BTK were set to
Predominantly Antibody Deficiency v0.87 BTK Zornitza Stark Mode of inheritance for gene: BTK was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Predominantly Antibody Deficiency v0.86 BTK Zornitza Stark reviewed gene: BTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8013627, 7849697; Phenotypes: Agammaglobulinaemia, X-linked 1, MIM# 300755, Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8821 MOCOS Zornitza Stark Marked gene: MOCOS as ready
Mendeliome v0.8821 MOCOS Zornitza Stark Gene: mocos has been classified as Green List (High Evidence).
Mendeliome v0.8821 MOCOS Zornitza Stark Phenotypes for gene: MOCOS were changed from to Xanthinuria type II, MIM#603592
Mendeliome v0.8820 MOCOS Zornitza Stark Publications for gene: MOCOS were set to
Mendeliome v0.8819 MOCOS Zornitza Stark Mode of inheritance for gene: MOCOS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8818 MOCOS Zornitza Stark reviewed gene: MOCOS: Rating: GREEN; Mode of pathogenicity: None; Publications: 11302742, 17368066, 14624414, 25967871, 34356852, 32073534, 30758870, 27919260; Phenotypes: Xanthinuria type II, MIM#603592; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8818 HNMT Zornitza Stark Marked gene: HNMT as ready
Mendeliome v0.8818 HNMT Zornitza Stark Gene: hnmt has been classified as Green List (High Evidence).
Mendeliome v0.8818 HNMT Zornitza Stark Phenotypes for gene: HNMT were changed from to Mental retardation, autosomal recessive 51, MIM#616739
Mendeliome v0.8817 HNMT Zornitza Stark Publications for gene: HNMT were set to
Mendeliome v0.8816 HNMT Zornitza Stark Mode of inheritance for gene: HNMT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8815 HNMT Zornitza Stark reviewed gene: HNMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 26206890, 30744146, 33310825, 33739554; Phenotypes: Mental retardation, autosomal recessive 51, MIM#616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4053 HNMT Zornitza Stark Publications for gene: HNMT were set to 26206890; 30744146
Intellectual disability syndromic and non-syndromic v0.4052 HNMT Zornitza Stark edited their review of gene: HNMT: Added comment: Verhoeven et al. 2020 (PMID: 33310825) report an adult male patient with severe intellectual disability and autism, born to second cousins, with a homozygous nonsense variant (c.88C>T; p.Gln30*). Treatment with antihistaminergic medication and a histamine-restricted diet resulted in significant general improvement, supporting an etiological role for HNMT deficiency. Taskiran et al. 2021 (PMID: 33739554) report an adult male patient with severe intellectual disability, pervasive developmental disorder and ADHD, born to consanguineous parents, with a homozygous nonsense variant (c.100G>T; p.Glu34*).; Changed publications: 26206890, 30744146, 33310825, 33739554
Predominantly Antibody Deficiency v0.86 BLNK Zornitza Stark Marked gene: BLNK as ready
Predominantly Antibody Deficiency v0.86 BLNK Zornitza Stark Gene: blnk has been classified as Green List (High Evidence).
Mendeliome v0.8815 BLNK Zornitza Stark Marked gene: BLNK as ready
Mendeliome v0.8815 BLNK Zornitza Stark Gene: blnk has been classified as Green List (High Evidence).
Mendeliome v0.8815 BLNK Zornitza Stark Phenotypes for gene: BLNK were changed from to Agammaglobulinaemia 4, MIM# 613502
Mendeliome v0.8814 BLNK Zornitza Stark Publications for gene: BLNK were set to
Mendeliome v0.8813 BLNK Zornitza Stark Mode of inheritance for gene: BLNK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.86 BLNK Zornitza Stark Phenotypes for gene: BLNK were changed from to Agammaglobulinaemia 4, MIM# 613502
Mendeliome v0.8812 BLNK Zornitza Stark reviewed gene: BLNK: Rating: GREEN; Mode of pathogenicity: None; Publications: 10583958, 32194234, 25893637; Phenotypes: Agammaglobulinaemia 4, MIM# 613502; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.85 BLNK Zornitza Stark Publications for gene: BLNK were set to
Predominantly Antibody Deficiency v0.84 BLNK Zornitza Stark Mode of inheritance for gene: BLNK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.83 BLNK Zornitza Stark edited their review of gene: BLNK: Changed phenotypes: Agammaglobulinaemia 4, MIM# 613502
Predominantly Antibody Deficiency v0.83 BLNK Zornitza Stark edited their review of gene: BLNK: Changed rating: GREEN
Predominantly Antibody Deficiency v0.83 BLNK Zornitza Stark reviewed gene: BLNK: Rating: ; Mode of pathogenicity: None; Publications: 10583958, 32194234, 25893637; Phenotypes: Agammaglobulinemia 4, MIM# 613502; Mode of inheritance: None
Mendeliome v0.8812 AICDA Zornitza Stark Marked gene: AICDA as ready
Mendeliome v0.8812 AICDA Zornitza Stark Gene: aicda has been classified as Green List (High Evidence).
Mendeliome v0.8812 AICDA Zornitza Stark Phenotypes for gene: AICDA were changed from to Immunodeficiency with hyper-IgM, type 2, MIM# 605258
Mendeliome v0.8811 AICDA Zornitza Stark Publications for gene: AICDA were set to
Mendeliome v0.8810 AICDA Zornitza Stark Mode of inheritance for gene: AICDA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8809 AICDA Zornitza Stark reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11007475; Phenotypes: Immunodeficiency with hyper-IgM, type 2, MIM# 605258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.83 AICDA Zornitza Stark Marked gene: AICDA as ready
Predominantly Antibody Deficiency v0.83 AICDA Zornitza Stark Gene: aicda has been classified as Green List (High Evidence).
Predominantly Antibody Deficiency v0.83 AICDA Zornitza Stark Phenotypes for gene: AICDA were changed from to Immunodeficiency with hyper-IgM, type 2, MIM# 605258
Predominantly Antibody Deficiency v0.82 AICDA Zornitza Stark Publications for gene: AICDA were set to
Predominantly Antibody Deficiency v0.81 AICDA Zornitza Stark Mode of inheritance for gene: AICDA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.80 AICDA Zornitza Stark reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11007475; Phenotypes: Immunodeficiency with hyper-IgM, type 2, MIM# 605258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v0.202 SLC51B Zornitza Stark Marked gene: SLC51B as ready
Cholestasis v0.202 SLC51B Zornitza Stark Gene: slc51b has been classified as Red List (Low Evidence).
Cholestasis v0.202 SLC51B Zornitza Stark gene: SLC51B was added
gene: SLC51B was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: SLC51B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51B were set to 28898457
Phenotypes for gene: SLC51B were set to Bile acid malabsorption, primary, 2, MIM# 619481; Congenital diarrhoea; Cholestasis
Review for gene: SLC51B was set to RED
Added comment: Two siblings reported with homozygous LOF variant in this gene and congenital diarrhoea/cholestasis.
Sources: Literature
Mendeliome v0.8809 SLC51B Zornitza Stark Phenotypes for gene: SLC51B were changed from Congenital diarrhoea; Cholestasis to Bile acid malabsorption, primary, 2, MIM# 619481; Congenital diarrhoea; Cholestasis
Mendeliome v0.8808 SLC51B Zornitza Stark edited their review of gene: SLC51B: Changed phenotypes: Bile acid malabsorption, primary, 2, MIM# 619481, Congenital diarrhoea, Cholestasis
Congenital Diarrhoea v1.6 SLC51B Zornitza Stark Phenotypes for gene: SLC51B were changed from Congenital diarrhoea; Cholestasis to Bile acid malabsorption, primary, 2, MIM# 619481; Congenital diarrhoea; Cholestasis
Congenital Diarrhoea v1.5 SLC51B Zornitza Stark edited their review of gene: SLC51B: Changed phenotypes: Bile acid malabsorption, primary, 2, MIM# 619481, Congenital diarrhoea, Cholestasis
Microcephaly v1.40 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Microcephaly v1.40 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.40 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Microcephaly v1.40 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.39 VPS50 Zornitza Stark gene: VPS50 was added
gene: VPS50 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

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

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

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

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

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

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

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.
Sources: Literature
Cholestasis v0.201 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Cholestasis v0.201 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Cholestasis v0.201 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Cholestasis v0.201 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Cholestasis v0.200 VPS50 Zornitza Stark gene: VPS50 was added
gene: VPS50 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

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

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

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

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

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

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

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.
Sources: Literature
Mendeliome v0.8808 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Mendeliome v0.8808 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8808 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Mendeliome v0.8808 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8807 VPS50 Zornitza Stark gene: VPS50 was added
gene: VPS50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

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

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

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

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

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

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

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.
Sources: Literature
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4052 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1168 VPS50 Konstantinos Varvagiannis gene: VPS50 was added
gene: VPS50 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

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

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

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

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

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

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

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4051 VPS50 Konstantinos Varvagiannis gene: VPS50 was added
gene: VPS50 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

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

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

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

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

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

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

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature
Amelogenesis imperfecta v1.0 Zornitza Stark promoted panel to version 1.0
Amelogenesis imperfecta v0.72 SMARCD2 Zornitza Stark Marked gene: SMARCD2 as ready
Amelogenesis imperfecta v0.72 SMARCD2 Zornitza Stark Gene: smarcd2 has been classified as Red List (Low Evidence).
Amelogenesis imperfecta v0.72 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Amelogenesis imperfecta v0.71 Zornitza Stark removed gene:TUFT1 from the panel
Amelogenesis imperfecta v0.70 TP63 Zornitza Stark Marked gene: TP63 as ready
Amelogenesis imperfecta v0.70 TP63 Zornitza Stark Gene: tp63 has been classified as Red List (Low Evidence).
Amelogenesis imperfecta v0.70 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Split hand-split foot-ectodermal dysplasia and amelogenesis imperfecta to Split-hand/foot malformation 4, MIM# 605289
Amelogenesis imperfecta v0.69 TP63 Zornitza Stark Publications for gene: TP63 were set to
Amelogenesis imperfecta v0.68 TP63 Zornitza Stark reviewed gene: TP63: Rating: RED; Mode of pathogenicity: None; Publications: 22065540; Phenotypes: Split-hand/foot malformation 4, MIM# 605289; Mode of inheritance: None
Amelogenesis imperfecta v0.68 TMEM165 Zornitza Stark Marked gene: TMEM165 as ready
Amelogenesis imperfecta v0.68 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Red List (Low Evidence).
Amelogenesis imperfecta v0.68 TMEM165 Zornitza Stark Phenotypes for gene: TMEM165 were changed from amelogenesis imperfecta to Congenital disorder of glycosylation, type IIk, MIM# 614727; amelogenesis imperfecta
Amelogenesis imperfecta v0.67 TMEM165 Zornitza Stark reviewed gene: TMEM165: Rating: RED; Mode of pathogenicity: None; Publications: 22683087; Phenotypes: Congenital disorder of glycosylation, type IIk, MIM# 614727; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.67 SMARCD2 Zornitza Stark reviewed gene: SMARCD2: Rating: RED; Mode of pathogenicity: None; Publications: 28369036; Phenotypes: Specific granule deficiency 2, MIM# 617475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.67 KCNJ1 Zornitza Stark Marked gene: KCNJ1 as ready
Amelogenesis imperfecta v0.67 KCNJ1 Zornitza Stark Gene: kcnj1 has been classified as Red List (Low Evidence).
Mendeliome v0.8806 SP6 Zornitza Stark Publications for gene: SP6 were set to 32167558; 18156176; 18297738; 22676574
Mendeliome v0.8805 SP6 Zornitza Stark Mode of inheritance for gene: SP6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8804 SP6 Zornitza Stark Classified gene: SP6 as Green List (high evidence)
Mendeliome v0.8804 SP6 Zornitza Stark Gene: sp6 has been classified as Green List (High Evidence).
Mendeliome v0.8803 SP6 Zornitza Stark reviewed gene: SP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33652941; Phenotypes: Hypoplastic amelogenesis imperfecta; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v0.67 SP6 Zornitza Stark Marked gene: SP6 as ready
Amelogenesis imperfecta v0.67 SP6 Zornitza Stark Gene: sp6 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.67 SP6 Zornitza Stark Publications for gene: SP6 were set to 18297738; 32167558; 18156176; 22676574
Amelogenesis imperfecta v0.66 SP6 Zornitza Stark Classified gene: SP6 as Green List (high evidence)
Amelogenesis imperfecta v0.66 SP6 Zornitza Stark Gene: sp6 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.65 SP6 Zornitza Stark edited their review of gene: SP6: Changed rating: GREEN
Amelogenesis imperfecta v0.65 SP6 Zornitza Stark reviewed gene: SP6: Rating: ; Mode of pathogenicity: None; Publications: 18297738, 32167558, 18156176, 22676574, 33652941; Phenotypes: Amelogenesis imperfecta; Mode of inheritance: None
Amelogenesis imperfecta v0.65 LAMC2 Zornitza Stark Classified gene: LAMC2 as Green List (high evidence)
Amelogenesis imperfecta v0.65 LAMC2 Zornitza Stark Gene: lamc2 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.64 LAMC2 Zornitza Stark Marked gene: LAMC2 as ready
Amelogenesis imperfecta v0.64 LAMC2 Zornitza Stark Gene: lamc2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v0.64 LAMC2 Zornitza Stark Phenotypes for gene: LAMC2 were changed from Amelogenesis Imperfecta; Epidermolysis bullosa, junctional, non-Herlitz type, 226650; Epidermolysis bullosa, junctional, Herlitz type, 226700 to Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Amelogenesis imperfecta v0.63 LAMC2 Zornitza Stark Mode of inheritance for gene: LAMC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.62 LAMC2 Zornitza Stark edited their review of gene: LAMC2: Changed publications: 26956061
Amelogenesis imperfecta v0.62 LAMC2 Zornitza Stark reviewed gene: LAMC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Usher Syndrome v1.4 PEX26 Zornitza Stark Marked gene: PEX26 as ready
Usher Syndrome v1.4 PEX26 Zornitza Stark Gene: pex26 has been classified as Green List (High Evidence).
Usher Syndrome v1.4 PEX26 Zornitza Stark Classified gene: PEX26 as Green List (high evidence)
Usher Syndrome v1.4 PEX26 Zornitza Stark Gene: pex26 has been classified as Green List (High Evidence).
Usher Syndrome v1.3 PEX26 Zornitza Stark gene: PEX26 was added
gene: PEX26 was added to Usher Syndrome. Sources: Expert Review
Mode of inheritance for gene: PEX26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PEX26 were set to 28944237; 33926089; 28944237
Phenotypes for gene: PEX26 were set to Heimler syndrome
Review for gene: PEX26 was set to GREEN
Added comment: 5 families reported with Heimler syndrome phenotype.
Sources: Expert Review
Amelogenesis imperfecta v0.62 PEX26 Zornitza Stark Marked gene: PEX26 as ready
Amelogenesis imperfecta v0.62 PEX26 Zornitza Stark Gene: pex26 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.62 PEX26 Zornitza Stark Phenotypes for gene: PEX26 were changed from Peroxisome biogenesis disorder 7B, 614873; Peroxisome biogenesis disorder 7A (Zellweger), 614872; enamel dysplasia; Heimler syndrome; Amelogenesis imperfecta to Heimler syndrome; Amelogenesis imperfecta
Amelogenesis imperfecta v0.61 PEX26 Zornitza Stark Publications for gene: PEX26 were set to 28944237
Amelogenesis imperfecta v0.60 PEX26 Zornitza Stark Classified gene: PEX26 as Green List (high evidence)
Amelogenesis imperfecta v0.60 PEX26 Zornitza Stark Gene: pex26 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.59 PEX26 Zornitza Stark reviewed gene: PEX26: Rating: GREEN; Mode of pathogenicity: None; Publications: 28944237, 33926089; Phenotypes: Heimler syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.59 ITGB4 Zornitza Stark Marked gene: ITGB4 as ready
Amelogenesis imperfecta v0.59 ITGB4 Zornitza Stark Gene: itgb4 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.59 ITGB4 Zornitza Stark Phenotypes for gene: ITGB4 were changed from Epidermolysis bullosa, junctional, non-Herlitz type, 226650 (includes enamel pitting); Amelogenesis Imperfecta; Epidermolysis bullosa, junctional, with pyloric atresia, 226730 (includes Enamel hypoplasia) to Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730
Amelogenesis imperfecta v0.58 ITGB4 Zornitza Stark Mode of inheritance for gene: ITGB4 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.57 ITGB4 Zornitza Stark Classified gene: ITGB4 as Green List (high evidence)
Amelogenesis imperfecta v0.57 ITGB4 Zornitza Stark Gene: itgb4 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.56 ITGB4 Zornitza Stark reviewed gene: ITGB4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650, Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.56 CLDN19 Zornitza Stark Marked gene: CLDN19 as ready
Amelogenesis imperfecta v0.56 CLDN19 Zornitza Stark Gene: cldn19 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.56 CLDN19 Zornitza Stark Phenotypes for gene: CLDN19 were changed from Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis (FHHNC) to Hypomagnesaemia 5, renal, with ocular involvement, MIM# 248190; Amelogenesis imperfecta
Amelogenesis imperfecta v0.55 CLDN19 Zornitza Stark Classified gene: CLDN19 as Green List (high evidence)
Amelogenesis imperfecta v0.55 CLDN19 Zornitza Stark Gene: cldn19 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.54 CLDN19 Zornitza Stark reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: None; Publications: 27530400; Phenotypes: Hypomagnesaemia 5, renal, with ocular involvement, MIM# 248190; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.54 CLDN16 Zornitza Stark Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal, MIM# 248250; Amelogenesis imperfecta to Hypomagnesaemia 3, renal, MIM# 248250; Amelogenesis imperfecta
Amelogenesis imperfecta v0.53 CLDN16 Zornitza Stark edited their review of gene: CLDN16: Changed phenotypes: Hypomagnesaemia 3, renal, MIM# 248250; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.53 CLDN16 Zornitza Stark Marked gene: CLDN16 as ready
Amelogenesis imperfecta v0.53 CLDN16 Zornitza Stark Gene: cldn16 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.53 CLDN16 Zornitza Stark Phenotypes for gene: CLDN16 were changed from Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis (FHHNC) to Hypomagnesemia 3, renal, MIM# 248250; Amelogenesis imperfecta
Amelogenesis imperfecta v0.52 CLDN16 Zornitza Stark Classified gene: CLDN16 as Green List (high evidence)
Amelogenesis imperfecta v0.52 CLDN16 Zornitza Stark Gene: cldn16 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.51 CLDN16 Zornitza Stark reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 26426912; Phenotypes: Hypomagnesemia 3, renal, MIM# 248250; Mode of inheritance: None
Amelogenesis imperfecta v0.51 C4orf26 Zornitza Stark Marked gene: C4orf26 as ready
Amelogenesis imperfecta v0.51 C4orf26 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name: ODAPH
Amelogenesis imperfecta v0.51 C4orf26 Zornitza Stark Gene: c4orf26 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.51 C4orf26 Zornitza Stark Tag new gene name tag was added to gene: C4orf26.
Mendeliome v0.8803 AMTN Zornitza Stark Marked gene: AMTN as ready
Mendeliome v0.8803 AMTN Zornitza Stark Gene: amtn has been classified as Red List (Low Evidence).
Amelogenesis imperfecta v0.51 AMTN Zornitza Stark Mode of pathogenicity for gene: AMTN was changed from None to Other
Mendeliome v0.8803 AMTN Zornitza Stark gene: AMTN was added
gene: AMTN was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: AMTN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMTN were set to 27412008; 25715379; 26620968
Phenotypes for gene: AMTN were set to Amelogenesis imperfecta, type IIIB
Mode of pathogenicity for gene: AMTN was set to Other
Review for gene: AMTN was set to RED
Added comment: In a Costa Rican family segregating autosomal dominant hypomineralized amelogenesis imperfecta, Smith et al. (2016) identified a heterozygous deletion/insertion mutation in the amelotin gene that segregated with the phenotype in the family. The mutation was predicted to result in an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 amino acids. Mode of pathogenicity not established. Toxic gain of function proposed as Atmn KO and +/- mice did not recapitulate the human phenotype.
Sources: Expert Review
Amelogenesis imperfecta v0.50 AMTN Zornitza Stark Mode of pathogenicity for gene: AMTN was changed from to None
Amelogenesis imperfecta v0.49 AMTN Zornitza Stark Marked gene: AMTN as ready
Amelogenesis imperfecta v0.49 AMTN Zornitza Stark Gene: amtn has been classified as Red List (Low Evidence).
Amelogenesis imperfecta v0.49 AMTN Zornitza Stark Phenotypes for gene: AMTN were changed from dominant hypomineralised AI; Amelogenesis imperfecta; ?Amelogenesis imperfecta, type IIIB, 617607; Amelogenesis imperfecta, hypomaturation type to Amelogenesis imperfecta, type IIIB
Amelogenesis imperfecta v0.48 AMTN Zornitza Stark Publications for gene: AMTN were set to 27412008
Amelogenesis imperfecta v0.47 AMTN Zornitza Stark Classified gene: AMTN as Red List (low evidence)
Amelogenesis imperfecta v0.47 AMTN Zornitza Stark Gene: amtn has been classified as Red List (Low Evidence).
Amelogenesis imperfecta v0.46 AMTN Zornitza Stark reviewed gene: AMTN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v0.8802 WDR72 Zornitza Stark Marked gene: WDR72 as ready
Mendeliome v0.8802 WDR72 Zornitza Stark Gene: wdr72 has been classified as Green List (High Evidence).
Mendeliome v0.8802 WDR72 Zornitza Stark Phenotypes for gene: WDR72 were changed from to Amelogenesis imperfecta, type IIA3, MIM# 613211
Mendeliome v0.8801 WDR72 Zornitza Stark Publications for gene: WDR72 were set to
Mendeliome v0.8800 WDR72 Zornitza Stark Mode of inheritance for gene: WDR72 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8799 WDR72 Zornitza Stark reviewed gene: WDR72: Rating: GREEN; Mode of pathogenicity: None; Publications: 21196691, 27259663, 20938048, 26502894, 23293580, 25008349, 19853237; Phenotypes: Amelogenesis imperfecta, type IIA3, MIM# 613211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.46 WDR72 Zornitza Stark Marked gene: WDR72 as ready
Amelogenesis imperfecta v0.46 WDR72 Zornitza Stark Gene: wdr72 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.46 WDR72 Zornitza Stark Phenotypes for gene: WDR72 were changed from Amelogenesis Imperfecta, Type IIA3, 613211; Amelogenesis imperfecta, type IIA3, 613211; Amelogenesis Imperfecta, Recessive; Hypomaturation AI to Amelogenesis imperfecta, type IIA3, MIM# 613211
Amelogenesis imperfecta v0.45 WDR72 Zornitza Stark reviewed gene: WDR72: Rating: GREEN; Mode of pathogenicity: None; Publications: 21196691, 27259663, 20938048, 26502894, 23293580, 25008349, 19853237; Phenotypes: Amelogenesis imperfecta, type IIA3, MIM# 613211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.45 STIM1 Zornitza Stark Marked gene: STIM1 as ready
Amelogenesis imperfecta v0.45 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.45 STIM1 Zornitza Stark Phenotypes for gene: STIM1 were changed from Immunodeficiency 10, 612783 to Immunodeficiency 10, MIM# 612783; Hypomineralised amelogenesis imperfecta
Amelogenesis imperfecta v0.44 STIM1 Zornitza Stark Publications for gene: STIM1 were set to 19420366; 26560041; 24621671; 22190180; 28732182
Amelogenesis imperfecta v0.43 STIM1 Zornitza Stark reviewed gene: STIM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31448844; Phenotypes: Immunodeficiency 10, MIM# 612783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8799 SLC24A4 Zornitza Stark Marked gene: SLC24A4 as ready
Mendeliome v0.8799 SLC24A4 Zornitza Stark Gene: slc24a4 has been classified as Green List (High Evidence).
Mendeliome v0.8799 SLC24A4 Zornitza Stark Phenotypes for gene: SLC24A4 were changed from to Amelogenesis imperfecta, type IIA5, MIM# 615887
Mendeliome v0.8798 SLC24A4 Zornitza Stark Publications for gene: SLC24A4 were set to
Mendeliome v0.8797 SLC24A4 Zornitza Stark Mode of inheritance for gene: SLC24A4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8796 SLC24A4 Zornitza Stark reviewed gene: SLC24A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23375655, 24621671, 25442250, 24532815, 26502894, 27129268; Phenotypes: Amelogenesis imperfecta, type IIA5, MIM# 615887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.43 SLC24A4 Zornitza Stark Marked gene: SLC24A4 as ready
Amelogenesis imperfecta v0.43 SLC24A4 Zornitza Stark Gene: slc24a4 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.43 SLC24A4 Zornitza Stark Phenotypes for gene: SLC24A4 were changed from Amelogenesis imperfecta, type IIA5, 615887; amelogenesis imperfecta (non-syndromic form); hypomaturation/hypomineralised amelogenesis imperfecta to Amelogenesis imperfecta, type IIA5, MIM# 615887
Amelogenesis imperfecta v0.42 SLC24A4 Zornitza Stark changed review comment from: At least 3 families and a mouse model.; to: Multiple families and a mouse model.
Amelogenesis imperfecta v0.42 SLC24A4 Zornitza Stark edited their review of gene: SLC24A4: Changed publications: 23375655, 24621671, 25442250, 24532815, 26502894, 27129268
Amelogenesis imperfecta v0.42 SLC24A4 Zornitza Stark reviewed gene: SLC24A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23375655, 24621671; Phenotypes: Amelogenesis imperfecta, type IIA5, MIM# 615887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.42 SLC13A5 Zornitza Stark Marked gene: SLC13A5 as ready
Amelogenesis imperfecta v0.42 SLC13A5 Zornitza Stark Gene: slc13a5 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.42 SLC13A5 Zornitza Stark Phenotypes for gene: SLC13A5 were changed from Kohlsch tter-T nz syndrome(KTZS); Epileptic encephalopathy, early infantile, 25 615905; hypoplastic amelogenesis imperfecta to Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905
Amelogenesis imperfecta v0.41 SLC10A7 Zornitza Stark Marked gene: SLC10A7 as ready
Amelogenesis imperfecta v0.41 SLC10A7 Zornitza Stark Gene: slc10a7 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.41 SLC10A7 Zornitza Stark Phenotypes for gene: SLC10A7 were changed from short stature; amelogenesis imperfect hypo mineralised; skeletal dysplasia; Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS) 618363; skeletal dysplasia and amelogenesis imperfecta; scoliosis to Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (MIM#618363)
Intellectual disability syndromic and non-syndromic v0.4051 ROGDI Zornitza Stark Marked gene: ROGDI as ready
Intellectual disability syndromic and non-syndromic v0.4051 ROGDI Zornitza Stark Gene: rogdi has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4051 ROGDI Zornitza Stark Phenotypes for gene: ROGDI were changed from to Kohlschutter-Tonz syndrome, MIM# 226750
Intellectual disability syndromic and non-syndromic v0.4050 ROGDI Zornitza Stark Publications for gene: ROGDI were set to
Intellectual disability syndromic and non-syndromic v0.4049 ROGDI Zornitza Stark Mode of inheritance for gene: ROGDI was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4048 ROGDI Zornitza Stark reviewed gene: ROGDI: Rating: GREEN; Mode of pathogenicity: None; Publications: 22424600, 23086778, 33866847; Phenotypes: Kohlschutter-Tonz syndrome, MIM# 226750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Marked gene: ROGDI as ready
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Gene: rogdi has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Phenotypes for gene: ROGDI were changed from to Kohlschutter-Tonz syndrome, MIM# 226750
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Publications for gene: ROGDI were set to
Genetic Epilepsy v0.1167 ROGDI Zornitza Stark Mode of inheritance for gene: ROGDI was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1166 ROGDI Zornitza Stark reviewed gene: ROGDI: Rating: GREEN; Mode of pathogenicity: None; Publications: 22424600, 23086778, 33866847; Phenotypes: Kohlschutter-Tonz syndrome, MIM# 226750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8796 ROGDI Zornitza Stark Marked gene: ROGDI as ready
Mendeliome v0.8796 ROGDI Zornitza Stark Gene: rogdi has been classified as Green List (High Evidence).
Mendeliome v0.8796 ROGDI Zornitza Stark Phenotypes for gene: ROGDI were changed from to Kohlschutter-Tonz syndrome, MIM# 226750
Mendeliome v0.8795 ROGDI Zornitza Stark Publications for gene: ROGDI were set to
Mendeliome v0.8794 ROGDI Zornitza Stark Mode of inheritance for gene: ROGDI was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8793 ROGDI Zornitza Stark reviewed gene: ROGDI: Rating: GREEN; Mode of pathogenicity: None; Publications: 22424600, 23086778, 33866847; Phenotypes: Kohlschutter-Tonz syndrome, MIM# 226750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.40 ROGDI Zornitza Stark Marked gene: ROGDI as ready
Amelogenesis imperfecta v0.40 ROGDI Zornitza Stark Gene: rogdi has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.40 ROGDI Zornitza Stark Phenotypes for gene: ROGDI were changed from Amelogenesis imperfecta, hypocalcified type (primary and secondary teeth); Kohlschutter-Tonz syndrome, 226750 to Kohlschutter-Tonz syndrome MIM #226750; Amelogenesis imperfecta, hypocalcified type (primary and secondary teeth)
Mendeliome v0.8793 RELT Zornitza Stark Marked gene: RELT as ready
Mendeliome v0.8793 RELT Zornitza Stark Gene: relt has been classified as Green List (High Evidence).
Mendeliome v0.8793 RELT Zornitza Stark Classified gene: RELT as Green List (high evidence)
Mendeliome v0.8793 RELT Zornitza Stark Gene: relt has been classified as Green List (High Evidence).
Mendeliome v0.8792 RELT Zornitza Stark gene: RELT was added
gene: RELT was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: RELT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RELT were set to 30506946
Phenotypes for gene: RELT were set to Amelogenesis imperfecta, type IIIC, MIM# 618386
Review for gene: RELT was set to GREEN
Added comment: Amelogenesis imperfecta type IIIC is characterized by hypocalcified enamel in both the primary and secondary dentition. The enamel is rough and yellow-brown; under normal use, the enamel disintegrates from occlusal surfaces of the molars, leaving a ring of intact enamel remaining on the sides. At least 3 families and a mouse model.
Sources: Expert Review
Amelogenesis imperfecta v0.39 RELT Zornitza Stark Marked gene: RELT as ready
Amelogenesis imperfecta v0.39 RELT Zornitza Stark Gene: relt has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.39 RELT Zornitza Stark Phenotypes for gene: RELT were changed from amelogenesis imperfecta (hypoplastic); Amelogenesis imperfecta, type IIIC, 618386 to Amelogenesis imperfecta, type IIIC, MIM# 618386
Amelogenesis imperfecta v0.38 RELT Zornitza Stark reviewed gene: RELT: Rating: GREEN; Mode of pathogenicity: None; Publications: 30506946; Phenotypes: Amelogenesis imperfecta, type IIIC, MIM# 618386; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.38 PEX6 Zornitza Stark Marked gene: PEX6 as ready
Amelogenesis imperfecta v0.38 PEX6 Zornitza Stark Gene: pex6 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.38 PEX6 Zornitza Stark Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger), 614862; Heimler Syndrome 2, 616617 (includes amelogenesis imperfecta); Peroxisome biogenesis disorder 4B, 614863 to Heimler syndrome 2, MIM# 616617
Amelogenesis imperfecta v0.37 PEX6 Zornitza Stark Publications for gene: PEX6 were set to 26387595; 27302843; 16530715
Amelogenesis imperfecta v0.36 PEX6 Zornitza Stark reviewed gene: PEX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 26387595, 27633571, 27302843; Phenotypes: Heimler syndrome 2, MIM# 616617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.36 PEX1 Zornitza Stark edited their review of gene: PEX1: Changed publications: 26387595, 27633571, 27302843
Amelogenesis imperfecta v0.36 PEX1 Zornitza Stark Marked gene: PEX1 as ready
Amelogenesis imperfecta v0.36 PEX1 Zornitza Stark Gene: pex1 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.36 PEX1 Zornitza Stark Phenotypes for gene: PEX1 were changed from Peroxisome biogenesis disorder 1A (Zellweger), 214100; Heimler Syndrome 1, 234580 (includes amelogenesis imperfecta); Peroxisomal Biogenesis Disorder 1A (NALD / IRD) 601539; hypomineralized amelogenesis imperfecta; amelogenesis imperfecta to Heimler syndrome 1, MIM# 234580
Amelogenesis imperfecta v0.35 PEX1 Zornitza Stark reviewed gene: PEX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Heimler syndrome 1, MIM# 234580; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.35 ORAI1 Zornitza Stark Marked gene: ORAI1 as ready
Amelogenesis imperfecta v0.35 ORAI1 Zornitza Stark Gene: orai1 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.35 ORAI1 Zornitza Stark Phenotypes for gene: ORAI1 were changed from Immunodeficiency 9, 612782 to Immunodeficiency 9, MIM# 612782; Hypocalcified amelogenesis imperfecta
Amelogenesis imperfecta v0.34 ORAI1 Zornitza Stark reviewed gene: ORAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26469693, 16582901, 20004786; Phenotypes: Immunodeficiency 9, MIM# 612782; Mode of inheritance: None
Amelogenesis imperfecta v0.34 MMP20 Zornitza Stark Marked gene: MMP20 as ready
Amelogenesis imperfecta v0.34 MMP20 Zornitza Stark Gene: mmp20 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.34 MMP20 Zornitza Stark Phenotypes for gene: MMP20 were changed from Amelogenesis Imperfecta, Hypomaturation Type, IIA2, 612529; Amelogenesis imperfecta, type IIA2, 612529; Amelogenesis Imperfecta, Recessive to Amelogenesis imperfecta, type IIA2, MIM# 612529
Amelogenesis imperfecta v0.33 MMP20 Zornitza Stark reviewed gene: MMP20: Rating: GREEN; Mode of pathogenicity: None; Publications: 23625376, 26124219, 28659819, 19966041, 26502894, 28473773, 23355523, 18096894, 16246936, 15744043; Phenotypes: Amelogenesis imperfecta, type IIA2, MIM# 612529; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8791 LAMB3 Zornitza Stark Phenotypes for gene: LAMB3 were changed from Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650 to Amelogenesis imperfecta, type IA, MIM# 104530; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Mendeliome v0.8790 LAMB3 Zornitza Stark Publications for gene: LAMB3 were set to 11023379; 7706760
Mendeliome v0.8789 LAMB3 Zornitza Stark Mode of inheritance for gene: LAMB3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.8788 LAMB3 Zornitza Stark edited their review of gene: LAMB3: Changed publications: 11023379, 7706760, 23958762, 7706760, 23632796, 26502894, 27220909, 25769099, 24494736; Changed phenotypes: Amelogenesis imperfecta, type IA, MIM# 104530, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Amelogenesis imperfecta v0.33 LAMB3 Zornitza Stark Marked gene: LAMB3 as ready
Amelogenesis imperfecta v0.33 LAMB3 Zornitza Stark Gene: lamb3 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.33 LAMB3 Zornitza Stark Phenotypes for gene: LAMB3 were changed from Amelogenesis Imperfecta, Type IA, 104530; Epidermolysis bullosa, junctional, Herlitz type, 26700; Amelogenesis imperfecta, type IA, 104530; Epidermolysis bullosa, junctional, non-Herlitz type, 226650 to Amelogenesis imperfecta, type IA, MIM# 104530; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Amelogenesis imperfecta v0.32 LAMB3 Zornitza Stark edited their review of gene: LAMB3: Changed publications: 23958762, 7706760, 23632796, 26502894, 27220909, 25769099, 24494736
Amelogenesis imperfecta v0.32 LAMB3 Zornitza Stark reviewed gene: LAMB3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amelogenesis imperfecta, type IA, MIM# 104530, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal Ciliopathies v1.5 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from Short-rib skeletal dysplasia to Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Skeletal Ciliopathies v1.4 KIAA0753 Zornitza Stark Publications for gene: KIAA0753 were set to 29138412
Skeletal Ciliopathies v1.3 KIAA0753 Zornitza Stark edited their review of gene: KIAA0753: Added comment: Additional families reported.; Changed publications: 29138412, 31816441, 33875766, 34016807; Changed phenotypes: Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Mendeliome v0.8788 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from Orofaciodigital syndrome XV, MIM# 617127; Joubert syndrome 38, MIM# 619476 to Orofaciodigital syndrome XV, MIM# 617127; Joubert syndrome 38, MIM# 619476; Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Mendeliome v0.8787 KIAA0753 Zornitza Stark Publications for gene: KIAA0753 were set to 31816441; 28220259; 29138412; 26643951
Mendeliome v0.8786 KIAA0753 Zornitza Stark edited their review of gene: KIAA0753: Added comment: At least 5 families reported with a skeletal ciliopathy.; Changed publications: 29138412, 31816441, 33875766, 34016807; Changed phenotypes: Orofaciodigital syndrome XV 617127, Joubert syndrome, Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Ciliopathies v1.10 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from Orofaciodigital syndrome XV 617127; Joubert syndrome 38, MIM# 619476 to Orofaciodigital syndrome XV 617127; Joubert syndrome 38, MIM# 619476; Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479
Ciliopathies v1.9 KIAA0753 Zornitza Stark Publications for gene: KIAA0753 were set to 31816441; 28220259; 29138412; 26643951
Ciliopathies v1.8 KIAA0753 Zornitza Stark edited their review of gene: KIAA0753: Added comment: At least 5 families reported with a skeletal ciliopathy.; Changed rating: GREEN; Changed publications: 29138412, 31816441, 33875766, 34016807; Changed phenotypes: Short-rib thoracic dysplasia 21 without polydactyly, MIM# 619479; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4048 SPTBN1 Zornitza Stark Phenotypes for gene: SPTBN1 were changed from Neurodevelopmental Syndrome to Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475
Genetic Epilepsy v0.1166 SPTBN1 Zornitza Stark Phenotypes for gene: SPTBN1 were changed from Neurodevelopmental Syndrome to Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475
Genetic Epilepsy v0.1165 SPTBN1 Zornitza Stark reviewed gene: SPTBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475; Mode of inheritance: None
Mendeliome v0.8786 SPTBN1 Zornitza Stark Phenotypes for gene: SPTBN1 were changed from Neurodevelopmental Syndrome; Intellectual disability; Seizures to Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475; Neurodevelopmental Syndrome; Intellectual disability; Seizures
Mendeliome v0.8785 SPTBN1 Zornitza Stark reviewed gene: SPTBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475; Mode of inheritance: None
Mendeliome v0.8785 NIID Zornitza Stark Phenotypes for STR: NIID were changed from Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866 to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866; Oculopharyngodistal myopathy 3, MIM# 619473
Mendeliome v0.8784 NIID Zornitza Stark reviewed STR: NIID: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oculopharyngodistal myopathy 3, MIM# 619473; Mode of inheritance: None
Motor Neurone Disease v0.127 NIID Zornitza Stark Phenotypes for STR: NIID were changed from Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866 to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866; Oculopharyngodistal myopathy 3, MIM# 619473
Motor Neurone Disease v0.126 NIID Zornitza Stark reviewed STR: NIID: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oculopharyngodistal myopathy 3, MIM# 619473; Mode of inheritance: None
Amelogenesis imperfecta v0.32 LAMA3 Zornitza Stark Marked gene: LAMA3 as ready
Amelogenesis imperfecta v0.32 LAMA3 Zornitza Stark Gene: lama3 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.32 LAMA3 Zornitza Stark Phenotypes for gene: LAMA3 were changed from Laryngoonychocutaneous syndrome 245660; Epidermolysis bullosa, junctional, Herlitz type 226700; Epidermolysis bullosa, generalized atrophic benign 226650; Amelogenesis imperfecta, hypoplastic type to Epidermolysis bullosa, generalized atrophic benign, MIM# 226650; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Laryngoonychocutaneous syndrome, MIM# 245660
Amelogenesis imperfecta v0.31 LAMA3 Zornitza Stark Mode of inheritance for gene: LAMA3 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.30 LAMA3 Zornitza Stark reviewed gene: LAMA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa, generalized atrophic benign, MIM# 226650, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Laryngoonychocutaneous syndrome, MIM# 245660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8784 KLK4 Zornitza Stark Marked gene: KLK4 as ready
Mendeliome v0.8784 KLK4 Zornitza Stark Gene: klk4 has been classified as Green List (High Evidence).
Mendeliome v0.8784 KLK4 Zornitza Stark Phenotypes for gene: KLK4 were changed from to Amelogenesis imperfecta, type IIA1, MIM# 204700
Mendeliome v0.8783 KLK4 Zornitza Stark Publications for gene: KLK4 were set to
Mendeliome v0.8782 KLK4 Zornitza Stark Mode of inheritance for gene: KLK4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8781 KLK4 Zornitza Stark reviewed gene: KLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 15235027, 23355523, 28611678, 27066511; Phenotypes: Amelogenesis imperfecta, type IIA1, MIM# 204700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v0.96 STAT3 Zornitza Stark Marked gene: STAT3 as ready
Disorders of immune dysregulation v0.96 STAT3 Zornitza Stark Gene: stat3 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.96 STAT3 Zornitza Stark Phenotypes for gene: STAT3 were changed from to Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952; Lymphoproliferation; solid organ autoimmunity; recurrent infections; short stature; eczema; delayed puberty; dental abnormalities; autoimmune interstitial lung disease; juvenile-onset arthritis; primary hypothyroidism
Amelogenesis imperfecta v0.30 KLK4 Zornitza Stark Marked gene: KLK4 as ready
Amelogenesis imperfecta v0.30 KLK4 Zornitza Stark Gene: klk4 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.30 KLK4 Zornitza Stark Phenotypes for gene: KLK4 were changed from Amelogenesis Imperfecta, Hypomaturation Type, IIA1, 204700; Amelogenesis imperfecta, type IIA1, 204700 to Amelogenesis imperfecta, type IIA1, MIM# 204700
Amelogenesis imperfecta v0.29 KLK4 Zornitza Stark Publications for gene: KLK4 were set to 15235027; 23355523; 26124219; 28611678
Amelogenesis imperfecta v0.28 KLK4 Zornitza Stark reviewed gene: KLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 15235027, 23355523, 28611678, 27066511; Phenotypes: Amelogenesis imperfecta, type IIA1, MIM# 204700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8781 ITGB6 Zornitza Stark Marked gene: ITGB6 as ready
Mendeliome v0.8781 ITGB6 Zornitza Stark Gene: itgb6 has been classified as Green List (High Evidence).
Mendeliome v0.8781 ITGB6 Zornitza Stark Classified gene: ITGB6 as Green List (high evidence)
Mendeliome v0.8781 ITGB6 Zornitza Stark Gene: itgb6 has been classified as Green List (High Evidence).
Mendeliome v0.8780 ITGB6 Zornitza Stark gene: ITGB6 was added
gene: ITGB6 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ITGB6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGB6 were set to 25431241; 26695873; 24305999; 24319098
Phenotypes for gene: ITGB6 were set to Amelogenesis imperfecta, type IH, MIM# 616221
Review for gene: ITGB6 was set to GREEN
Added comment: At least 3 unrelated families reported.
Sources: Expert Review
Amelogenesis imperfecta v0.28 ITGB6 Zornitza Stark Publications for gene: ITGB6 were set to 25431241; 26695873; 24305999; 24319098
Amelogenesis imperfecta v0.27 ITGB6 Zornitza Stark Marked gene: ITGB6 as ready
Amelogenesis imperfecta v0.27 ITGB6 Zornitza Stark Gene: itgb6 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.27 ITGB6 Zornitza Stark Phenotypes for gene: ITGB6 were changed from Amelogenesis imperfecta, type IH, 616221; amelogenesis imperfecta (non-syndromic form); Amelogenesis imperfecta, type IH, 616221 to Amelogenesis imperfecta, type IH, MIM# 616221
Amelogenesis imperfecta v0.26 ITGB6 Zornitza Stark reviewed gene: ITGB6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24305999, 24319098; Phenotypes: Amelogenesis imperfecta, type IH, MIM# 616221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8779 STAT3 Zornitza Stark Marked gene: STAT3 as ready
Mendeliome v0.8779 STAT3 Zornitza Stark Gene: stat3 has been classified as Green List (High Evidence).
Mendeliome v0.8779 STAT3 Zornitza Stark Phenotypes for gene: STAT3 were changed from to Hyper-IgE recurrent infection syndrome MIM# 147060; Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952
Mendeliome v0.8778 STAT3 Zornitza Stark Publications for gene: STAT3 were set to
Mendeliome v0.8777 STAT3 Zornitza Stark Mode of inheritance for gene: STAT3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8776 STAT3 Zornitza Stark reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17881745, 14566054, 25349174, 25038750, 25359994; Phenotypes: Hyper-IgE recurrent infection syndrome MIM# 147060, Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Disorders of immune dysregulation v0.95 STAT3 Zornitza Stark Publications for gene: STAT3 were set to
Disorders of immune dysregulation v0.94 STAT3 Zornitza Stark Mode of pathogenicity for gene: STAT3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Disorders of immune dysregulation v0.93 STAT3 Zornitza Stark Mode of inheritance for gene: STAT3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Disorders of immune dysregulation v0.92 STAT3 Danielle Ariti reviewed gene: STAT3: 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: 25349174, 25038750, 25359994, 16783372; Phenotypes: Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952, Lymphoproliferation, solid organ autoimmunity, recurrent infections, short stature, eczema, delayed puberty, dental abnormalities, autoimmune interstitial lung disease, juvenile-onset arthritis, primary hypothyroidism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.125 STK4 Zornitza Stark Marked gene: STK4 as ready
Congenital Heart Defect v0.125 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.125 STK4 Zornitza Stark Classified gene: STK4 as Green List (high evidence)
Congenital Heart Defect v0.125 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.328 STAT3 Zornitza Stark Marked gene: STAT3 as ready
Combined Immunodeficiency v0.328 STAT3 Zornitza Stark Gene: stat3 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.328 STAT3 Zornitza Stark Phenotypes for gene: STAT3 were changed from to Hyper-IgE recurrent infection syndrome MIM# 147060; Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952
Combined Immunodeficiency v0.327 STAT3 Zornitza Stark Publications for gene: STAT3 were set to
Combined Immunodeficiency v0.326 STAT3 Zornitza Stark Mode of pathogenicity for gene: STAT3 was changed from to Other
Combined Immunodeficiency v0.325 STAT3 Zornitza Stark Mode of inheritance for gene: STAT3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.324 STK4 Zornitza Stark Marked gene: STK4 as ready
Combined Immunodeficiency v0.324 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.324 STK4 Zornitza Stark Phenotypes for gene: STK4 were changed from to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868; CD4/CD8 lymphopaenia; cardiac malformations; reduced naïve T cells; increased TEM and TEMRA cells; poor T cell Proliferation; Reduced memory B cells; Reduced IgM, increased IgG, IgA, IgE; impaired antibody responses; intermittent neutropaenia; bacterial/ viral/ fungal infections; autoimmune cytopaenias; mucocutaneous candidiasis; cutaneous warts
Congenital Heart Defect v0.124 STK4 Danielle Ariti gene: STK4 was added
gene: STK4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK4 were set to 22294732; 26117625; 22174160; 22952854
Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868; CD4/CD8 lymphopaenia; cardiac malformations; reduced naïve T cells; increased TEM and TEMRA cells; poor T cell Proliferation; Reduced memory B cells; Reduced IgM, increased IgG, IgA, IgE; impaired antibody responses; intermittent neutropaenia; bacterial/ viral/ fungal infections; autoimmune cytopaenias; mucocutaneous candidiasis; cutaneous warts
Review for gene: STK4 was set to GREEN
Added comment: 12 individuals from 5 unrelated families have been reported with STK4 deficiency; two mouse model.

Homozygous and compound heterozygous (deletion, missense and nonsense) variants have been identified, resulting in premature stop codons and reduced protein.

All individuals displayed a similar immunological phenotype, characterised by naive CD4+ and CD8+ T-cell lymphopaenia in particular. Other typical features included cardiac malformations, recurrent bacterial/viral infections, mucocutaneous candidiasis and cutaneous warts.
Sources: Literature
Combined Immunodeficiency v0.323 STK4 Zornitza Stark Publications for gene: STK4 were set to
Mendeliome v0.8776 STK4 Zornitza Stark Marked gene: STK4 as ready
Mendeliome v0.8776 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Mendeliome v0.8776 STK4 Zornitza Stark Phenotypes for gene: STK4 were changed from to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868; CD4/CD8 lymphopaenia; cardiac malformations; reduced naïve T cells; increased TEM and TEMRA cells; poor T cell Proliferation; Reduced memory B cells; Reduced IgM, increased IgG, IgA, IgE; impaired antibody responses; intermittent neutropaenia; bacterial/ viral/ fungal infections; autoimmune cytopaenias; mucocutaneous candidiasis; cutaneous warts
Mendeliome v0.8775 STK4 Zornitza Stark Publications for gene: STK4 were set to
Combined Immunodeficiency v0.322 STK4 Zornitza Stark Mode of inheritance for gene: STK4 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8774 STK4 Zornitza Stark Mode of inheritance for gene: STK4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.322 STK4 Zornitza Stark Mode of inheritance for gene: STK4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8773 SP110 Zornitza Stark Marked gene: SP110 as ready
Mendeliome v0.8773 SP110 Zornitza Stark Gene: sp110 has been classified as Green List (High Evidence).
Mendeliome v0.8773 SP110 Zornitza Stark Tag founder tag was added to gene: SP110.
Mendeliome v0.8773 SP110 Zornitza Stark Phenotypes for gene: SP110 were changed from to Hepatic veno-occlusive disease with immunodeficiency MIM#235550; Hepatic veno-occlusive disease; susceptibility to Pneumocystis jirovecii pneumonia; cytomegalovirus; thrombocytopaenia; hepatosplenomegaly; cerebrospinal leukodystrophy; memory T/B cell deficiency; low Ig levels; absent tissue plasma cells; absent lymph node germinal centers; hypogammaglobulinaemia
Mendeliome v0.8772 SP110 Zornitza Stark Publications for gene: SP110 were set to
Combined Immunodeficiency v0.321 SPINK5 Zornitza Stark Marked gene: SPINK5 as ready
Combined Immunodeficiency v0.321 SPINK5 Zornitza Stark Gene: spink5 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.321 SPINK5 Zornitza Stark Phenotypes for gene: SPINK5 were changed from to Netherton syndrome MIM# 256500; Low switched and non-switched B cells; High IgE and IgA; Antibody variably decreased; Congenital ichthyosis; bamboo hair; atopic diathesis; increased bacterial infections; failure to thrive; food allergies
Combined Immunodeficiency v0.320 SPINK5 Zornitza Stark Publications for gene: SPINK5 were set to
Combined Immunodeficiency v0.319 SPINK5 Zornitza Stark Mode of inheritance for gene: SPINK5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8771 SP110 Zornitza Stark Mode of inheritance for gene: SP110 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8770 SMARCAL1 Zornitza Stark Marked gene: SMARCAL1 as ready
Mendeliome v0.8770 SMARCAL1 Zornitza Stark Gene: smarcal1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.318 SP110 Zornitza Stark Marked gene: SP110 as ready
Combined Immunodeficiency v0.318 SP110 Zornitza Stark Gene: sp110 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.318 SP110 Zornitza Stark Phenotypes for gene: SP110 were changed from to Hepatic veno-occlusive disease with immunodeficiency MIM#235550; Hepatic veno-occlusive disease; susceptibility to Pneumocystis jirovecii pneumonia; cytomegalovirus; thrombocytopaenia; hepatosplenomegaly; cerebrospinal leukodystrophy; memory T/B cell deficiency; low Ig levels; absent tissue plasma cells; absent lymph node germinal centers; hypogammaglobulinaemia
Combined Immunodeficiency v0.317 SP110 Zornitza Stark Tag founder tag was added to gene: SP110.
Combined Immunodeficiency v0.317 SP110 Zornitza Stark Publications for gene: SP110 were set to
Combined Immunodeficiency v0.316 SP110 Zornitza Stark Mode of inheritance for gene: SP110 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.315 SMARCAL1 Zornitza Stark Marked gene: SMARCAL1 as ready
Combined Immunodeficiency v0.315 SMARCAL1 Zornitza Stark Gene: smarcal1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.315 SMARCAL1 Zornitza Stark Phenotypes for gene: SMARCAL1 were changed from to Schimke immune-osseous dysplasia MIM# 242900; T cell deficiency; Short stature; spondyloepiphyseal dysplasia; renal dysfunction; lymphocytopaenia; nephropathy; bacterial/viral/fungal infections; may present as SCID; bone marrow failure
Mendeliome v0.8770 SMARCAL1 Zornitza Stark Phenotypes for gene: SMARCAL1 were changed from to Schimke immune-osseous dysplasia MIM# 242900; T cell deficiency; Short stature; spondyloepiphyseal dysplasia; renal dysfunction; lymphocytopaenia; nephropathy; bacterial/viral/fungal infections; may present as SCID; bone marrow failure
Mendeliome v0.8769 SMARCAL1 Zornitza Stark Publications for gene: SMARCAL1 were set to
Combined Immunodeficiency v0.314 SMARCAL1 Zornitza Stark Publications for gene: SMARCAL1 were set to
Genetic Epilepsy v0.1165 SLC46A1 Danielle Ariti gene: SLC46A1 was added
gene: SLC46A1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SLC46A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC46A1 were set to 20301716
Phenotypes for gene: SLC46A1 were set to Folate malabsorption, hereditary MIM# 229050; Decreased Ig levels; megaloblastic anaemia; failure to thrive; Immunodeficiency; if untreated for prolonged periods results in intellectual disability; oral mucositis; hypoimmunoglobulinaemia; recurrent infections; seizures; motor impairment; leukopaenia; thrombocytopaenia
Review for gene: SLC46A1 was set to GREEN
Added comment: ver 30 unrelated individuals reported with variants in SLC46A1 presenting with hereditary folate malabsorption; two mouse model.

In-frame deletion variant has been commonly reported among individuals of Puerto Rican heritage: c.1082-1G>A;
Other variants include homozygous and compound heterozygous deletions, insertion, missense and nonsense report in individuals of other origins (Chinese, Moroccan, Turkish, African American).

Clinically presents in infancy with failure to thrive, recurrent diarrhoea, anaemia, recurrent infections and, frequently, seizures.
Sources: Literature
Mendeliome v0.8768 SMARCAL1 Zornitza Stark Mode of inheritance for gene: SMARCAL1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.313 SMARCAL1 Zornitza Stark Mode of inheritance for gene: SMARCAL1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.312 SLC46A1 Zornitza Stark Marked gene: SLC46A1 as ready
Combined Immunodeficiency v0.312 SLC46A1 Zornitza Stark Gene: slc46a1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.312 SLC46A1 Zornitza Stark Phenotypes for gene: SLC46A1 were changed from to Folate malabsorption, hereditary MIM# 229050; Decreased Ig levels; megaloblastic anaemia; failure to thrive; Immunodeficiency; if untreated for prolonged periods results in intellectual disability; oral mucositis; hypoimmunoglobulinaemia; recurrent infections; seizures; motor impairment; leukopaenia; thrombocytopaenia
Combined Immunodeficiency v0.311 SLC46A1 Zornitza Stark Publications for gene: SLC46A1 were set to
Combined Immunodeficiency v0.310 SLC46A1 Zornitza Stark Mode of inheritance for gene: SLC46A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.309 SLC46A1 Zornitza Stark Tag founder tag was added to gene: SLC46A1.
Mendeliome v0.8767 STK4 Danielle Ariti reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22294732, 26117625, 22174160, 22952854; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868, CD4/CD8 lymphopaenia, cardiac malformations, reduced naïve T cells, increased TEM and TEMRA cells, poor T cell Proliferation, Reduced memory B cells, Reduced IgM, increased IgG, IgA, IgE, impaired antibody responses, intermittent neutropaenia, bacterial/ viral/ fungal infections, autoimmune cytopaenias, mucocutaneous candidiasis, cutaneous warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SPINK5 Danielle Ariti reviewed gene: SPINK5: Rating: ; Mode of pathogenicity: None; Publications: 33534181, 20657595; Phenotypes: Netherton syndrome MIM# 256500, Low switched and non-switched B cells, High IgE and IgA, Antibody variably decreased, Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive, food allergies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SP110 Danielle Ariti reviewed gene: SP110: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301448, 31721003; Phenotypes: Hepatic veno-occlusive disease with immunodeficiency MIM#235550, Hepatic veno-occlusive disease, susceptibility to Pneumocystis jirovecii pneumonia, cytomegalovirus, thrombocytopaenia, hepatosplenomegaly, cerebrospinal leukodystrophy, memory T/B cell deficiency, low Ig levels, absent tissue plasma cells, absent lymph node germinal centers, hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8767 SMARCAL1 Danielle Ariti reviewed gene: SMARCAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301550, 17089404, 20036229; Phenotypes: Schimke immune-osseous dysplasia MIM# 242900, T cell deficiency, Short stature, spondyloepiphyseal dysplasia, renal dysfunction, lymphocytopaenia, nephropathy, bacterial/viral/fungal infections, may present as SCID, bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.309 STAT3 Danielle Ariti changed review comment from: Well-established disease-gene association for hyper-IgE syndrome; identified heterozygous STAT3 variants in over 50 familial and sporadic cases; dominant-negative loss of function; multiple mouse models

Hyper IgE individuals presented with the triad of staphylococcal abscesses, pneumonia with pneumatocele formation, and extremely elevated IgE.


15 unrelated families with Autoimmune disease, multisystem, infantile-onset, 1; 13 STAT3 variants identified (5 were de novo); gain of function; multiple mouse models

Autoimmune disease, multisystem, infantile-onset, 1 individuals exhibited various clinical features, with most presenting with lymphadenopathy, autoimmune cytopaenias, multiorgan autoimmunity, infections, and short stature.

STAT3 monoallelic variants were missense and in-frame deletions in both diseases.

(Hyper IgE- Loss of Function AND Autoimmune disease- Gain of function); to: Well-established disease-gene association for hyper-IgE syndrome; identified heterozygous STAT3 variants in over 50 familial and sporadic cases; dominant-negative loss of function; multiple mouse models

Hyper IgE individuals presented with the triad of staphylococcal abscesses, pneumonia with pneumatocele formation, and extremely elevated IgE.

15 unrelated families with Autoimmune disease, multisystem, infantile-onset, 1; 13 STAT3 variants identified (5 were de novo); gain of function; multiple mouse models

Autoimmune disease, multisystem, infantile-onset, 1 individuals exhibited various clinical features, with most presenting with lymphadenopathy, autoimmune cytopaenias, multiorgan autoimmunity, infections, and short stature.

STAT3 monoallelic variants were missense and in-frame deletions in both diseases.

(Hyper IgE- Loss of Function AND Autoimmune disease- Gain of function)
Combined Immunodeficiency v0.309 STAT3 Danielle Ariti reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 17881745, 14566054, 25349174, 25038750, 25359994; Phenotypes: Hyper-IgE recurrent infection syndrome MIM# 147060, Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.309 STAT3 Danielle Ariti Deleted their review
Combined Immunodeficiency v0.309 STAT3 Danielle Ariti edited their review of gene: STAT3: Added comment: 18 individuals from 15 unrelated families; Multiple mouse models

All 13 heterozygous variants reported have been missense or in-frame deletions that result in a gain of function; 5 of these de novo

Individuals exhibited various clinical features, with most presenting with lymphadenopathy, autoimmune cytopaenias, multiorgan autoimmunity, infections, and short stature.; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 25349174, 25038750, 25359994, 16783372; Changed phenotypes: Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952, Lymphoproliferation, solid organ autoimmunity, recurrent infections, short stature, eczema, delayed puberty, dental abnormalities, autoimmune cytopaenias, juvenile-onset arthritis, primary hypothyroidism
Combined Immunodeficiency v0.309 STAT3 Danielle Ariti reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17881745, 14566054, 15194489; Phenotypes: Hyper-IgE recurrent infection syndrome MIM# 147060, NKT cells decreased, Very high IgE, specific antibody production decreased, Distinctive facial features (broad nasal bridge), bacterial infections, staphylococcal abscesses, eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth, coronary and cerebral aneurysms; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8767 GPR68 Zornitza Stark Marked gene: GPR68 as ready
Mendeliome v0.8767 GPR68 Zornitza Stark Gene: gpr68 has been classified as Green List (High Evidence).
Mendeliome v0.8767 GPR68 Zornitza Stark Phenotypes for gene: GPR68 were changed from to Amelogenesis imperfecta, hypomaturation type, IIA6 MIM#617217
Mendeliome v0.8766 GPR68 Zornitza Stark Publications for gene: GPR68 were set to
Mendeliome v0.8765 GPR68 Zornitza Stark Mode of inheritance for gene: GPR68 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8764 GPR68 Zornitza Stark reviewed gene: GPR68: Rating: GREEN; Mode of pathogenicity: None; Publications: 27693231, 32279993; Phenotypes: Amelogenesis imperfecta, hypomaturation type, IIA6 MIM#617217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.26 GPR68 Zornitza Stark Marked gene: GPR68 as ready
Amelogenesis imperfecta v0.26 GPR68 Zornitza Stark Gene: gpr68 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.26 GPR68 Zornitza Stark Phenotypes for gene: GPR68 were changed from Amelogenesis imperfecta, hypomaturation type, IIA6, 617217 to Amelogenesis imperfecta, hypomaturation type, IIA6 MIM#617217
Amelogenesis imperfecta v0.25 GPR68 Zornitza Stark Publications for gene: GPR68 were set to 27693231
Mendeliome v0.8764 FAM83H Zornitza Stark Marked gene: FAM83H as ready
Mendeliome v0.8764 FAM83H Zornitza Stark Gene: fam83h has been classified as Green List (High Evidence).
Mendeliome v0.8764 FAM83H Zornitza Stark Phenotypes for gene: FAM83H were changed from to Amelogenesis imperfecta, type IIIA MIM#130900
Mendeliome v0.8763 FAM83H Zornitza Stark Publications for gene: FAM83H were set to
Mendeliome v0.8762 FAM83H Zornitza Stark Mode of inheritance for gene: FAM83H was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8761 FAM83H Zornitza Stark reviewed gene: FAM83H: Rating: GREEN; Mode of pathogenicity: None; Publications: 18484629, 19407157, 19825039, 26481691, 21702852, 20160442, 26142250, 22414746, 19828885, 19220331, 26502894, 18252228, 21597265, 21118793, 26788537, 26171361; Phenotypes: Amelogenesis imperfecta, type IIIA MIM#130900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v0.24 FAM83H Zornitza Stark Publications for gene: FAM83H were set to 18484629; 19407157; 19825039; 26481691; 21702852; 20160442; 26142250; 22414746; 19828885; 19220331; 26502894; 18252228; 21597265; 21118793; 26788537; 26171361
Amelogenesis imperfecta v0.23 FAM83H Zornitza Stark Marked gene: FAM83H as ready
Amelogenesis imperfecta v0.23 FAM83H Zornitza Stark Gene: fam83h has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.23 FAM83H Zornitza Stark Phenotypes for gene: FAM83H were changed from Amelogenesis imperfecta, type III, 130900; Amelogenesis Imperfecta, Type III, 130900; Hypocalcified AI to Amelogenesis imperfecta, type IIIA MIM#130900
Amelogenesis imperfecta v0.22 FAM20C Zornitza Stark Marked gene: FAM20C as ready
Amelogenesis imperfecta v0.22 FAM20C Zornitza Stark Gene: fam20c has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.22 FAM20C Zornitza Stark Phenotypes for gene: FAM20C were changed from hypoplastic Amelogenesis Imperfecta; Raine Syndrome, 259775 to Raine syndrome MIM#259775; hypoplastic Amelogenesis Imperfecta
Mendeliome v0.8761 ENAM Zornitza Stark Marked gene: ENAM as ready
Mendeliome v0.8761 ENAM Zornitza Stark Gene: enam has been classified as Green List (High Evidence).
Mendeliome v0.8761 ENAM Zornitza Stark Phenotypes for gene: ENAM were changed from to Amelogenesis imperfecta, type IB, MIM# 104500; Amelogenesis imperfecta, type IC, MIM# 204650
Mendeliome v0.8760 ENAM Zornitza Stark Publications for gene: ENAM were set to
Mendeliome v0.8759 ENAM Zornitza Stark Mode of inheritance for gene: ENAM was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8758 ENAM Zornitza Stark reviewed gene: ENAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 11487571, 28334996, 14684688, 33864320; Phenotypes: Amelogenesis imperfecta, type IB, MIM# 104500, Amelogenesis imperfecta, type IC, MIM# 204650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Calcium and Phosphate disorders v0.34 FAM20A Zornitza Stark Marked gene: FAM20A as ready
Calcium and Phosphate disorders v0.34 FAM20A Zornitza Stark Gene: fam20a has been classified as Green List (High Evidence).
Calcium and Phosphate disorders v0.34 FAM20A Zornitza Stark Phenotypes for gene: FAM20A were changed from to Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690
Calcium and Phosphate disorders v0.33 FAM20A Zornitza Stark Publications for gene: FAM20A were set to
Calcium and Phosphate disorders v0.32 FAM20A Zornitza Stark Mode of inheritance for gene: FAM20A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Calcium and Phosphate disorders v0.31 FAM20A Zornitza Stark reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23434854, 23697977, 23468644, 24756937, 21549343, 24259279, 24196488, 26502894, 25827751, 21990045; Phenotypes: Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690; Mode of inheritance: None
Mendeliome v0.8758 FAM20A Zornitza Stark Marked gene: FAM20A as ready
Mendeliome v0.8758 FAM20A Zornitza Stark Gene: fam20a has been classified as Green List (High Evidence).
Mendeliome v0.8758 FAM20A Zornitza Stark Phenotypes for gene: FAM20A were changed from to Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690
Mendeliome v0.8757 FAM20A Zornitza Stark Publications for gene: FAM20A were set to
Mendeliome v0.8756 FAM20A Zornitza Stark Mode of inheritance for gene: FAM20A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8755 FAM20A Zornitza Stark reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23434854, 23697977, 23468644, 24756937, 21549343, 24259279, 24196488, 26502894, 25827751, 21990045; Phenotypes: Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.21 FAM20A Zornitza Stark Publications for gene: FAM20A were set to 23434854; 23697977; 23468644; 24756937; 21549343; 24259279; 24196488; 26502894; 25827751; 21990045
Amelogenesis imperfecta v0.20 FAM20A Zornitza Stark Marked gene: FAM20A as ready
Amelogenesis imperfecta v0.20 FAM20A Zornitza Stark Gene: fam20a has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.20 FAM20A Zornitza Stark Phenotypes for gene: FAM20A were changed from Amelogenesis Imperfecta, Type IG, 204690; Hypomieralised AI; Amelogenesis imperfecta, type IG (enamel-renal syndrome), 204690 to Amelogenesis imperfecta, type IG (enamel-renal syndrome) MIM#204690
Combined Immunodeficiency v0.309 STK4 Danielle Ariti reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22294732, 26117625, 22174160, 22952854; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868, CD4/CD8 lymphopaenia, cardiac malformations, reduced naïve T cells, increased TEM and TEMRA cells, poor T cell Proliferation, Reduced memory B cells, Reduced IgM, increased IgG, IgA, IgE, impaired antibody responses, intermittent neutropaenia, bacterial/ viral/ fungal infections, autoimmune cytopaenias, mucocutaneous candidiasis, cutaneous warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.19 ENAM Zornitza Stark Marked gene: ENAM as ready
Amelogenesis imperfecta v0.19 ENAM Zornitza Stark Gene: enam has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.19 ENAM Zornitza Stark Phenotypes for gene: ENAM were changed from Amelogenesis imperfecta, type IB, 104500; Amelogenesis imperfecta, type IC, 204650; autosomal recessive amelogenesis imperfecta; Amelogenesis Imperfecta, Dominant to Amelogenesis imperfecta, type IB, MIM# 104500; Amelogenesis imperfecta, type IC, MIM# 204650
Amelogenesis imperfecta v0.18 ENAM Zornitza Stark Publications for gene: ENAM were set to 14684688; 11978766; 12407086; 20439930; 25769099; 22540999; 25143514; 22029166; 19329462; 28334996; 26502894; 17316551; 21597265; 16246937; 15723871; 11487571
Amelogenesis imperfecta v0.17 ENAM Zornitza Stark reviewed gene: ENAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 11487571, 28334996, 14684688, 33864320; Phenotypes: Amelogenesis imperfecta, type IB, MIM# 104500, Amelogenesis imperfecta, type IC, MIM# 204650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Combined Immunodeficiency v0.309 SPINK5 Danielle Ariti reviewed gene: SPINK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33534181, 20657595; Phenotypes: Netherton syndrome MIM# 256500, Low switched and non-switched B cells, High IgE and IgA, Antibody variably decreased, Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive, food allergies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.309 SP110 Danielle Ariti reviewed gene: SP110: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301448, 31721003; Phenotypes: Hepatic veno-occlusive disease with immunodeficiency MIM#235550, Hepatic veno-occlusive disease, susceptibility to Pneumocystis jirovecii pneumonia, cytomegalovirus, thrombocytopaenia, hepatosplenomegaly, cerebrospinal leukodystrophy, memory T/B cell deficiency, low Ig levels, absent tissue plasma cells, absent lymph node germinal centers, hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.17 DLX3 Zornitza Stark Marked gene: DLX3 as ready
Amelogenesis imperfecta v0.17 DLX3 Zornitza Stark Gene: dlx3 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.17 DLX3 Zornitza Stark Phenotypes for gene: DLX3 were changed from amelogenesis imperfecta with taurodontism; hypoplastic AI, taurodontism and kinky hair; Tricho-dento-osseous syndrome (TDO) (includes enamel hypoplasia); Amelogenesis Imperfecta, Dominant; Tricho-Dento-Osseous syndrome , Amelogenesis Imperfecta, hypoplastic; Trichodontoosseous syndrome, 190320; Amelogenesis imperfecta, type IV, 104510; Amelogenesis Imperfecta, Type IV, 104510 to Amelogenesis imperfecta, type IV, MIM# 104510; Trichodontoosseous syndrome, MIM# 190320
Amelogenesis imperfecta v0.16 DLX3 Zornitza Stark Publications for gene: DLX3 were set to 15666299; 23949819; 26104267; 21252474; 20151948; 9467018
Amelogenesis imperfecta v0.15 DLX3 Zornitza Stark reviewed gene: DLX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9467018, 15666299, 18203197; Phenotypes: Amelogenesis imperfecta, type IV, MIM# 104510, Trichodontoosseous syndrome, MIM# 190320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v0.15 COL17A1 Zornitza Stark Marked gene: COL17A1 as ready
Amelogenesis imperfecta v0.15 COL17A1 Zornitza Stark Gene: col17a1 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.15 COL17A1 Zornitza Stark Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional, non-Herlitz type, MIM#226650 (includes enamel pitting); Amelogenesis Imperfecta; hypoplastic amelogenesis imperfecta to Epidermolysis bullosa, junctional, non-Herlitz type, MIM#226650 (includes enamel pitting); hypoplastic amelogenesis imperfecta
Amelogenesis imperfecta v0.14 COL17A1 Zornitza Stark Phenotypes for gene: COL17A1 were changed from non-Herlitz junctional epidermolysis bullosa (nH-JEB) and amelogenesis imperfecta; Epidermolysis bullosa, junctional, non-Herlitz type, 226650 (includes enamel pitting); Amelogenesis Imperfecta; hypoplastic amelogenesis imperfecta to Epidermolysis bullosa, junctional, non-Herlitz type, MIM#226650 (includes enamel pitting); Amelogenesis Imperfecta; hypoplastic amelogenesis imperfecta
Amelogenesis imperfecta v0.13 COL17A1 Zornitza Stark Mode of inheritance for gene: COL17A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.12 COL17A1 Zornitza Stark commented on gene: COL17A1: This type of EB has prominent dental involvement, including enamel pitting.
Amelogenesis imperfecta v0.12 COL17A1 Zornitza Stark reviewed gene: COL17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.309 SMARCAL1 Danielle Ariti reviewed gene: SMARCAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301550, 17089404, 20036229; Phenotypes: Schimke immune-osseous dysplasia MIM# 242900, T cell deficiency, Short stature, spondyloepiphyseal dysplasia, renal dysfunction, lymphocytopaenia, nephropathy, bacterial/viral/fungal infections, may present as SCID, bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.12 CNNM4 Zornitza Stark Publications for gene: CNNM4 were set to 19200527; 19200525
Amelogenesis imperfecta v0.11 CNNM4 Zornitza Stark changed review comment from: Jalili syndrome is an autosomal recessive disorder consisting of cone-rod dystrophy and amelogenesis imperfecta. Significant visual impairment with nystagmus and photophobia is present from infancy or early childhood and progresses with age. Enamel of primary and secondary dentitions is grossly abnormal and prone to rapid posteruptive failure, in part reflecting hypomineralization.

At least 8 unrelated families reported.; to: Jalili syndrome is an autosomal recessive disorder consisting of cone-rod dystrophy and amelogenesis imperfecta. Significant visual impairment with nystagmus and photophobia is present from infancy or early childhood and progresses with age. Enamel of primary and secondary dentitions is grossly abnormal and prone to rapid posteruptive failure, in part reflecting hypomineralization.

>100 affected individuals reported.
Amelogenesis imperfecta v0.11 CNNM4 Zornitza Stark edited their review of gene: CNNM4: Changed publications: 19200527, 19200525, 30705057
Amelogenesis imperfecta v0.11 CNNM4 Zornitza Stark Marked gene: CNNM4 as ready
Amelogenesis imperfecta v0.11 CNNM4 Zornitza Stark Gene: cnnm4 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.11 CNNM4 Zornitza Stark Phenotypes for gene: CNNM4 were changed from cone-rod dystrophy and amelogenesis imperfecta; Jalili syndrome, 217080 (includes amelogenesis imperfecta) to Jalili syndrome, MIM#217080; cone-rod dystrophy and amelogenesis imperfecta
Amelogenesis imperfecta v0.10 CNNM4 Zornitza Stark Publications for gene: CNNM4 were set to
Amelogenesis imperfecta v0.9 CNNM4 Zornitza Stark reviewed gene: CNNM4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19200527, 19200525; Phenotypes: Jalili syndrome, MIM# 217080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8755 C4orf26 Zornitza Stark Marked gene: C4orf26 as ready
Mendeliome v0.8755 C4orf26 Zornitza Stark Gene: c4orf26 has been classified as Green List (High Evidence).
Mendeliome v0.8755 C4orf26 Zornitza Stark Phenotypes for gene: C4orf26 were changed from to Amelogenesis imperfecta, type IIA4, MIM# 614832
Mendeliome v0.8754 C4orf26 Zornitza Stark Publications for gene: C4orf26 were set to
Mendeliome v0.8753 C4orf26 Zornitza Stark Mode of inheritance for gene: C4orf26 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8752 C4orf26 Zornitza Stark reviewed gene: C4orf26: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901946, 27558265; Phenotypes: Amelogenesis imperfecta, type IIA4, MIM# 614832; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.9 C4orf26 Zornitza Stark Marked gene: C4orf26 as ready
Amelogenesis imperfecta v0.9 C4orf26 Zornitza Stark Gene: c4orf26 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.9 C4orf26 Zornitza Stark Phenotypes for gene: C4orf26 were changed from Amelogenesis imperfecta, type IIA4, 614832; Amelogenesis Imperfecta, Type IIA4, 614832; hypomineralized amelogenesis imperfecta to Amelogenesis Imperfecta, Type IIA4, MIM#614832; hypomineralized amelogenesis imperfecta
Amelogenesis imperfecta v0.8 C4orf26 Zornitza Stark reviewed gene: C4orf26: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901946, 27558265; Phenotypes: Amelogenesis imperfecta, type IIA4, MIM# 614832; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8752 AMELX Zornitza Stark Marked gene: AMELX as ready
Mendeliome v0.8752 AMELX Zornitza Stark Gene: amelx has been classified as Green List (High Evidence).
Mendeliome v0.8752 AMELX Zornitza Stark Phenotypes for gene: AMELX were changed from Amelogenesis imperfecta, type 1E, MIM# 301200 to Amelogenesis imperfecta, type 1E, MIM# 301200
Mendeliome v0.8752 AMELX Zornitza Stark Phenotypes for gene: AMELX were changed from to Amelogenesis imperfecta, type 1E, MIM# 301200
Mendeliome v0.8751 AMELX Zornitza Stark Publications for gene: AMELX were set to
Mendeliome v0.8750 AMELX Zornitza Stark Mode of inheritance for gene: AMELX was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.8749 AMELX Zornitza Stark Tag SV/CNV tag was added to gene: AMELX.
Mendeliome v0.8749 AMELX Zornitza Stark reviewed gene: AMELX: Rating: GREEN; Mode of pathogenicity: None; Publications: 17189466, 22243263, 7599636, 23251683, 1483698 1916828, 9188994, 15111628, 11201048, 26502894, 7782077, 11922869, 28130977, 8406474, 11839357, 25117480, 19610109; Phenotypes: Amelogenesis imperfecta, type 1E, MIM# 301200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v0.8749 AMBN Zornitza Stark Marked gene: AMBN as ready
Mendeliome v0.8749 AMBN Zornitza Stark Gene: ambn has been classified as Green List (High Evidence).
Mendeliome v0.8749 AMBN Zornitza Stark Phenotypes for gene: AMBN were changed from to Amelogenesis imperfecta, type IF MIM#616270
Amelogenesis imperfecta v0.8 AMELX Zornitza Stark Marked gene: AMELX as ready
Amelogenesis imperfecta v0.8 AMELX Zornitza Stark Gene: amelx has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.8 AMELX Zornitza Stark Phenotypes for gene: AMELX were changed from Amelogenesis imperfecta, type 1E, 301200; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI; iX-linked hypoplastic amelogenesis imperfecta to Amelogenesis imperfecta, type 1E, 301200; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI
Amelogenesis imperfecta v0.7 AMELX Zornitza Stark Tag SV/CNV tag was added to gene: AMELX.
Amelogenesis imperfecta v0.7 AMELX Zornitza Stark reviewed gene: AMELX: Rating: GREEN; Mode of pathogenicity: None; Publications: 1916828, 15111628, 23251683; Phenotypes: Amelogenesis imperfecta, type 1E, MIM# 301200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Combined Immunodeficiency v0.309 SLC46A1 Danielle Ariti reviewed gene: SLC46A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301716; Phenotypes: Folate malabsorption, hereditary MIM# 229050, Decreased Ig levels, megaloblastic anaemia, failure to thrive, Immunodeficiency, if untreated for prolonged periods results in intellectual disability, oral mucositis, hypoimmunoglobulinaemia, recurrent infections, seizures, motor impairment, leukopaenia, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8748 AMBN Zornitza Stark Publications for gene: AMBN were set to
Mendeliome v0.8747 AMBN Zornitza Stark Mode of inheritance for gene: AMBN was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8746 AMBN Zornitza Stark reviewed gene: AMBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24858907, 26502894, 31402633, 30174330; Phenotypes: Amelogenesis imperfecta, type IF MIM#616270; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.7 AMBN Zornitza Stark Marked gene: AMBN as ready
Amelogenesis imperfecta v0.7 AMBN Zornitza Stark Gene: ambn has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.7 AMBN Zornitza Stark Phenotypes for gene: AMBN were changed from Amelogenesis imperfecta, type IF, 616270 to Amelogenesis imperfecta, type IF, MIM#616270
Amelogenesis imperfecta v0.6 AMBN Zornitza Stark Publications for gene: AMBN were set to 24858907; 26502894
Amelogenesis imperfecta v0.5 AMBN Zornitza Stark Mode of inheritance for gene: AMBN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v0.4 AMBN Zornitza Stark reviewed gene: AMBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 31402633, 30174330; Phenotypes: Amelogenesis imperfecta, type IF MIM#616270; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8746 ACP4 Zornitza Stark reviewed gene: ACP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28513613, 27843125, 33552707; Phenotypes: Amelogenesis imperfecta, type IJ MIM#617297; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v0.113 KIAA0753 Zornitza Stark Marked gene: KIAA0753 as ready
Skeletal dysplasia v0.113 KIAA0753 Zornitza Stark Gene: kiaa0753 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.4 ACP4 Zornitza Stark Marked gene: ACP4 as ready
Amelogenesis imperfecta v0.4 ACP4 Zornitza Stark Gene: acp4 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.4 ACP4 Zornitza Stark Phenotypes for gene: ACP4 were changed from Amelogenesis imperfecta, type IJ, 617297; hypoplastic amelogenesis imperfecta to Amelogenesis imperfecta, type IJ, MIM#617297; hypoplastic amelogenesis imperfecta
Amelogenesis imperfecta v0.3 ACP4 Zornitza Stark Publications for gene: ACP4 were set to 28513613; 27843125
Skeletal dysplasia v0.113 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from ?Orofaciodigital syndrome XV 617127; Joubert syndrome; Short-rib skeletal dysplasia to ?Orofaciodigital syndrome XV 617127; Joubert syndrome 38, MIM# 619476; Short-rib skeletal dysplasia
Mendeliome v0.8746 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from Orofaciodigital syndrome XV, MIM# 617127; Joubert syndrome to Orofaciodigital syndrome XV, MIM# 617127; Joubert syndrome 38, MIM# 619476
Joubert syndrome and other neurological ciliopathies v1.11 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from ?Orofaciodigital syndrome XV 617127; Joubert syndrome to ?Orofaciodigital syndrome XV 617127; Joubert syndrome 38, MIM# 619476
Ciliopathies v1.8 KIAA0753 Zornitza Stark Phenotypes for gene: KIAA0753 were changed from Orofaciodigital syndrome XV 617127; Joubert syndrome to Orofaciodigital syndrome XV 617127; Joubert syndrome 38, MIM# 619476
Intellectual disability syndromic and non-syndromic v0.4047 TMEM222 Zornitza Stark Marked gene: TMEM222 as ready
Intellectual disability syndromic and non-syndromic v0.4047 TMEM222 Zornitza Stark Gene: tmem222 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4047 TMEM222 Zornitza Stark Phenotypes for gene: TMEM222 were changed from Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality to Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Intellectual disability syndromic and non-syndromic v0.4046 TMEM222 Zornitza Stark reviewed gene: TMEM222: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1165 TMEM222 Zornitza Stark Phenotypes for gene: TMEM222 were changed from Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality to Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Genetic Epilepsy v0.1164 TMEM222 Zornitza Stark reviewed gene: TMEM222: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.38 TMEM222 Zornitza Stark Phenotypes for gene: TMEM222 were changed from Intellectual disability; Epilepsy; Microcephaly to Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Intellectual disability; Epilepsy; Microcephaly
Microcephaly v1.37 TMEM222 Zornitza Stark edited their review of gene: TMEM222: Changed phenotypes: Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470, Intellectual disability, Epilepsy, Microcephaly
Mendeliome v0.8745 TMEM222 Zornitza Stark Phenotypes for gene: TMEM222 were changed from Intellectual disability; Epilepsy; Microcephaly to Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Intellectual disability; Epilepsy; Microcephaly
Mendeliome v0.8744 TMEM222 Zornitza Stark edited their review of gene: TMEM222: Changed phenotypes: Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470, Intellectual disability, Epilepsy, Microcephaly
Mendeliome v0.8744 TCF7L2 Zornitza Stark Phenotypes for gene: TCF7L2 were changed from Developmental disorders to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system
Mendeliome v0.8743 TCF7L2 Zornitza Stark Publications for gene: TCF7L2 were set to 33057194
Mendeliome v0.8742 TCF7L2 Zornitza Stark Classified gene: TCF7L2 as Green List (high evidence)
Mendeliome v0.8742 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Marked gene: TCF7L2 as ready
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Added comment: Comment when marking as ready: Sufficient cases/detail to upgrade to Green.
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Green List (High Evidence).
Mendeliome v0.8741 TCF7L2 Zornitza Stark changed review comment from: 2 reviews
Konstantinos Varvagiannis (Other)
I don't know

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.
Mendeliome v0.8741 TCF7L2 Zornitza Stark reviewed gene: TCF7L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34003604; Phenotypes: Global developmental delay, Intellectual disability, Autism, Attention deficit hyperactivity disorder, Myopia, Abnormality of skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4046 TCF7L2 Zornitza Stark Phenotypes for gene: TCF7L2 were changed from Developmental disorders to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system
Intellectual disability syndromic and non-syndromic v0.4045 TCF7L2 Zornitza Stark Publications for gene: TCF7L2 were set to 33057194
Intellectual disability syndromic and non-syndromic v0.4044 TCF7L2 Zornitza Stark Classified gene: TCF7L2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4044 TCF7L2 Zornitza Stark Gene: tcf7l2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4043 TCF7L2 Konstantinos Varvagiannis reviewed gene: TCF7L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 34003604; Phenotypes: Global developmental delay, Intellectual disability, Autism, Attention deficit hyperactivity disorder, Myopia, Abnormality of skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v0.2 LTBP3 Zornitza Stark Marked gene: LTBP3 as ready
Amelogenesis imperfecta v0.2 LTBP3 Zornitza Stark Gene: ltbp3 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v0.2 LTBP3 Zornitza Stark Publications for gene: LTBP3 were set to 28084688; 25669657
Amelogenesis imperfecta v0.1 LTBP3 Zornitza Stark reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19344874, 25899461, 25669657, 29625025; Phenotypes: Dental anomalies and short stature, MIM# 601216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8741 LTBP3 Zornitza Stark Marked gene: LTBP3 as ready
Mendeliome v0.8741 LTBP3 Zornitza Stark Gene: ltbp3 has been classified as Green List (High Evidence).
Mendeliome v0.8741 LTBP3 Zornitza Stark Phenotypes for gene: LTBP3 were changed from to Dental anomalies and short stature, MIM# 601216; Geleophysic dysplasia 3, MIM# 617809; Thoracic aneurysm
Mendeliome v0.8740 LTBP3 Zornitza Stark Publications for gene: LTBP3 were set to
Mendeliome v0.8739 LTBP3 Zornitza Stark Mode of inheritance for gene: LTBP3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8738 LTBP3 Zornitza Stark reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19344874, 25899461, 25669657, 29625025, 27068007, 34150014; Phenotypes: Dental anomalies and short stature, MIM# 601216, Geleophysic dysplasia 3, MIM# 617809, Thoracic aneurysm; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mackenzie's Mission_Reproductive Carrier Screening v0.102 LTBP3 Zornitza Stark changed review comment from: Consider changing the listed disease association relevant to this panel.; to: Consider changing the listed disease association relevant to this panel: currently set to 'tooth agenesis'.
Mackenzie's Mission_Reproductive Carrier Screening v0.102 LTBP3 Zornitza Stark reviewed gene: LTBP3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Dental anomalies and short stature, MIM# 601216; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.54 LTBP3 Zornitza Stark Marked gene: LTBP3 as ready
Aortopathy_Connective Tissue Disorders v1.54 LTBP3 Zornitza Stark Gene: ltbp3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8738 ARIH1 Zornitza Stark reviewed gene: ARIH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8738 ARIH1 Zornitza Stark Mode of inheritance for gene: ARIH1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Lissencephaly and Band Heterotopia v1.6 PIDD1 Zornitza Stark Marked gene: PIDD1 as ready
Lissencephaly and Band Heterotopia v1.6 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Lissencephaly and Band Heterotopia v1.6 PIDD1 Zornitza Stark Classified gene: PIDD1 as Green List (high evidence)
Lissencephaly and Band Heterotopia v1.6 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Lissencephaly and Band Heterotopia v1.5 PIDD1 Zornitza Stark gene: PIDD1 was added
gene: PIDD1 was added to Lissencephaly and Band Heterotopia. Sources: Expert Review
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

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

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

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

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

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

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

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

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

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

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.
Sources: Expert Review
Mendeliome v0.8737 PIDD1 Zornitza Stark Marked gene: PIDD1 as ready
Mendeliome v0.8737 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Mendeliome v0.8737 PIDD1 Zornitza Stark Classified gene: PIDD1 as Green List (high evidence)
Mendeliome v0.8737 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Mendeliome v0.8736 PIDD1 Zornitza Stark gene: PIDD1 was added
gene: PIDD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

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

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

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

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

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

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

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

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

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

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

There is currently no associated phenotype in OMIM. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.
Sources: Expert Review
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Marked gene: PIDD1 as ready
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Classified gene: PIDD1 as Green List (high evidence)
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Marked gene: PIDD1 as ready
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Classified gene: PIDD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4043 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Leukodystrophy v0.228 COLGALT1 Bryony Thompson Marked gene: COLGALT1 as ready
Leukodystrophy v0.228 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Leukodystrophy v0.228 COLGALT1 Bryony Thompson Classified gene: COLGALT1 as Green List (high evidence)
Leukodystrophy v0.228 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Leukodystrophy v0.227 COLGALT1 Bryony Thompson gene: COLGALT1 was added
gene: COLGALT1 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3 MIM#618360
Review for gene: COLGALT1 was set to GREEN
Added comment: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy (paediatric onset), lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications.
Sources: Literature
Stroke v1.6 COLGALT1 Bryony Thompson Marked gene: COLGALT1 as ready
Stroke v1.6 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Stroke v1.6 COLGALT1 Bryony Thompson Classified gene: COLGALT1 as Green List (high evidence)
Stroke v1.6 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Stroke v1.5 COLGALT1 Bryony Thompson gene: COLGALT1 was added
gene: COLGALT1 was added to Stroke. Sources: Literature
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3 MIM#618360
Review for gene: COLGALT1 was set to GREEN
Added comment: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos
Sources: Literature
Brain Calcification v1.10 COLGALT1 Bryony Thompson Marked gene: COLGALT1 as ready
Brain Calcification v1.10 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Brain Calcification v1.10 COLGALT1 Bryony Thompson Classified gene: COLGALT1 as Green List (high evidence)
Brain Calcification v1.10 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Brain Calcification v1.9 COLGALT1 Bryony Thompson gene: COLGALT1 was added
gene: COLGALT1 was added to Brain Calcification. Sources: Literature
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3 MIM#618360
Review for gene: COLGALT1 was set to GREEN
Added comment: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos
Sources: Literature
Mendeliome v0.8735 COLGALT1 Bryony Thompson Marked gene: COLGALT1 as ready
Mendeliome v0.8735 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Mendeliome v0.8735 COLGALT1 Bryony Thompson Classified gene: COLGALT1 as Green List (high evidence)
Mendeliome v0.8735 COLGALT1 Bryony Thompson Gene: colgalt1 has been classified as Green List (High Evidence).
Mendeliome v0.8734 COLGALT1 Bryony Thompson gene: COLGALT1 was added
gene: COLGALT1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3 MIM#618360
Review for gene: COLGALT1 was set to GREEN
Added comment: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.54 COL11A1 Bryony Thompson Classified gene: COL11A1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.54 COL11A1 Bryony Thompson Gene: col11a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.53 COL11A1 Bryony Thompson gene: COL11A1 was added
gene: COL11A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: COL11A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL11A1 were set to 8872475; 20301479
Phenotypes for gene: COL11A1 were set to Stickler syndrome, type II MIM#604841
Review for gene: COL11A1 was set to GREEN
gene: COL11A1 was marked as current diagnostic
Added comment: Stickler syndrome is a multi-system connective tissue disorder. Monoallelic loss of function variants in COL11A1 are a well-established cause of Stickler syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Marked gene: COL2A1 as ready
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Gene: col2a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Classified gene: COL2A1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Gene: col2a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.51 COL2A1 Bryony Thompson gene: COL2A1 was added
gene: COL2A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: COL2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL2A1 were set to 1677770; 20301479
Phenotypes for gene: COL2A1 were set to Stickler syndrome, type I MIM#108300
Review for gene: COL2A1 was set to GREEN
gene: COL2A1 was marked as current diagnostic
Added comment: Stickler syndrome is a multi-system connective tissue disorder. Monoallelic loss of function variants in COL2A1 are the most common cause of Stickler syndrome.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.50 LTBP3 Bryony Thompson Classified gene: LTBP3 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.50 LTBP3 Bryony Thompson Gene: ltbp3 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.49 LTBP3 Bryony Thompson gene: LTBP3 was added
gene: LTBP3 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: LTBP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LTBP3 were set to 29625025; 34150014
Phenotypes for gene: LTBP3 were set to Thoracic aortic aneurysms and dissections
Review for gene: LTBP3 was set to AMBER
Added comment: 2 families with biallelic variants with thoracic aortic aneurysms and dissections and other arterial aneurysms, along with skeletal and dental defects. TAA hasn't been reported in other dental anomalies and short stature cases with biallelic LTBP3 variants. Individuals with heterozygous mutations in LTBP3 may also be at increased risk for later-onset thoracic aortic disease, 9/338 isolated TAD individuals had rare heterozygous variants. Null mouse model had thoracic aortic aneurysms
Sources: Other
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Marked gene: JAKMIP1 as ready
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Marked gene: JAKMIP1 as ready
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Classified gene: JAKMIP1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.4042 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Classified gene: JAKMIP1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1162 JAKMIP1 Seb Lunke gene: JAKMIP1 was added
gene: JAKMIP1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; Seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalisations, and other autistic-like behaviours.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4041 JAKMIP1 Seb Lunke gene: JAKMIP1 was added
gene: JAKMIP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; Seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Mendeliome v0.8733 JAKMIP1 Seb Lunke Marked gene: JAKMIP1 as ready
Mendeliome v0.8733 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8733 JAKMIP1 Seb Lunke Classified gene: JAKMIP1 as Amber List (moderate evidence)
Mendeliome v0.8733 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8732 JAKMIP1 Seb Lunke gene: JAKMIP1 was added
gene: JAKMIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; Seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model.

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

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

KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Mendeliome v0.8731 ARIH1 Bryony Thompson Marked gene: ARIH1 as ready
Mendeliome v0.8731 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Mendeliome v0.8731 ARIH1 Bryony Thompson Classified gene: ARIH1 as Green List (high evidence)
Mendeliome v0.8731 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Mendeliome v0.8730 ARIH1 Bryony Thompson gene: ARIH1 was added
gene: ARIH1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ARIH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARIH1 were set to 29689197; 32102558
Phenotypes for gene: ARIH1 were set to Thoracic aortic aneurysm
Review for gene: ARIH1 was set to GREEN
Added comment: 3 unrelated families: A de novo case (R171*) with thoracic aortic aneurysm (TAA), and 2 siblings with TAA and a missense (E15Q). Another proband with cerebrovascular aneurysm (family history of TAA) and a missense variant (E44G). Supporting functional assays of the variants and a drosophila model.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Marked gene: ARIH1 as ready
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Classified gene: ARIH1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.47 ARIH1 Bryony Thompson gene: ARIH1 was added
gene: ARIH1 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: ARIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARIH1 were set to 29689197; 32102558
Phenotypes for gene: ARIH1 were set to Thoracic aortic aneurysm
Review for gene: ARIH1 was set to GREEN
Added comment: 3 unrelated families: A de novo case (R171*) with thoracic aortic aneurysm (TAA), and 2 siblings with TAA and a missense (E15Q). Another proband with cerebrovascular aneurysm (family history of TAA) and a missense variant (E44G). Supporting functional assays of the variants and a drosophila model.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Marked gene: ADAMTS17 as ready
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Gene: adamts17 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Classified gene: ADAMTS17 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Gene: adamts17 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.45 ADAMTS17 Bryony Thompson gene: ADAMTS17 was added
gene: ADAMTS17 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: ADAMTS17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS17 were set to 19836009; 20301293
Phenotypes for gene: ADAMTS17 were set to Weill-Marchesani 4 syndrome, recessive MIM#613195
Review for gene: ADAMTS17 was set to GREEN
gene: ADAMTS17 was marked as current diagnostic
Added comment: Weill-Marchesani syndrome is a multi-system connective tissue disorder. Biallelic variants in ADAMTS17 have been reported in at least 6 families.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Marked gene: ADAMTS10 as ready
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Gene: adamts10 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Classified gene: ADAMTS10 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Gene: adamts10 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.43 ADAMTS10 Bryony Thompson gene: ADAMTS10 was added
gene: ADAMTS10 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: ADAMTS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS10 were set to 15368195; 20301293
Phenotypes for gene: ADAMTS10 were set to Weill-Marchesani syndrome 1, recessive MIM#277600
Review for gene: ADAMTS10 was set to GREEN
gene: ADAMTS10 was marked as current diagnostic
Added comment: Weill-Marchesani syndrome is a multi-system connective tissue disorder. Biallelic variants in ADAMTS10 have been reported in >10 families.
Sources: Other
Genetic Epilepsy v0.1161 PIDD1 Konstantinos Varvagiannis gene: PIDD1 was added
gene: PIDD1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Penetrance for gene: PIDD1 were set to Complete
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

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

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

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

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

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

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

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

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

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

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

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4040 PIDD1 Konstantinos Varvagiannis gene: PIDD1 was added
gene: PIDD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Penetrance for gene: PIDD1 were set to Complete
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

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

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

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

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

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

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

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

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

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

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

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature
Growth failure v0.85 UBE2T Zornitza Stark Marked gene: UBE2T as ready
Growth failure v0.85 UBE2T Zornitza Stark Gene: ube2t has been classified as Green List (High Evidence).
Growth failure v0.85 UBE2T Zornitza Stark Phenotypes for gene: UBE2T were changed from Falcon anemia; 616435 Fanconi anemia, complementation group T; Fanconi anemia, complementation group T, 616435 to Fanconi anemia, complementation group T, MIM# 616435
Growth failure v0.84 UBE2T Zornitza Stark Publications for gene: UBE2T were set to 26046368
Growth failure v0.83 UBE2T Zornitza Stark commented on gene: UBE2T: Poor growth is an early feature of FA.
Growth failure v0.83 TOP3A Zornitza Stark Marked gene: TOP3A as ready
Growth failure v0.83 TOP3A Zornitza Stark Gene: top3a has been classified as Green List (High Evidence).
Growth failure v0.83 TOP3A Zornitza Stark Phenotypes for gene: TOP3A were changed from Microcephaly, growth restriction, and increased sister chromatid exchange 2; MGRISCE2 (Bloom-like syndrome) 618097; 618097 MGRISCE2 (Bloom-like syndrome) to Microcephaly, growth restriction, and increased sister chromatid exchange 2, MIM# 618097
Growth failure v0.82 TOP3A Zornitza Stark Publications for gene: TOP3A were set to
Growth failure v0.81 SOS2 Zornitza Stark Marked gene: SOS2 as ready
Growth failure v0.81 SOS2 Zornitza Stark Gene: sos2 has been classified as Green List (High Evidence).
Growth failure v0.81 SOS2 Zornitza Stark Phenotypes for gene: SOS2 were changed from Noonan syndrome 9 to Noonan syndrome 9, MIM# 616559
Growth failure v0.80 SOS2 Zornitza Stark Publications for gene: SOS2 were set to 25795793; 26173643
Growth failure v0.79 SOS2 Zornitza Stark Mode of pathogenicity for gene: SOS2 was changed from Other - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Growth failure v0.78 SOS2 Zornitza Stark Mode of inheritance for gene: SOS2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.77 SOS1 Zornitza Stark Marked gene: SOS1 as ready
Growth failure v0.77 SOS1 Zornitza Stark Gene: sos1 has been classified as Green List (High Evidence).
Growth failure v0.77 SOS1 Zornitza Stark Phenotypes for gene: SOS1 were changed from Noonan syndrome; Rasopathy; Noonan syndrome 4 to Noonan syndrome 4, MIM# 610733
Growth failure v0.76 SLX4 Zornitza Stark Marked gene: SLX4 as ready
Growth failure v0.76 SLX4 Zornitza Stark Gene: slx4 has been classified as Green List (High Evidence).
Growth failure v0.76 SLX4 Zornitza Stark Phenotypes for gene: SLX4 were changed from 613951 Fanconi Anemia Fanconi anemia, complementation group P; Fanconi anemia, complementation group P, 613951; Fanconi Anemia to Fanconi anemia, complementation group P, MIM# 613951
Growth failure v0.75 SLX4 Zornitza Stark commented on gene: SLX4: Poor growth is an early feature.
Intellectual disability syndromic and non-syndromic v0.4040 SHOC2 Zornitza Stark Marked gene: SHOC2 as ready
Intellectual disability syndromic and non-syndromic v0.4040 SHOC2 Zornitza Stark Gene: shoc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4040 SHOC2 Zornitza Stark Phenotypes for gene: SHOC2 were changed from to Noonan syndrome-like with loose anagen hair 1, MIM# 607721
Intellectual disability syndromic and non-syndromic v0.4039 SHOC2 Zornitza Stark Publications for gene: SHOC2 were set to
Intellectual disability syndromic and non-syndromic v0.4038 SHOC2 Zornitza Stark Mode of pathogenicity for gene: SHOC2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability syndromic and non-syndromic v0.4037 SHOC2 Zornitza Stark Mode of inheritance for gene: SHOC2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4036 SHOC2 Zornitza Stark reviewed gene: SHOC2: 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: 19684605, 23918763, 20882035; Phenotypes: Noonan syndrome-like with loose anagen hair 1, MIM# 607721; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.75 SHOC2 Zornitza Stark Marked gene: SHOC2 as ready
Growth failure v0.75 SHOC2 Zornitza Stark Gene: shoc2 has been classified as Green List (High Evidence).
Growth failure v0.75 SHOC2 Zornitza Stark Phenotypes for gene: SHOC2 were changed from Noonan with loss of anagen hair; Noonan-like syndrome with loose anagen hair to Noonan syndrome-like with loose anagen hair 1, MIM# 607721
Additional findings_Paediatric v0.256 SLC41A1 Zornitza Stark Marked gene: SLC41A1 as ready
Additional findings_Paediatric v0.256 SLC41A1 Zornitza Stark Gene: slc41a1 has been classified as Red List (Low Evidence).
Additional findings_Paediatric v0.256 SLC41A1 Zornitza Stark Phenotypes for gene: SLC41A1 were changed from Parkinson disease, idiopathic to Nephronophthisis-like nephropathy 2, MIM# 619468
Additional findings_Paediatric v0.255 SLC41A1 Zornitza Stark Publications for gene: SLC41A1 were set to
Additional findings_Paediatric v0.254 SLC41A1 Zornitza Stark Mode of inheritance for gene: SLC41A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Additional findings_Paediatric v0.253 SLC41A1 Zornitza Stark reviewed gene: SLC41A1: Rating: RED; Mode of pathogenicity: None; Publications: 23661805; Phenotypes: Nephronophthisis-like nephropathy 2, MIM# 619468; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8729 SLC41A1 Zornitza Stark Phenotypes for gene: SLC41A1 were changed from Nephronophthisis to Nephronophthisis-like nephropathy 2, MIM# 619468
Mendeliome v0.8728 SLC41A1 Zornitza Stark edited their review of gene: SLC41A1: Changed phenotypes: Nephronophthisis-like nephropathy 2, MIM# 619468
Renal Ciliopathies and Nephronophthisis v1.2 SLC41A1 Zornitza Stark Phenotypes for gene: SLC41A1 were changed from Nephronophthisis; no OMIM number to Nephronophthisis-like nephropathy 2, MIM# 619468
Renal Ciliopathies and Nephronophthisis v1.1 SLC41A1 Zornitza Stark reviewed gene: SLC41A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis-like nephropathy 2, MIM# 619468; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory Disorders v0.118 RBCK1 Zornitza Stark Marked gene: RBCK1 as ready
Autoinflammatory Disorders v0.118 RBCK1 Zornitza Stark Gene: rbck1 has been classified as Green List (High Evidence).
Autoinflammatory Disorders v0.118 RBCK1 Zornitza Stark Phenotypes for gene: RBCK1 were changed from to Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895; muscular weakness; cardiomyopathy; recurrent bacterial/viral infections; autoinflammation; immunodeficiency; Poor antibody responses to polysaccharides; failure to thrive; fever; pneumonia
Autoinflammatory Disorders v0.117 RBCK1 Zornitza Stark Publications for gene: RBCK1 were set to
Autoinflammatory Disorders v0.116 RBCK1 Zornitza Stark Mode of inheritance for gene: RBCK1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.124 MYH7 Zornitza Stark Marked gene: MYH7 as ready
Congenital Heart Defect v0.124 MYH7 Zornitza Stark Gene: myh7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.124 MYH7 Zornitza Stark Phenotypes for gene: MYH7 were changed from to Ebstein anomaly
Congenital Heart Defect v0.123 MYH7 Zornitza Stark Publications for gene: MYH7 were set to
Congenital Heart Defect v0.122 MYH7 Zornitza Stark Mode of pathogenicity for gene: MYH7 was changed from to Other
Congenital Heart Defect v0.121 MYH7 Zornitza Stark Mode of inheritance for gene: MYH7 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8728 PRPF31 Zornitza Stark Marked gene: PRPF31 as ready
Mendeliome v0.8728 PRPF31 Zornitza Stark Gene: prpf31 has been classified as Green List (High Evidence).
Mendeliome v0.8728 PRPF31 Zornitza Stark Phenotypes for gene: PRPF31 were changed from to Retinitis pigmentosa 11, MIM#600138
Mendeliome v0.8727 PRPF31 Zornitza Stark Publications for gene: PRPF31 were set to
Mendeliome v0.8726 PRPF31 Zornitza Stark Mode of inheritance for gene: PRPF31 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8725 PRPF31 Zornitza Stark Tag SV/CNV tag was added to gene: PRPF31.
Mendeliome v0.8725 PRPF31 Zornitza Stark reviewed gene: PRPF31: Rating: GREEN; Mode of pathogenicity: None; Publications: 32014492; Phenotypes: Retinitis pigmentosa 11, MIM#600138; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8725 RNF168 Zornitza Stark Marked gene: RNF168 as ready
Mendeliome v0.8725 RNF168 Zornitza Stark Gene: rnf168 has been classified as Green List (High Evidence).
Mendeliome v0.8725 RNF168 Zornitza Stark Phenotypes for gene: RNF168 were changed from to RIDDLE syndrome MIM# 611943; Radiosensitivity; Immune Deficiency; Dysmorphic Features; Learning difficulties; Low IgG or IgA; Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly
Chromosome Breakage Disorders v1.3 RNF168 Zornitza Stark Marked gene: RNF168 as ready
Chromosome Breakage Disorders v1.3 RNF168 Zornitza Stark Gene: rnf168 has been classified as Green List (High Evidence).
Chromosome Breakage Disorders v1.3 RNF168 Zornitza Stark Classified gene: RNF168 as Green List (high evidence)
Chromosome Breakage Disorders v1.3 RNF168 Zornitza Stark Gene: rnf168 has been classified as Green List (High Evidence).
Mendeliome v0.8724 RNF168 Zornitza Stark Publications for gene: RNF168 were set to
Chromosome Breakage Disorders v1.2 RNF168 Danielle Ariti gene: RNF168 was added
gene: RNF168 was added to Chromosome Breakage Disorders. Sources: Literature
Mode of inheritance for gene: RNF168 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF168 were set to 19203578; 21394101; 29255463; 21552324
Phenotypes for gene: RNF168 were set to RIDDLE syndrome MIM# 611943; Radiosensitivity; Immune Deficiency; Dysmorphic Features; Learning difficulties; Low IgG or IgA; Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly
Review for gene: RNF168 was set to GREEN
Added comment: 4 individuals from 3 unrelated families have been reported with RNF168 variants and display RIDDLE syndrome phenotype.

One mouse model; demonstrated RNF168 deficient mice are immunodeficient and exhibit increased radiosensitivity.

Homozygous and Compound heterozygous (duplications, deletions and nonsense) variants identified resulting in frameshift, aberrant protein and alteration of binding motifs.

Typically presents with increased radiosensitivity, immunodeficiency (decrease IgA), mild motor control and learning difficulties, facial dysmorphism, and short stature.
Sources: Literature
Mendeliome v0.8723 RNF168 Zornitza Stark Mode of inheritance for gene: RNF168 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.309 RNF168 Zornitza Stark Marked gene: RNF168 as ready
Combined Immunodeficiency v0.309 RNF168 Zornitza Stark Gene: rnf168 has been classified as Green List (High Evidence).
Mendeliome v0.8722 RFXAP Zornitza Stark Marked gene: RFXAP as ready
Mendeliome v0.8722 RFXAP Zornitza Stark Gene: rfxap has been classified as Green List (High Evidence).
Mendeliome v0.8722 RFXAP Zornitza Stark Phenotypes for gene: RFXAP were changed from to Bare lymphocyte syndrome, type II, complementation group D MIM# 209920; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia
Combined Immunodeficiency v0.309 RNF168 Zornitza Stark Phenotypes for gene: RNF168 were changed from to RIDDLE syndrome MIM# 611943; Radiosensitivity; Immune Deficiency; Dysmorphic Features; Learning difficulties; Low IgG or IgA; Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly
Mendeliome v0.8721 RFXAP Zornitza Stark Publications for gene: RFXAP were set to
Combined Immunodeficiency v0.308 RNF168 Zornitza Stark Publications for gene: RNF168 were set to
Combined Immunodeficiency v0.307 RNF168 Zornitza Stark Mode of inheritance for gene: RNF168 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8720 RFXAP Zornitza Stark Mode of inheritance for gene: RFXAP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8719 RFXAP Zornitza Stark Tag founder tag was added to gene: RFXAP.
Mendeliome v0.8719 RFXANK Zornitza Stark Marked gene: RFXANK as ready
Mendeliome v0.8719 RFXANK Zornitza Stark Gene: rfxank has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.306 RFXAP Zornitza Stark Marked gene: RFXAP as ready
Combined Immunodeficiency v0.306 RFXAP Zornitza Stark Gene: rfxap has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.306 RFXAP Zornitza Stark Phenotypes for gene: RFXAP were changed from to Bare lymphocyte syndrome, type II, complementation group D MIM# 209920; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia
Mendeliome v0.8719 RFXANK Zornitza Stark Phenotypes for gene: RFXANK were changed from to MHC class II deficiency, complementation group B MIM# 209920; Bare Lymphocyte Syndrome, type II, complementation group B; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia
Combined Immunodeficiency v0.305 RFXAP Zornitza Stark Publications for gene: RFXAP were set to
Mendeliome v0.8718 RFXANK Zornitza Stark Publications for gene: RFXANK were set to
Combined Immunodeficiency v0.304 RFXAP Zornitza Stark Mode of inheritance for gene: RFXAP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8717 RFXANK Zornitza Stark Tag founder tag was added to gene: RFXANK.
Autoinflammatory Disorders v0.115 RBCK1 Danielle Ariti reviewed gene: RBCK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29260357, 29695863; Phenotypes: Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895, muscular weakness, cardiomyopathy, recurrent bacterial/viral infections, autoinflammation, immunodeficiency, Poor antibody responses to polysaccharides, failure to thrive, fever, pneumonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8717 RFXANK Zornitza Stark Mode of inheritance for gene: RFXANK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.303 RFXANK Zornitza Stark Marked gene: RFXANK as ready
Combined Immunodeficiency v0.303 RFXANK Zornitza Stark Gene: rfxank has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.303 RFXANK Zornitza Stark Phenotypes for gene: RFXANK were changed from to MHC class II deficiency, complementation group B MIM# 209920; Bare Lymphocyte Syndrome, type II, complementation group B; Low CD4+ T cells; reduced MHC II expression on lymphocytes; Normal-low Ig levels; Failure to thrive; respiratory/gastrointestinal infections; liver/biliary tract disease; diarrhoea; Severe autoimmune cytopaenia; agammaglobulinaemia
Combined Immunodeficiency v0.302 RFXANK Zornitza Stark Publications for gene: RFXANK were set to
Mendeliome v0.8716 RBCK1 Zornitza Stark Marked gene: RBCK1 as ready
Mendeliome v0.8716 RBCK1 Zornitza Stark Gene: rbck1 has been classified as Green List (High Evidence).
Mendeliome v0.8716 RBCK1 Zornitza Stark Phenotypes for gene: RBCK1 were changed from to Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895; muscular weakness; cardiomyopathy; recurrent bacterial/viral infections; autoinflammation; immunodeficiency; Poor antibody responses to polysaccharides; failure to thrive; fever; pneumonia
Combined Immunodeficiency v0.301 RFXANK Zornitza Stark Mode of inheritance for gene: RFXANK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.300 RFXANK Zornitza Stark Tag founder tag was added to gene: RFXANK.
Combined Immunodeficiency v0.300 RBCK1 Zornitza Stark Marked gene: RBCK1 as ready
Combined Immunodeficiency v0.300 RBCK1 Zornitza Stark Gene: rbck1 has been classified as Green List (High Evidence).
Mendeliome v0.8715 RBCK1 Zornitza Stark Publications for gene: RBCK1 were set to
Combined Immunodeficiency v0.300 RBCK1 Zornitza Stark Phenotypes for gene: RBCK1 were changed from to Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895; muscular weakness; cardiomyopathy; recurrent bacterial/viral infections; autoinflammation; immunodeficiency; Poor antibody responses to polysaccharides; failure to thrive; fever; pneumonia
Mendeliome v0.8714 RBCK1 Zornitza Stark Mode of inheritance for gene: RBCK1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.299 RBCK1 Zornitza Stark Publications for gene: RBCK1 were set to
Combined Immunodeficiency v0.298 RBCK1 Zornitza Stark Mode of inheritance for gene: RBCK1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.297 PNP Zornitza Stark Marked gene: PNP as ready
Combined Immunodeficiency v0.297 PNP Zornitza Stark Gene: pnp has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.297 PNP Zornitza Stark Phenotypes for gene: PNP were changed from to Immunodeficiency due to purine nucleoside phosphorylase deficiency MIM# 613179; Autoimmune hemolytic anaemia; neurological impairment; SCID; CID; hypouricaemia; failure to thrive; chronic diarrhoea; recurrent respiratory/ gastrointestinal infections; normal-low Ig levels; spastic paresis; tremor; ataxia; DD
Combined Immunodeficiency v0.296 PNP Zornitza Stark Publications for gene: PNP were set to
Combined Immunodeficiency v0.295 PNP Zornitza Stark Mode of inheritance for gene: PNP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.294 NHP2 Zornitza Stark Marked gene: NHP2 as ready
Combined Immunodeficiency v0.294 NHP2 Zornitza Stark Gene: nhp2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.294 NHP2 Zornitza Stark Phenotypes for gene: NHP2 were changed from to Dyskeratosis congenita, autosomal recessive 2 MIM# 613987; Shortened telomeres; Leukoplakia; Nail dystrophy; Bone marrow failure; Pancytopaenia; reticulate skin pigmentation; Thrombocytopaenia; recurrent opportunistic infections
Combined Immunodeficiency v0.293 NHP2 Zornitza Stark Publications for gene: NHP2 were set to
Combined Immunodeficiency v0.292 NHP2 Zornitza Stark Mode of inheritance for gene: NHP2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.291 NHP2 Zornitza Stark changed review comment from: Third family reported with extreme end of the spectrum of DKC,; to: Third family reported with extreme end of the spectrum of DKC, Høyeraal-Hreidarsson syndrome.
Combined Immunodeficiency v0.291 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2 MIM# 613987, Shortened telomeres, Leukoplakia, Nail dystrophy, Bone marrow failure, Pancytopaenia, reticulate skin pigmentation, Thrombocytopaenia, recurrent opportunistic infections; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RFXANK Danielle Ariti reviewed gene: RFXANK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12618906; Phenotypes: MHC class II deficiency, complementation group B MIM# 209920, Bare Lymphocyte Syndrome, type II, complementation group B, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RFXAP Danielle Ariti reviewed gene: RFXAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9118943, 32875002, 11258423; Phenotypes: Bare lymphocyte syndrome, type II, complementation group D MIM# 209920, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RNF168 Danielle Ariti reviewed gene: RNF168: Rating: GREEN; Mode of pathogenicity: None; Publications: 19203578, 21394101, 29255463, 21552324; Phenotypes: RIDDLE syndrome MIM# 611943, Radiosensitivity, Immune Deficiency, Dysmorphic Features, Learning difficulties, Low IgG or IgA, Short stature, mild defect of motor control to ataxia, normal intelligence to learning difficulties, mild facial dysmorphism to microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.291 RNF168 Danielle Ariti reviewed gene: RNF168: Rating: GREEN; Mode of pathogenicity: None; Publications: 19203578, 21394101, 29255463, 21552324; Phenotypes: RIDDLE syndrome MIM# 611943, Radiosensitivity, Immune Deficiency, Dysmorphic Features, Learning difficulties, Low IgG or IgA, Short stature, mild defect of motor control to ataxia, normal intelligence to learning difficulties, mild facial dysmorphism to microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.291 RFXAP Danielle Ariti reviewed gene: RFXAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9118943, 32875002, 11258423; Phenotypes: Bare lymphocyte syndrome, type II, complementation group D MIM# 209920, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.120 MYH7 Teresa Zhao reviewed gene: MYH7: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 21127202; Phenotypes: Ebstein anomaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Combined Immunodeficiency v0.291 RFXANK Danielle Ariti reviewed gene: RFXANK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12618906; Phenotypes: MHC class II deficiency, complementation group B MIM# 209920, Bare Lymphocyte Syndrome, type II, complementation group B, Low CD4+ T cells, reduced MHC II expression on lymphocytes, Normal-low Ig levels, Failure to thrive, respiratory/gastrointestinal infections, liver/biliary tract disease, diarrhoea, Severe autoimmune cytopaenia, agammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 RBCK1 Danielle Ariti reviewed gene: RBCK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29260357, 29695863; Phenotypes: Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895, muscular weakness, cardiomyopathy, recurrent bacterial/viral infections, autoinflammation, immunodeficiency, Poor antibody responses to polysaccharides, failure to thrive, fever, pneumonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.291 RBCK1 Danielle Ariti reviewed gene: RBCK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29260357, 29695863; Phenotypes: Polyglucosan body myopathy 1 with or without immunodeficiency MIM# 615895, muscular weakness, cardiomyopathy, recurrent bacterial/viral infections, autoinflammation, immunodeficiency, Poor antibody responses to polysaccharides, failure to thrive, fever, pneumonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.291 PNP Danielle Ariti reviewed gene: PNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 22132981, 9122228, 10859343; Phenotypes: Immunodeficiency due to purine nucleoside phosphorylase deficiency MIM# 613179, Autoimmune hemolytic anaemia, neurological impairment, SCID, CID, hypouricaemia, failure to thrive, chronic diarrhoea, recurrent respiratory/ gastrointestinal infections, normal-low Ig levels, spastic paresis, tremor, ataxia, DD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.291 NHP2 Danielle Ariti reviewed gene: NHP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 20301779, 18523010; Phenotypes: Dyskeratosis congenita, autosomal recessive 2 MIM# 613987, Shortened telomeres, Leukoplakia, Nail dystrophy, Bone marrow failure, Pancytopaenia, reticulate skin pigmentation, Thrombocytopaenia, recurrent opportunistic infections; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8713 ABCC2 Zornitza Stark Marked gene: ABCC2 as ready
Mendeliome v0.8713 ABCC2 Zornitza Stark Gene: abcc2 has been classified as Green List (High Evidence).
Mendeliome v0.8713 ABCC2 Zornitza Stark Phenotypes for gene: ABCC2 were changed from to Dubin-Johnson syndrome, MIM# 237500
Mendeliome v0.8712 ABCC2 Zornitza Stark Mode of inheritance for gene: ABCC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8711 ABCC2 Zornitza Stark reviewed gene: ABCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dubin-Johnson syndrome, MIM# 237500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v0.199 ABCC2 Zornitza Stark Marked gene: ABCC2 as ready
Cholestasis v0.199 ABCC2 Zornitza Stark Gene: abcc2 has been classified as Green List (High Evidence).
Cholestasis v0.199 ABCC2 Zornitza Stark Phenotypes for gene: ABCC2 were changed from to Dubin-Johnson syndrome, MIM# 237500
Cholestasis v0.198 ABCC2 Zornitza Stark Mode of inheritance for gene: ABCC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Cholestasis v0.197 ABCC2 Zornitza Stark reviewed gene: ABCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dubin-Johnson syndrome, MIM# 237500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Deafness_IsolatedAndComplex v1.87 CLDN9 Bryony Thompson Publications for gene: CLDN9 were set to 31175426; 19696885
Deafness_IsolatedAndComplex v1.86 CLDN9 Bryony Thompson Classified gene: CLDN9 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.86 CLDN9 Bryony Thompson Gene: cldn9 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.85 CLDN9 Bryony Thompson reviewed gene: CLDN9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19696885, 31175426, 34265170; Phenotypes: Deafness, autosomal recessive 116, MIM#619093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8711 CLDN9 Bryony Thompson Publications for gene: CLDN9 were set to 31175426; 19696885
Mendeliome v0.8710 CLDN9 Bryony Thompson Classified gene: CLDN9 as Green List (high evidence)
Mendeliome v0.8710 CLDN9 Bryony Thompson Gene: cldn9 has been classified as Green List (High Evidence).
Mendeliome v0.8709 CLDN9 Bryony Thompson reviewed gene: CLDN9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19696885, 31175426, 34265170; Phenotypes: Deafness, autosomal recessive 116 MIM#619093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4036 UBR1 Zornitza Stark Marked gene: UBR1 as ready
Intellectual disability syndromic and non-syndromic v0.4036 UBR1 Zornitza Stark Gene: ubr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4036 UBR1 Zornitza Stark Phenotypes for gene: UBR1 were changed from to Johanson-Blizzard syndrome (MIM#243800)
Intellectual disability syndromic and non-syndromic v0.4035 UBR1 Zornitza Stark Publications for gene: UBR1 were set to
Intellectual disability syndromic and non-syndromic v0.4034 UBR1 Zornitza Stark Mode of inheritance for gene: UBR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8709 UBR1 Zornitza Stark changed review comment from: >50 unrelated families reported, reviewed in PMID: 24599544.

Common clinical features include poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.; to: >50 unrelated families reported, reviewed in PMID: 24599544.

Common clinical features include poor growth, intellectual disability, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.
Intellectual disability syndromic and non-syndromic v0.4033 UBR1 Zornitza Stark changed review comment from: >50 unrelated families reported, reviewed in PMID: 24599544. Common clinical features include poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.; to: >50 unrelated families reported, reviewed in PMID: 24599544. Common clinical features include poor growth, intellectual disability, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency.
Intellectual disability syndromic and non-syndromic v0.4033 UBR1 Zornitza Stark reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24599544; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8709 UBR1 Zornitza Stark Marked gene: UBR1 as ready
Mendeliome v0.8709 UBR1 Zornitza Stark Gene: ubr1 has been classified as Green List (High Evidence).
Mendeliome v0.8709 UBR1 Zornitza Stark Phenotypes for gene: UBR1 were changed from to Johanson-Blizzard syndrome (MIM#243800)
Mendeliome v0.8708 UBR1 Zornitza Stark Publications for gene: UBR1 were set to
Mendeliome v0.8707 UBR1 Zornitza Stark Mode of inheritance for gene: UBR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8706 UBR1 Zornitza Stark reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24599544; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.120 UBR1 Zornitza Stark Marked gene: UBR1 as ready
Congenital Heart Defect v0.120 UBR1 Zornitza Stark Gene: ubr1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.120 UBR1 Zornitza Stark Phenotypes for gene: UBR1 were changed from to Johanson-Blizzard syndrome (MIM#243800)
Congenital Heart Defect v0.119 UBR1 Zornitza Stark Publications for gene: UBR1 were set to
Congenital Heart Defect v0.118 UBR1 Zornitza Stark Mode of inheritance for gene: UBR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.117 UBR1 Zornitza Stark reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8706 ACTL6A Zornitza Stark Marked gene: ACTL6A as ready
Mendeliome v0.8706 ACTL6A Zornitza Stark Gene: actl6a has been classified as Green List (High Evidence).
Mendeliome v0.8706 ACTL6A Zornitza Stark Phenotypes for gene: ACTL6A were changed from to Intellectual disability
Mendeliome v0.8705 ACTL6A Zornitza Stark Publications for gene: ACTL6A were set to
Congenital Heart Defect v0.117 UBR1 Teresa Zhao reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24599544; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8704 ACTL6A Zornitza Stark Mode of inheritance for gene: ACTL6A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8703 ACTL6A Zornitza Stark changed review comment from: Two individuals from unrelated families reported with missense variants in this gene. Part of the BAF complex. Only one confirmed de novo.; to: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.
PMID 31994175: fourth individual reported, recurrent de novo p.Arg377Trp
Mendeliome v0.8703 ACTL6A Zornitza Stark edited their review of gene: ACTL6A: Changed publications: 28649782, 31994175
Intellectual disability syndromic and non-syndromic v0.4033 ACTL6A Zornitza Stark changed review comment from: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.; to: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.
PMID 31994175: fourth individual reported, recurrent de novo p.Arg377Trp
Intellectual disability syndromic and non-syndromic v0.4033 ACTL6A Zornitza Stark edited their review of gene: ACTL6A: Changed publications: 28649782, 31994175
Intellectual disability syndromic and non-syndromic v0.4033 ACTL6A Zornitza Stark changed review comment from: Two individuals from unrelated families reported with missense variants in this gene. Part of the BAF complex. Only one confirmed de novo.; to: Two individuals from unrelated families reported with missense variants in this gene, and one with a splice-site variant. Part of the BAF complex. Only one missense confirmed de novo, pathogenicity of the other variant uncertain.
Mendeliome v0.8703 VAV1 Zornitza Stark Marked gene: VAV1 as ready
Mendeliome v0.8703 VAV1 Zornitza Stark Gene: vav1 has been classified as Red List (Low Evidence).
Mendeliome v0.8703 VAV1 Zornitza Stark gene: VAV1 was added
gene: VAV1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: VAV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VAV1 were set to 20638113; 23058036
Phenotypes for gene: VAV1 were set to Common variable immnodeficiency
Review for gene: VAV1 was set to RED
Added comment: Reduced VAV1 expression has been reported in multiple T-CVID cases, however only one large deletion (exon 2-27) has been reported in a single case in a publication from 2012. The CNV was detected using real-time qPCR, but was not confirmed by an orthogonal method.
Sources: Expert Review
Predominantly Antibody Deficiency v0.80 TCF3 Zornitza Stark Marked gene: TCF3 as ready
Predominantly Antibody Deficiency v0.80 TCF3 Zornitza Stark Gene: tcf3 has been classified as Green List (High Evidence).
Predominantly Antibody Deficiency v0.80 TCF3 Zornitza Stark Phenotypes for gene: TCF3 were changed from to Agammaglobulinaemia 8, autosomal dominant, MIM# 616941
Predominantly Antibody Deficiency v0.79 TCF3 Zornitza Stark Publications for gene: TCF3 were set to
Predominantly Antibody Deficiency v0.78 TCF3 Zornitza Stark Mode of inheritance for gene: TCF3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.77 TCF3 Zornitza Stark reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24216514, 28532655, 30063982, 8001124, 8001125; Phenotypes: Agammaglobulinaemia 8, autosomal dominant, MIM# 616941; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8702 TCF3 Zornitza Stark Marked gene: TCF3 as ready
Mendeliome v0.8702 TCF3 Zornitza Stark Gene: tcf3 has been classified as Green List (High Evidence).
Mendeliome v0.8702 TCF3 Zornitza Stark Phenotypes for gene: TCF3 were changed from to Agammaglobulinaemia 8, autosomal dominant, MIM# 616941
Mendeliome v0.8701 TCF3 Zornitza Stark Publications for gene: TCF3 were set to
Mendeliome v0.8700 TCF3 Zornitza Stark Mode of inheritance for gene: TCF3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8699 TCF3 Zornitza Stark reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24216514, 28532655, 30063982, 8001124, 8001125; Phenotypes: Agammaglobulinaemia 8, autosomal dominant, MIM# 616941; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Disorders of immune dysregulation v0.92 PRKCD Zornitza Stark Marked gene: PRKCD as ready
Disorders of immune dysregulation v0.92 PRKCD Zornitza Stark Gene: prkcd has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.92 PRKCD Zornitza Stark Phenotypes for gene: PRKCD were changed from to Autoimmune lymphoproliferative syndrome, type III, MIM# 615559; CVID 9
Disorders of immune dysregulation v0.91 PRKCD Zornitza Stark Publications for gene: PRKCD were set to
Disorders of immune dysregulation v0.90 PRKCD Zornitza Stark Mode of inheritance for gene: PRKCD was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v0.89 PRKCD Zornitza Stark reviewed gene: PRKCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 23319571, 23666743, 23430113, 11976687, 33047643, 29867916; Phenotypes: Autoimmune lymphoproliferative syndrome, type III, MIM# 615559, CVID 9; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8699 PRKCD Zornitza Stark Marked gene: PRKCD as ready
Mendeliome v0.8699 PRKCD Zornitza Stark Gene: prkcd has been classified as Green List (High Evidence).
Mendeliome v0.8699 PRKCD Zornitza Stark Phenotypes for gene: PRKCD were changed from to Autoimmune lymphoproliferative syndrome, type III, MIM# 615559; CVID 9
Mendeliome v0.8698 PRKCD Zornitza Stark Publications for gene: PRKCD were set to
Mendeliome v0.8697 PRKCD Zornitza Stark Mode of inheritance for gene: PRKCD was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8696 PRKCD Zornitza Stark reviewed gene: PRKCD: Rating: GREEN; Mode of pathogenicity: None; Publications: 23319571, 23666743, 23430113, 11976687, 33047643, 29867916; Phenotypes: Autoimmune lymphoproliferative syndrome, type III, MIM# 615559, CVID 9; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v0.89 CTLA4 Zornitza Stark Marked gene: CTLA4 as ready
Disorders of immune dysregulation v0.89 CTLA4 Zornitza Stark Gene: ctla4 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.89 CTLA4 Zornitza Stark Phenotypes for gene: CTLA4 were changed from to Autoimmune lymphoproliferative syndrome, type V, MIM# 616100
Disorders of immune dysregulation v0.88 CTLA4 Zornitza Stark Publications for gene: CTLA4 were set to
Disorders of immune dysregulation v0.87 CTLA4 Zornitza Stark Mode of inheritance for gene: CTLA4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Disorders of immune dysregulation v0.86 CTLA4 Zornitza Stark reviewed gene: CTLA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25213377, 25329329, 30377434; Phenotypes: Autoimmune lymphoproliferative syndrome, type V, MIM# 616100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Predominantly Antibody Deficiency v0.77 CD19 Zornitza Stark Marked gene: CD19 as ready
Predominantly Antibody Deficiency v0.77 CD19 Zornitza Stark Gene: cd19 has been classified as Green List (High Evidence).
Predominantly Antibody Deficiency v0.77 CD19 Zornitza Stark Phenotypes for gene: CD19 were changed from to Immunodeficiency, common variable, 3, MIM# 613493
Predominantly Antibody Deficiency v0.76 CD19 Zornitza Stark Publications for gene: CD19 were set to
Predominantly Antibody Deficiency v0.75 CD19 Zornitza Stark Mode of inheritance for gene: CD19 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Predominantly Antibody Deficiency v0.74 CD19 Zornitza Stark reviewed gene: CD19: Rating: GREEN; Mode of pathogenicity: None; Publications: 16672701, 17882224, 17882224, 21330302, 21159371; Phenotypes: Immunodeficiency, common variable, 3, MIM# 613493; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8696 CD19 Zornitza Stark changed review comment from: More than 5 unrelated families reported.; to: More than 5 unrelated families reported. Clinical features include increased susceptibility to infection, hypogammaglobulinaemia, and normal numbers of mature B cells in blood, indicating a B-cell antibody-deficient immunodeficiency disorder.
Mendeliome v0.8696 CD19 Zornitza Stark Marked gene: CD19 as ready
Mendeliome v0.8696 CD19 Zornitza Stark Gene: cd19 has been classified as Green List (High Evidence).
Mendeliome v0.8696 CD19 Zornitza Stark Phenotypes for gene: CD19 were changed from to Immunodeficiency, common variable, 3, MIM# 613493
Mendeliome v0.8695 CD19 Zornitza Stark Publications for gene: CD19 were set to
Mendeliome v0.8694 CD19 Zornitza Stark Mode of inheritance for gene: CD19 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8693 CD19 Zornitza Stark reviewed gene: CD19: Rating: GREEN; Mode of pathogenicity: None; Publications: 16672701, 17882224, 17882224, 21330302, 21159371; Phenotypes: Immunodeficiency, common variable, 3, MIM# 613493; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v1.0 Zornitza Stark promoted panel to version 1.0
Mandibulofacial Acrofacial dysostosis v0.105 RPS26 Zornitza Stark Classified gene: RPS26 as Amber List (moderate evidence)
Mandibulofacial Acrofacial dysostosis v0.105 RPS26 Zornitza Stark Gene: rps26 has been classified as Amber List (Moderate Evidence).
Mandibulofacial Acrofacial dysostosis v0.104 RPS26 Zornitza Stark changed review comment from: Well established gene-disease association. Craniofacial and limb anomalies are a feature.; to: Well established gene-disease association. Craniofacial and limb anomalies are a feature, though not classically a facial dysostosis syndrome, included as Amber due to possible phenotypic overlap.
Mandibulofacial Acrofacial dysostosis v0.104 RPS26 Zornitza Stark edited their review of gene: RPS26: Changed rating: AMBER
Mandibulofacial Acrofacial dysostosis v0.104 RPL5 Zornitza Stark Classified gene: RPL5 as Amber List (moderate evidence)
Mandibulofacial Acrofacial dysostosis v0.104 RPL5 Zornitza Stark Gene: rpl5 has been classified as Amber List (Moderate Evidence).
Mandibulofacial Acrofacial dysostosis v0.103 RPL5 Zornitza Stark changed review comment from: Well established gene-disease association. Craniofacial and limb anomalies are a feature.; to: Well established gene-disease association. Craniofacial and limb anomalies are a feature, though not classically a facial dysostosis syndrome, included as Amber due to possible phenotypic overlap.
Mandibulofacial Acrofacial dysostosis v0.103 RPL5 Zornitza Stark edited their review of gene: RPL5: Changed rating: AMBER
Mandibulofacial Acrofacial dysostosis v0.103 RPL11 Zornitza Stark Classified gene: RPL11 as Amber List (moderate evidence)
Mandibulofacial Acrofacial dysostosis v0.103 RPL11 Zornitza Stark Gene: rpl11 has been classified as Amber List (Moderate Evidence).
Mandibulofacial Acrofacial dysostosis v0.102 RPL11 Zornitza Stark changed review comment from: Well established gene-disease association. Craniofacial and limb abnormalities are common.; to: Well established gene-disease association. Craniofacial and limb abnormalities are common, though not classically a facial dysostosis syndrome, included as Amber due to possible phenotypic overlap.
Mandibulofacial Acrofacial dysostosis v0.102 RPL11 Zornitza Stark edited their review of gene: RPL11: Changed rating: AMBER
Mandibulofacial Acrofacial dysostosis v0.100 EVC2 Zornitza Stark Marked gene: EVC2 as ready
Mandibulofacial Acrofacial dysostosis v0.100 EVC2 Zornitza Stark Gene: evc2 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.100 EVC2 Zornitza Stark Phenotypes for gene: EVC2 were changed from to Ellis-van Creveld syndrome, MIM# 225500; Weyers acrofacial dysostosis, MIM# 193530
Mandibulofacial Acrofacial dysostosis v0.99 EVC2 Zornitza Stark Publications for gene: EVC2 were set to
Mandibulofacial Acrofacial dysostosis v0.98 EVC2 Zornitza Stark Mode of inheritance for gene: EVC2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.97 EVC2 Zornitza Stark reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16404586, 19810119; Phenotypes: Ellis-van Creveld syndrome, MIM# 225500, Weyers acrofacial dysostosis, MIM# 193530; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.97 EVC Zornitza Stark Marked gene: EVC as ready
Mandibulofacial Acrofacial dysostosis v0.97 EVC Zornitza Stark Gene: evc has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.97 EVC Zornitza Stark Phenotypes for gene: EVC were changed from to Weyers acrofacial dysostosis, MIM# 193530; Ellis-van Creveld syndrome, MIM# 225500
Mandibulofacial Acrofacial dysostosis v0.96 EVC Zornitza Stark Publications for gene: EVC were set to
Mandibulofacial Acrofacial dysostosis v0.95 EVC Zornitza Stark Mode of inheritance for gene: EVC was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.94 EVC Zornitza Stark edited their review of gene: EVC: Changed rating: GREEN
Mandibulofacial Acrofacial dysostosis v0.94 EVC Zornitza Stark reviewed gene: EVC: Rating: ; Mode of pathogenicity: None; Publications: 10700184, 23220543; Phenotypes: Weyers acrofacial dysostosis, MIM# 193530, Ellis-van Creveld syndrome, MIM# 225500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4033 SNRPB Zornitza Stark Marked gene: SNRPB as ready
Intellectual disability syndromic and non-syndromic v0.4033 SNRPB Zornitza Stark Gene: snrpb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4033 SNRPB Zornitza Stark Phenotypes for gene: SNRPB were changed from to Cerebrocostomandibular syndrome, MIM# 117650
Intellectual disability syndromic and non-syndromic v0.4032 SNRPB Zornitza Stark Publications for gene: SNRPB were set to
Intellectual disability syndromic and non-syndromic v0.4031 SNRPB Zornitza Stark Mode of inheritance for gene: SNRPB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4030 SNRPB Zornitza Stark reviewed gene: SNRPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25047197, 25504470, 26971886; Phenotypes: Cerebrocostomandibular syndrome, MIM# 117650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.94 SNRPB Zornitza Stark Tag 5'UTR tag was added to gene: SNRPB.
Tag deep intronic tag was added to gene: SNRPB.
Mendeliome v0.8693 SNRPB Zornitza Stark Marked gene: SNRPB as ready
Mendeliome v0.8693 SNRPB Zornitza Stark Gene: snrpb has been classified as Green List (High Evidence).
Mendeliome v0.8693 SNRPB Zornitza Stark Phenotypes for gene: SNRPB were changed from to Cerebrocostomandibular syndrome, MIM# 117650
Mendeliome v0.8692 SNRPB Zornitza Stark Publications for gene: SNRPB were set to
Mendeliome v0.8691 SNRPB Zornitza Stark Mode of inheritance for gene: SNRPB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8690 SNRPB Zornitza Stark Tag 5'UTR tag was added to gene: SNRPB.
Tag deep intronic tag was added to gene: SNRPB.
Mendeliome v0.8690 SNRPB Zornitza Stark reviewed gene: SNRPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25047197, 25504470, 26971886; Phenotypes: Cerebrocostomandibular syndrome, MIM# 117650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.94 SNRPB Zornitza Stark Marked gene: SNRPB as ready
Mandibulofacial Acrofacial dysostosis v0.94 SNRPB Zornitza Stark Gene: snrpb has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.94 SNRPB Zornitza Stark Phenotypes for gene: SNRPB were changed from to Cerebrocostomandibular syndrome, MIM# 117650
Mandibulofacial Acrofacial dysostosis v0.93 SNRPB Zornitza Stark Publications for gene: SNRPB were set to
Mandibulofacial Acrofacial dysostosis v0.92 SNRPB Zornitza Stark Mode of inheritance for gene: SNRPB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.91 SNRPB Zornitza Stark reviewed gene: SNRPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25047197, 25504470, 26971886; Phenotypes: Cerebrocostomandibular syndrome, MIM# 117650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.91 Zornitza Stark removed gene:SCARF2 from the panel
Mandibulofacial Acrofacial dysostosis v0.90 RPS26 Zornitza Stark Marked gene: RPS26 as ready
Mandibulofacial Acrofacial dysostosis v0.90 RPS26 Zornitza Stark Gene: rps26 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.90 RPS26 Zornitza Stark Phenotypes for gene: RPS26 were changed from to Diamond-Blackfan anemia 10, MIM# 613309; MONDO:0013217
Mandibulofacial Acrofacial dysostosis v0.89 RPS26 Zornitza Stark Publications for gene: RPS26 were set to
Mandibulofacial Acrofacial dysostosis v0.88 RPS26 Zornitza Stark Mode of inheritance for gene: RPS26 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.87 RPS26 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Craniofacial and limb anomalies are a feature.
Mandibulofacial Acrofacial dysostosis v0.87 RPL5 Zornitza Stark Marked gene: RPL5 as ready
Mandibulofacial Acrofacial dysostosis v0.87 RPL5 Zornitza Stark Gene: rpl5 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.87 RPL5 Zornitza Stark Phenotypes for gene: RPL5 were changed from to Diamond-Blackfan anemia 6, MIM# 612561; MONDO:0012937
Mandibulofacial Acrofacial dysostosis v0.86 RPL5 Zornitza Stark Publications for gene: RPL5 were set to
Mandibulofacial Acrofacial dysostosis v0.85 RPL5 Zornitza Stark Mode of inheritance for gene: RPL5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.84 RPL5 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Craniofacial and limb anomalies are a feature.
Clefting disorders v0.138 RBM10 Zornitza Stark Marked gene: RBM10 as ready
Clefting disorders v0.138 RBM10 Zornitza Stark Gene: rbm10 has been classified as Green List (High Evidence).
Clefting disorders v0.138 RBM10 Zornitza Stark Phenotypes for gene: RBM10 were changed from TARPS; Cleft palate; TARP SYNDROME to TARP syndrome, MIM# 311900
Clefting disorders v0.137 RBM10 Zornitza Stark Publications for gene: RBM10 were set to 20451169
Clefting disorders v0.136 RBM10 Zornitza Stark reviewed gene: RBM10: Rating: GREEN; Mode of pathogenicity: None; Publications: 20451169, 24259342, 30450804, 30189253, 33340101; Phenotypes: TARP syndrome, MIM# 311900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8690 RBM10 Zornitza Stark Marked gene: RBM10 as ready
Mendeliome v0.8690 RBM10 Zornitza Stark Gene: rbm10 has been classified as Green List (High Evidence).
Mendeliome v0.8690 RBM10 Zornitza Stark Phenotypes for gene: RBM10 were changed from to TARP syndrome, MIM# 311900
Mendeliome v0.8689 RBM10 Zornitza Stark Publications for gene: RBM10 were set to
Mendeliome v0.8688 RBM10 Zornitza Stark Mode of inheritance for gene: RBM10 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8687 RBM10 Zornitza Stark reviewed gene: RBM10: Rating: GREEN; Mode of pathogenicity: None; Publications: 20451169, 24259342, 30450804, 30189253, 33340101; Phenotypes: TARP syndrome, MIM# 311900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mandibulofacial Acrofacial dysostosis v0.84 RBM10 Zornitza Stark Marked gene: RBM10 as ready
Mandibulofacial Acrofacial dysostosis v0.84 RBM10 Zornitza Stark Gene: rbm10 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.84 RBM10 Zornitza Stark Phenotypes for gene: RBM10 were changed from to TARP syndrome, MIM# 311900
Mandibulofacial Acrofacial dysostosis v0.83 RBM10 Zornitza Stark Publications for gene: RBM10 were set to
Mandibulofacial Acrofacial dysostosis v0.82 RBM10 Zornitza Stark Mode of inheritance for gene: RBM10 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mandibulofacial Acrofacial dysostosis v0.81 RBM10 Zornitza Stark reviewed gene: RBM10: Rating: GREEN; Mode of pathogenicity: None; Publications: 20451169, 24259342, 30450804, 30189253, 33340101; Phenotypes: TARP syndrome, MIM# 311900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mandibulofacial Acrofacial dysostosis v0.81 Zornitza Stark removed gene:PUF60 from the panel
Disorders of immune dysregulation v0.86 IPO8 Zornitza Stark Phenotypes for gene: IPO8 were changed from Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities to Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472; Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Disorders of immune dysregulation v0.85 IPO8 Zornitza Stark edited their review of gene: IPO8: Changed phenotypes: Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472, Loeys-Dietz syndrome-like, cardiovascular, neurologic, skeletal and immunologic abnormalities
Mendeliome v0.8687 IPO8 Zornitza Stark Phenotypes for gene: IPO8 were changed from Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities to Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472; Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Mendeliome v0.8686 IPO8 Zornitza Stark edited their review of gene: IPO8: Changed phenotypes: Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472, Loeys-Dietz syndrome-like, cardiovascular, neurologic, skeletal and immunologic abnormalities
Aortopathy_Connective Tissue Disorders v1.42 IPO8 Zornitza Stark Phenotypes for gene: IPO8 were changed from Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities to Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472; Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Aortopathy_Connective Tissue Disorders v1.41 IPO8 Zornitza Stark edited their review of gene: IPO8: Changed phenotypes: Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472
Cardiomyopathy_Paediatric v0.101 MYL2 Zornitza Stark Publications for gene: MYL2 were set to 23365102; 27378946; 32453731
Cardiomyopathy_Paediatric v0.100 MYL2 Zornitza Stark changed review comment from: Monoallelic variants in this gene are a well established as a cause of cardiomyopathy. Thirteen infants from 9 families reported with bi-allelic variants in last exon and an infantile skeletal myopathy/DCM phenotype. Dutch families all had same founder variant; one Italian family had two different variants. Additional family reported in PMID 32453731; to: Monoallelic variants in this gene are a well established as a cause of cardiomyopathy. Thirteen infants from 9 families reported with bi-allelic variants in last exon and an infantile skeletal myopathy/DCM phenotype. Dutch families all had same founder variant; one Italian family had two different variants. Two additional families reported in PMID 32453731 and 33731536
Cardiomyopathy_Paediatric v0.100 MYL2 Zornitza Stark edited their review of gene: MYL2: Changed publications: 23365102, 27378946, 32453731, 33731536
Cardiomyopathy_Paediatric v0.100 MYL2 Zornitza Stark Marked gene: MYL2 as ready
Cardiomyopathy_Paediatric v0.100 MYL2 Zornitza Stark Gene: myl2 has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.100 MYL2 Zornitza Stark Phenotypes for gene: MYL2 were changed from Cardiomyopathy, familial hypertrophic, 10 to Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, MIM# 619424; Cardiomyopathy, hypertrophic, 10, MIM# 608758
Cardiomyopathy_Paediatric v0.99 MYL2 Zornitza Stark Publications for gene: MYL2 were set to
Cardiomyopathy_Paediatric v0.98 MYL2 Zornitza Stark Mode of inheritance for gene: MYL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v0.97 MYL2 Zornitza Stark reviewed gene: MYL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23365102, 27378946, 32453731; Phenotypes: Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, MIM# 619424, Cardiomyopathy, hypertrophic, 10 608758; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8686 OTX2 Zornitza Stark edited their review of gene: OTX2: Added comment: Three families reported with variants in OTX2 and otocyephaly-dysgnathia. Note variants were inherited in two of the families: in one family, from mother with microphthalmia (recognised OTX2 phenotype) and the other from an unaffected father. Lamb animal model reported.; Changed publications: 24167467, 25589041, 31969185; Changed phenotypes: Microphthalmia, syndromic 5, MIM# 610125, Pituitary hormone deficiency, combined, 6, MIM# 613986, Retinal dystrophy, early-onset, with or without pituitary dysfunction, MIM# 610125, Otocephaly-dysgnathia complex
Mandibulofacial Acrofacial dysostosis v0.80 OTX2 Zornitza Stark Marked gene: OTX2 as ready
Mandibulofacial Acrofacial dysostosis v0.80 OTX2 Zornitza Stark Gene: otx2 has been classified as Amber List (Moderate Evidence).
Mandibulofacial Acrofacial dysostosis v0.80 OTX2 Zornitza Stark Classified gene: OTX2 as Amber List (moderate evidence)
Mandibulofacial Acrofacial dysostosis v0.80 OTX2 Zornitza Stark Gene: otx2 has been classified as Amber List (Moderate Evidence).
Mandibulofacial Acrofacial dysostosis v0.79 OTX2 Zornitza Stark gene: OTX2 was added
gene: OTX2 was added to Mandibulofacial Acrofacial dysostosis. Sources: Expert Review
Mode of inheritance for gene: OTX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OTX2 were set to 24167467; 25589041; 31969185
Phenotypes for gene: OTX2 were set to Otocephaly-dysgnathia complex
Review for gene: OTX2 was set to AMBER
Added comment: Three families reported with variants in OTX2 and otocyephaly-dysgnathia. Note variants were inherited in two of the families: in one family, from mother with microphthalmia (recognised OTX2 phenotype) and the other from an unaffected father. Lamb animal model reported.
Sources: Expert Review
Mandibulofacial Acrofacial dysostosis v0.78 PRRX1 Zornitza Stark Phenotypes for gene: PRRX1 were changed from Agnathia-otocephaly complex, MIM# 202650 to Agnathia-otocephaly complex, MIM# 202650
Mandibulofacial Acrofacial dysostosis v0.77 PRRX1 Zornitza Stark Marked gene: PRRX1 as ready
Mandibulofacial Acrofacial dysostosis v0.77 PRRX1 Zornitza Stark Gene: prrx1 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.77 PRRX1 Zornitza Stark Phenotypes for gene: PRRX1 were changed from to Agnathia-otocephaly complex, MIM# 202650
Mandibulofacial Acrofacial dysostosis v0.77 PRRX1 Zornitza Stark Publications for gene: PRRX1 were set to 21294718; 22211708; 22674740; 23444262
Mandibulofacial Acrofacial dysostosis v0.76 PRRX1 Zornitza Stark Publications for gene: PRRX1 were set to
Mandibulofacial Acrofacial dysostosis v0.76 PRRX1 Zornitza Stark Mode of inheritance for gene: PRRX1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.75 PRRX1 Zornitza Stark reviewed gene: PRRX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21294718, 22211708, 22674740, 23444262; Phenotypes: Agnathia-otocephaly complex, MIM# 202650; Mode of inheritance: None
Mendeliome v0.8686 POLR1D Zornitza Stark Marked gene: POLR1D as ready
Mendeliome v0.8686 POLR1D Zornitza Stark Gene: polr1d has been classified as Green List (High Evidence).
Mendeliome v0.8686 POLR1D Zornitza Stark Phenotypes for gene: POLR1D were changed from to Treacher Collins syndrome 2, MIM# 613717
Mendeliome v0.8685 POLR1D Zornitza Stark Publications for gene: POLR1D were set to
Mendeliome v0.8684 POLR1D Zornitza Stark Mode of inheritance for gene: POLR1D was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.75 POLR1D Zornitza Stark edited their review of gene: POLR1D: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8683 POLR1D Zornitza Stark reviewed gene: POLR1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131976, 24603435, 27448281, 25790162; Phenotypes: Treacher Collins syndrome 2, MIM# 613717; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.75 POLR1D Zornitza Stark Mode of inheritance for gene: POLR1D was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.74 POLR1D Zornitza Stark Marked gene: POLR1D as ready
Mandibulofacial Acrofacial dysostosis v0.74 POLR1D Zornitza Stark Gene: polr1d has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.74 POLR1D Zornitza Stark Phenotypes for gene: POLR1D were changed from to Treacher Collins syndrome 2, MIM# 613717
Mandibulofacial Acrofacial dysostosis v0.73 POLR1D Zornitza Stark Publications for gene: POLR1D were set to
Mandibulofacial Acrofacial dysostosis v0.72 POLR1D Zornitza Stark Mode of inheritance for gene: POLR1D was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.71 POLR1D Zornitza Stark reviewed gene: POLR1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131976, 24603435, 27448281, 25790162; Phenotypes: Treacher Collins syndrome 2, MIM# 613717; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.71 RPL11 Zornitza Stark Marked gene: RPL11 as ready
Mandibulofacial Acrofacial dysostosis v0.71 RPL11 Zornitza Stark Gene: rpl11 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.71 RPL11 Zornitza Stark Phenotypes for gene: RPL11 were changed from to Diamond-Blackfan anemia 7, MIM# 612562; MONDO:0012938
Mandibulofacial Acrofacial dysostosis v0.70 RPL11 Zornitza Stark Publications for gene: RPL11 were set to
Mandibulofacial Acrofacial dysostosis v0.69 RPL11 Zornitza Stark Mode of inheritance for gene: RPL11 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.68 RPL11 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Craniofacial and limb abnormalities are common.
Ciliary Dyskinesia v1.12 TP73 Zornitza Stark Marked gene: TP73 as ready
Ciliary Dyskinesia v1.12 TP73 Zornitza Stark Gene: tp73 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.12 TP73 Zornitza Stark Classified gene: TP73 as Green List (high evidence)
Ciliary Dyskinesia v1.12 TP73 Zornitza Stark Gene: tp73 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.11 TP73 Zornitza Stark gene: TP73 was added
gene: TP73 was added to Ciliary Dyskinesia. Sources: Literature
Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP73 were set to 31130284; 34077761
Phenotypes for gene: TP73 were set to Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466
Review for gene: TP73 was set to GREEN
Added comment: 7 unrelated families reported. In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls.

Clinical features included recurrent respiratory infections and respiratory dysfunction caused by defective mucociliary clearance in early childhood. Affected individuals also had neurologic features, such as impaired intellectual development and central hypotonia, associated with structural brain abnormalities, most notably lissencephaly and thin or absent corpus callosum.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4030 TP73 Zornitza Stark Phenotypes for gene: TP73 were changed from Intellectual disability; lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Intellectual disability; lissencephaly
Intellectual disability syndromic and non-syndromic v0.4029 TP73 Zornitza Stark edited their review of gene: TP73: Added comment: Additional 5 families reported in PMID 34077761; Changed rating: GREEN; Changed publications: 31130284, 34077761; Changed phenotypes: Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466, Intellectual disability, lissencephaly
Mendeliome v0.8683 TP73 Zornitza Stark Phenotypes for gene: TP73 were changed from Cortical malformation; Lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Cortical malformation; Lissencephaly
Mendeliome v0.8682 TP73 Zornitza Stark reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Mode of inheritance: None
Lissencephaly and Band Heterotopia v1.4 TP73 Zornitza Stark Phenotypes for gene: TP73 were changed from brain malformation; lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; brain malformation; lissencephaly
Lissencephaly and Band Heterotopia v1.3 TP73 Zornitza Stark reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 47, and lissencephaly, MIM#619466; Mode of inheritance: None
Mendeliome v0.8682 SYT2 Zornitza Stark Phenotypes for gene: SYT2 were changed from Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040 to Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040; Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Mendeliome v0.8681 SYT2 Zornitza Stark edited their review of gene: SYT2: Changed phenotypes: Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040, Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Congenital Myasthenia v1.3 SYT2 Zornitza Stark Phenotypes for gene: SYT2 were changed from Myasthenic syndrome, congenital, 7, presynaptic, 616040 to Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040; Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Congenital Myasthenia v1.2 SYT2 Zornitza Stark edited their review of gene: SYT2: Changed phenotypes: Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040, Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive OMIM#619461
Mendeliome v0.8681 POLR1C Zornitza Stark Marked gene: POLR1C as ready
Mendeliome v0.8681 POLR1C Zornitza Stark Gene: polr1c has been classified as Green List (High Evidence).
Mendeliome v0.8681 POLR1C Zornitza Stark Phenotypes for gene: POLR1C were changed from to Treacher Collins syndrome 3, MIM# 248390; Leukodystrophy, hypomyelinating, 11, MIM# 616494
Mendeliome v0.8680 POLR1C Zornitza Stark Publications for gene: POLR1C were set to
Mendeliome v0.8679 POLR1C Zornitza Stark Mode of inheritance for gene: POLR1C was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8678 POLR1C Zornitza Stark reviewed gene: POLR1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131976, 30957429, 26151409, 32042905; Phenotypes: Treacher Collins syndrome 3, MIM# 248390, Leukodystrophy, hypomyelinating, 11, MIM# 616494; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.68 POLR1C Zornitza Stark Marked gene: POLR1C as ready
Mandibulofacial Acrofacial dysostosis v0.68 POLR1C Zornitza Stark Gene: polr1c has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.68 POLR1C Zornitza Stark Phenotypes for gene: POLR1C were changed from to Treacher Collins syndrome 3, MIM# 248390
Mandibulofacial Acrofacial dysostosis v0.67 POLR1C Zornitza Stark Publications for gene: POLR1C were set to
Mandibulofacial Acrofacial dysostosis v0.66 POLR1C Zornitza Stark Mode of inheritance for gene: POLR1C was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.65 POLR1C Zornitza Stark reviewed gene: POLR1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131976, 30957429; Phenotypes: Treacher Collins syndrome 3, MIM# 248390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8678 SF3B4 Zornitza Stark Marked gene: SF3B4 as ready
Mendeliome v0.8678 SF3B4 Zornitza Stark Gene: sf3b4 has been classified as Green List (High Evidence).
Mendeliome v0.8678 SF3B4 Zornitza Stark Phenotypes for gene: SF3B4 were changed from to Acrofacial dysostosis 1, Nager type, MIM# 154400
Mendeliome v0.8677 SF3B4 Zornitza Stark Publications for gene: SF3B4 were set to
Mendeliome v0.8676 SF3B4 Zornitza Stark Mode of inheritance for gene: SF3B4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8675 SF3B4 Zornitza Stark reviewed gene: SF3B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541558, 23568615, 24003905; Phenotypes: Acrofacial dysostosis 1, Nager type, MIM# 154400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.65 SF3B4 Zornitza Stark Marked gene: SF3B4 as ready
Mandibulofacial Acrofacial dysostosis v0.65 SF3B4 Zornitza Stark Gene: sf3b4 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.65 SF3B4 Zornitza Stark Phenotypes for gene: SF3B4 were changed from to Acrofacial dysostosis 1, Nager type, MIM# 154400
Mandibulofacial Acrofacial dysostosis v0.64 SF3B4 Zornitza Stark Publications for gene: SF3B4 were set to
Mandibulofacial Acrofacial dysostosis v0.63 SF3B4 Zornitza Stark Mode of inheritance for gene: SF3B4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.62 SF3B4 Zornitza Stark reviewed gene: SF3B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541558, 23568615, 24003905; Phenotypes: Acrofacial dysostosis 1, Nager type, MIM# 154400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8675 TMCO1 Zornitza Stark Marked gene: TMCO1 as ready
Mendeliome v0.8675 TMCO1 Zornitza Stark Gene: tmco1 has been classified as Green List (High Evidence).
Mendeliome v0.8675 TMCO1 Zornitza Stark Phenotypes for gene: TMCO1 were changed from to Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980
Mendeliome v0.8674 TMCO1 Zornitza Stark Publications for gene: TMCO1 were set to
Mendeliome v0.8673 TMCO1 Zornitza Stark Mode of inheritance for gene: TMCO1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8672 TMCO1 Zornitza Stark reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20018682, 23320496, 17351359, 30556256, 31102500; Phenotypes: Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.62 TMCO1 Zornitza Stark Marked gene: TMCO1 as ready
Mandibulofacial Acrofacial dysostosis v0.62 TMCO1 Zornitza Stark Gene: tmco1 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.62 TMCO1 Zornitza Stark Phenotypes for gene: TMCO1 were changed from to Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980
Mandibulofacial Acrofacial dysostosis v0.61 TMCO1 Zornitza Stark Publications for gene: TMCO1 were set to
Mandibulofacial Acrofacial dysostosis v0.60 TMCO1 Zornitza Stark Mode of inheritance for gene: TMCO1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.59 TMCO1 Zornitza Stark changed review comment from: Clinical features include severe intellectual disability, as well as distinctive craniofacial features, including brachycephaly, synophrys, arched eyebrows, "cupid's bow" upper lip, and microdontia. In addition, nonspecific skeletal anomalies are common, including bifid ribs, scoliosis, and spinal fusion.

More than 20 individuals reported.; to: Clinical features include severe intellectual disability, as well as distinctive craniofacial features, including brachycephaly, synophrys, arched eyebrows, "cupid's bow" upper lip, and microdontia. In addition, nonspecific skeletal anomalies are common, including bifid ribs, scoliosis, and spinal fusion.

More than 20 individuals reported. c.292_293del (p.Ser98*) variant has been identified in multiple individuals from different ethnicities.
Mandibulofacial Acrofacial dysostosis v0.59 TMCO1 Zornitza Stark reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20018682, 23320496, 17351359, 30556256, 31102500; Phenotypes: Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting disorders v0.136 SF3B2 Zornitza Stark Marked gene: SF3B2 as ready
Clefting disorders v0.136 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Clefting disorders v0.136 SF3B2 Zornitza Stark Classified gene: SF3B2 as Green List (high evidence)
Clefting disorders v0.136 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Clefting disorders v0.135 SF3B2 Zornitza Stark gene: SF3B2 was added
gene: SF3B2 was added to Clefting disorders. Sources: Literature
Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B2 were set to 34344887
Phenotypes for gene: SF3B2 were set to Craniofacial microsomia
Review for gene: SF3B2 was set to GREEN
Added comment: Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities.

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

The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
Sources: Literature
Mendeliome v0.8672 SEMA3D Zornitza Stark Phenotypes for gene: SEMA3D were changed from Hand and foot malformations to Hand and foot malformations; Hirschsprung disease
Mendeliome v0.8671 SPTBN4 Zornitza Stark reviewed gene: SPTBN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 33772159, 29861105; Phenotypes: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, MIM# 617519; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8671 RGS10 Zornitza Stark Marked gene: RGS10 as ready
Mendeliome v0.8671 RGS10 Zornitza Stark Gene: rgs10 has been classified as Red List (Low Evidence).
Mendeliome v0.8671 RGS10 Zornitza Stark gene: RGS10 was added
gene: RGS10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS10 were set to 34315806; 34339853
Phenotypes for gene: RGS10 were set to Immunodeficiency; short stature
Review for gene: RGS10 was set to RED
Added comment: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented. Further experimental data linking RGS10 to immune function presented in PMID 34339853.
Sources: Literature
Combined Immunodeficiency v0.291 RGS10 Zornitza Stark Marked gene: RGS10 as ready
Combined Immunodeficiency v0.291 RGS10 Zornitza Stark Gene: rgs10 has been classified as Red List (Low Evidence).
Combined Immunodeficiency v0.291 RGS10 Zornitza Stark Publications for gene: RGS10 were set to 34315806
Combined Immunodeficiency v0.290 RGS10 Zornitza Stark changed review comment from: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented.
Sources: Literature; to: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented. Further experimental data linking RGS10 to immune function presented in PMID 34339853.
Sources: Literature
Combined Immunodeficiency v0.290 RGS10 Zornitza Stark edited their review of gene: RGS10: Changed publications: 34315806, 34339853
Combined Immunodeficiency v0.290 RGS10 Zornitza Stark gene: RGS10 was added
gene: RGS10 was added to Combined Immunodeficiency. Sources: Literature
Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS10 were set to 34315806
Phenotypes for gene: RGS10 were set to Immunodeficiency; short stature
Review for gene: RGS10 was set to RED
Added comment: Three affected siblings with short stature and immunodeficiency and segregating biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals had recurrent infections, hypergammaglobulinaemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Limited functional data presented.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Marked gene: MAST3 as ready
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Classified gene: MAST3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4029 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4028 MAST3 Zornitza Stark gene: MAST3 was added
gene: MAST3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST3 were set to 34185323
Phenotypes for gene: MAST3 were set to Developmental and epileptic encephalopathy
Review for gene: MAST3 was set to GREEN
Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data.
Sources: Literature
Mendeliome v0.8670 MAST3 Zornitza Stark Marked gene: MAST3 as ready
Mendeliome v0.8670 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1161 MAST3 Zornitza Stark Marked gene: MAST3 as ready
Genetic Epilepsy v0.1161 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1161 MAST3 Zornitza Stark Phenotypes for gene: MAST3 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy
Mendeliome v0.8670 MAST3 Zornitza Stark Classified gene: MAST3 as Green List (high evidence)
Mendeliome v0.8670 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1160 MAST3 Zornitza Stark Phenotypes for gene: MAST3 were changed from Epilepsy to Developmental and epileptic encephalopathy
Mendeliome v0.8669 MAST3 Zornitza Stark gene: MAST3 was added
gene: MAST3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST3 were set to 34185323
Phenotypes for gene: MAST3 were set to Developmental and epileptic encephalopathy
Review for gene: MAST3 was set to GREEN
Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data.
Sources: Literature
Genetic Epilepsy v0.1159 MAST3 Zornitza Stark Classified gene: MAST3 as Green List (high evidence)
Genetic Epilepsy v0.1159 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1158 MAST3 Zornitza Stark gene: MAST3 was added
gene: MAST3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST3 were set to 34185323
Phenotypes for gene: MAST3 were set to Epilepsy
Review for gene: MAST3 was set to GREEN
Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data.
Sources: Literature
Mandibulofacial Acrofacial dysostosis v0.59 SF3B2 Zornitza Stark Marked gene: SF3B2 as ready
Mandibulofacial Acrofacial dysostosis v0.59 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.59 SF3B2 Zornitza Stark Classified gene: SF3B2 as Green List (high evidence)
Mandibulofacial Acrofacial dysostosis v0.59 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.58 SF3B2 Zornitza Stark gene: SF3B2 was added
gene: SF3B2 was added to Mandibulofacial Acrofacial dysostosis. Sources: Literature
Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B2 were set to 34344887
Phenotypes for gene: SF3B2 were set to Craniofacial microsomia
Review for gene: SF3B2 was set to GREEN
Added comment: Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities.

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

The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
Sources: Literature
Mendeliome v0.8668 SF3B2 Zornitza Stark Marked gene: SF3B2 as ready
Mendeliome v0.8668 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Mendeliome v0.8668 SF3B2 Zornitza Stark Classified gene: SF3B2 as Green List (high evidence)
Mendeliome v0.8668 SF3B2 Zornitza Stark Gene: sf3b2 has been classified as Green List (High Evidence).
Mendeliome v0.8667 SF3B2 Zornitza Stark gene: SF3B2 was added
gene: SF3B2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B2 were set to 34344887
Phenotypes for gene: SF3B2 were set to Craniofacial microsomia
Review for gene: SF3B2 was set to GREEN
Added comment: Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities.

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

The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
Sources: Literature
Retinitis pigmentosa v0.99 IMPG1 Zornitza Stark Marked gene: IMPG1 as ready
Retinitis pigmentosa v0.99 IMPG1 Zornitza Stark Gene: impg1 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa v0.99 IMPG1 Zornitza Stark Classified gene: IMPG1 as Amber List (moderate evidence)
Retinitis pigmentosa v0.99 IMPG1 Zornitza Stark Gene: impg1 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa v0.98 IMPG1 Zornitza Stark gene: IMPG1 was added
gene: IMPG1 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: IMPG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IMPG1 were set to 32817297
Phenotypes for gene: IMPG1 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: IMPG1 was set to AMBER
Added comment: Variants in this gene are classically associated with macular dystrophy.

However note recent paper by Olivier et al. 2021 (PMID: 32817297) who identified seven variants in IMPG1 (including five novel) in 11 families with VMD or retinitis pigmentosa (RP).

4 families were diagnosed with autosomal dominant RP, 2 families had autosomal recessive RP, while 5 families developed VMD in association with heterozygous IMPG1 variants. Notably, inter- and intrafamilial phenotypic variation was evident with some individuals presenting RP while others had VMD, despite harbouring the same IMPG1 variant.

Knockdown of Impg1 in medaka fish resulted in a phenotype consistent with that observed in human patients, including a decreased length of rod and cone photoreceptor outer segments.
Sources: Literature
Macular Dystrophy/Stargardt Disease v0.30 IMPG1 Zornitza Stark Marked gene: IMPG1 as ready
Macular Dystrophy/Stargardt Disease v0.30 IMPG1 Zornitza Stark Gene: impg1 has been classified as Green List (High Evidence).
Macular Dystrophy/Stargardt Disease v0.30 IMPG1 Zornitza Stark Phenotypes for gene: IMPG1 were changed from Macular dystrophy, vitelliform, 4 to Macular dystrophy, vitelliform, 4, OMIM:616151; Retinitis pigmentosa, MONDO:0019200
Macular Dystrophy/Stargardt Disease v0.29 IMPG1 Zornitza Stark Publications for gene: IMPG1 were set to
Macular Dystrophy/Stargardt Disease v0.28 IMPG1 Zornitza Stark Mode of inheritance for gene: IMPG1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Macular Dystrophy/Stargardt Disease v0.27 IMPG1 Zornitza Stark reviewed gene: IMPG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23993198, 28644393, 30589393, 30688845, 32817297; Phenotypes: Macular dystrophy, vitelliform, 4, OMIM:616151, Retinitis pigmentosa, MONDO:0019200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8666 IMPG1 Zornitza Stark Marked gene: IMPG1 as ready
Mendeliome v0.8666 IMPG1 Zornitza Stark Gene: impg1 has been classified as Green List (High Evidence).
Mendeliome v0.8666 IMPG1 Zornitza Stark Phenotypes for gene: IMPG1 were changed from to Macular dystrophy, vitelliform, 4, OMIM:616151; Retinitis pigmentosa, MONDO:0019200
Mendeliome v0.8665 IMPG1 Zornitza Stark Publications for gene: IMPG1 were set to
Mendeliome v0.8664 IMPG1 Zornitza Stark Mode of inheritance for gene: IMPG1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8663 IMPG1 Arina Puzriakova reviewed gene: IMPG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23993198, 28644393, 30589393, 30688845, 32817297; Phenotypes: Macular dystrophy, vitelliform, 4, OMIM:616151, Retinitis pigmentosa, MONDO:0019200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure v0.74 Zornitza Stark removed gene:SPRED1 from the panel
Growth failure v0.73 XRCC4 Zornitza Stark Marked gene: XRCC4 as ready
Growth failure v0.73 XRCC4 Zornitza Stark Gene: xrcc4 has been classified as Green List (High Evidence).
Growth failure v0.73 XRCC4 Zornitza Stark Phenotypes for gene: XRCC4 were changed from short stature, microcephaly, hypothyroidism, diabetes mellitus, progressive ataxia, hypergonadotrophic hypogonadism to Short stature, microcephaly, and endocrine dysfunction, MIM# 616541; MONDO:0014686
Growth failure v0.72 XRCC4 Zornitza Stark Publications for gene: XRCC4 were set to 25728776
Growth failure v0.71 XRCC4 Zornitza Stark Classified gene: XRCC4 as Green List (high evidence)
Growth failure v0.71 XRCC4 Zornitza Stark Gene: xrcc4 has been classified as Green List (High Evidence).
Growth failure v0.70 XRCC4 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Growth failure is an early and prominent feature.
Growth failure v0.70 RIT1 Zornitza Stark Marked gene: RIT1 as ready
Growth failure v0.70 RIT1 Zornitza Stark Gene: rit1 has been classified as Green List (High Evidence).
Growth failure v0.70 RIT1 Zornitza Stark Phenotypes for gene: RIT1 were changed from Rasopathy; Noonan syndrome type 8; Noonan syndrome 8 to Noonan syndrome 8, MIM# 615355
Growth failure v0.69 RIT1 Zornitza Stark Publications for gene: RIT1 were set to 24939608; 25124994; 23791108
Growth failure v0.68 RAF1 Zornitza Stark Marked gene: RAF1 as ready
Growth failure v0.68 RAF1 Zornitza Stark Gene: raf1 has been classified as Green List (High Evidence).
Growth failure v0.68 RAF1 Zornitza Stark Phenotypes for gene: RAF1 were changed from Noonan syndrome 5; Noonan syndrome; LEOPARD syndrome 2; Rasopathy; LEOPARD syndrome to Noonan syndrome 5, MIM# 611553
Growth failure v0.67 RAF1 Zornitza Stark Publications for gene: RAF1 were set to 17603483; 17603482
Growth failure v0.66 RAF1 Zornitza Stark changed review comment from: Over 20 affected individuals reported.; to: Over 20 affected individuals reported. Short stature is a key feature.
Growth failure v0.66 PTPN11 Zornitza Stark Marked gene: PTPN11 as ready
Growth failure v0.66 PTPN11 Zornitza Stark Gene: ptpn11 has been classified as Green List (High Evidence).
Growth failure v0.66 PTPN11 Zornitza Stark Phenotypes for gene: PTPN11 were changed from Noonan syndrome; LEOPARD syndrome 1; Noonan syndrome 1; LEOPARD syndrome to LEOPARD syndrome 1, 151100 AD (for reporting use Noonan syndrome with multiple lentigines); Noonan syndrome 1, MIM#163950
Growth failure v0.65 PTPN11 Zornitza Stark Mode of pathogenicity for gene: PTPN11 was changed from Other - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Growth failure v0.64 ZPR1 Zornitza Stark Marked gene: ZPR1 as ready
Growth failure v0.64 ZPR1 Zornitza Stark Gene: zpr1 has been classified as Red List (Low Evidence).
Growth failure v0.64 ZPR1 Zornitza Stark Phenotypes for gene: ZPR1 were changed from ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321 to Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies, MIM# 619321
Growth failure v0.63 ZPR1 Zornitza Stark Tag founder tag was added to gene: ZPR1.
Growth failure v0.63 ZPR1 Zornitza Stark reviewed gene: ZPR1: Rating: RED; Mode of pathogenicity: None; Publications: 29851065; Phenotypes: Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies, MIM# 619321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.63 PPP1CB Zornitza Stark Marked gene: PPP1CB as ready
Growth failure v0.63 PPP1CB Zornitza Stark Gene: ppp1cb has been classified as Green List (High Evidence).
Growth failure v0.63 PPP1CB Zornitza Stark Phenotypes for gene: PPP1CB were changed from Noonan syndrome-like disorder with loose anagen hair 2, 617506; Rasopathy with developmental delay, short stature and sparse slow-growing hair to Noonan syndrome-like disorder with loose anagen hair 2; OMIM # 617506
Growth failure v0.62 PPP1CB Zornitza Stark Publications for gene: PPP1CB were set to 27264673; 27681385; 28211982
Growth failure v0.61 PPP1CB Zornitza Stark Mode of inheritance for gene: PPP1CB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.60 PALB2 Zornitza Stark Marked gene: PALB2 as ready
Growth failure v0.60 PALB2 Zornitza Stark Gene: palb2 has been classified as Green List (High Evidence).
Growth failure v0.60 PALB2 Zornitza Stark Phenotypes for gene: PALB2 were changed from Fanconi anemia, complementation group N, 610832; 610832 Fanconi anemia, complementation group N to Fanconi anaemia, complementation group N, MIM# 610832
Growth failure v0.59 PALB2 Zornitza Stark changed review comment from: Established gene-disease association.; to: Established gene-disease association. Short stature is a key feature of FA.
Growth failure v0.59 NRAS Zornitza Stark Marked gene: NRAS as ready
Growth failure v0.59 NRAS Zornitza Stark Gene: nras has been classified as Green List (High Evidence).
Growth failure v0.59 NRAS Zornitza Stark Phenotypes for gene: NRAS were changed from Cardio-Facio-cutanenous syndrome; A restricted spectrum of NRAS mutations causes Noonan syndrome. (Nat Genet. 42: 27-29, 2010.); Noonan syndrome; CFC Syndrome; Noonan syndrome 6 to Noonan syndrome 6, MIM# 613224
Growth failure v0.58 NRAS Zornitza Stark Publications for gene: NRAS were set to 19966803; 19775298
Growth failure v0.57 NRAS Zornitza Stark changed review comment from: Over 20 affected individuals reported, well established gene-disease association.; to: Over 20 affected individuals reported, well established gene-disease association. Short stature is a key feature.
Growth failure v0.57 NBN Zornitza Stark Marked gene: NBN as ready
Growth failure v0.57 NBN Zornitza Stark Gene: nbn has been classified as Green List (High Evidence).
Growth failure v0.57 NBN Zornitza Stark Phenotypes for gene: NBN were changed from Nijmegen; Nijmegen breakage syndrome, 251260 to Nijmegen breakage syndrome, MIM# 251260; MONDO:0009623
Growth failure v0.56 NBN Zornitza Stark Publications for gene: NBN were set to
Growth failure v0.55 MAP2K2 Zornitza Stark Marked gene: MAP2K2 as ready
Growth failure v0.55 MAP2K2 Zornitza Stark Gene: map2k2 has been classified as Green List (High Evidence).
Growth failure v0.55 MAP2K2 Zornitza Stark Phenotypes for gene: MAP2K2 were changed from CFC syndrome; Cardiofaciocutaneous Syndrome; Cardiofaciocutaneous syndrome; Cardiofaciocutaneous syndrome 4; Cardio-Facio-Cutaneous syndrome; Cardio-Facio-Cutaneous syndrome type 4 to Cardiofaciocutaneous syndrome 4, MIM# 615280
Growth failure v0.54 MAP2K2 Zornitza Stark Publications for gene: MAP2K2 were set to 16439621; 21396583; 23379592
Growth failure v0.53 MAP2K1 Zornitza Stark Marked gene: MAP2K1 as ready
Growth failure v0.53 MAP2K1 Zornitza Stark Gene: map2k1 has been classified as Green List (High Evidence).
Growth failure v0.53 MAP2K1 Zornitza Stark Phenotypes for gene: MAP2K1 were changed from Cardiofaciocutaneous syndrome 3; CFC syndrome; ?Noonan syndrome; Cardiofaciocutaneous Syndrome; Cardiofaciocutaneous syndrome; Cardio-Facio-Cutaneous syndrome; LEOPARD syndrome to Cardiofaciocutaneous syndrome 3, MIM# 615279
Growth failure v0.52 MAP2K1 Zornitza Stark Publications for gene: MAP2K1 were set to 23321623; 16439621; 21396583; 16825433
Growth failure v0.51 LZTR1 Zornitza Stark Marked gene: LZTR1 as ready
Growth failure v0.51 LZTR1 Zornitza Stark Gene: lztr1 has been classified as Green List (High Evidence).
Growth failure v0.51 LZTR1 Zornitza Stark Phenotypes for gene: LZTR1 were changed from increased nuchal translucency; Prenatal hydrops; cardiac findings; Noonan syndrome 10 to Noonan syndrome 10; Noonan syndrome 2
Growth failure v0.50 LZTR1 Zornitza Stark Publications for gene: LZTR1 were set to 29469822; 25795793
Growth failure v0.49 KRAS Zornitza Stark Marked gene: KRAS as ready
Growth failure v0.49 KRAS Zornitza Stark Gene: kras has been classified as Green List (High Evidence).
Growth failure v0.49 KRAS Zornitza Stark Phenotypes for gene: KRAS were changed from Noonan syndrome 3; CFC syndrome; Cardiofaciocutaneous syndrome 2; Cardiofaciocutaneous Syndrome; Noonan syndrome; Rasopathy; Cardio-Facio-Cutaneous syndrome to Noonan syndrome 3, MIM# 609942; Cardiofaciocutaneous syndrome 2, MIM# 615278
Growth failure v0.48 KRAS Zornitza Stark Publications for gene: KRAS were set to 21396583
Growth failure v0.47 KRAS Zornitza Stark changed review comment from: Well established gene-disease association in individuals with Noonan syndrome, CFC and overlapping Noonan-CFC.; to: Well established gene-disease association in individuals with Noonan syndrome, CFC and overlapping Noonan-CFC. Short stature is a key feature.
Growth failure v0.47 HRAS Zornitza Stark Marked gene: HRAS as ready
Growth failure v0.47 HRAS Zornitza Stark Gene: hras has been classified as Green List (High Evidence).
Growth failure v0.47 HRAS Zornitza Stark Phenotypes for gene: HRAS were changed from Costello syndrome, 218040; Costello; Costello syndrome to Costello syndrome, MIM# 218040
Growth failure v0.46 HRAS Zornitza Stark Publications for gene: HRAS were set to 16969868; 16443854; 21396583; 16170316
Growth failure v0.45 HMGA2 Zornitza Stark Marked gene: HMGA2 as ready
Growth failure v0.45 HMGA2 Zornitza Stark Gene: hmga2 has been classified as Green List (High Evidence).
Growth failure v0.45 HMGA2 Zornitza Stark Phenotypes for gene: HMGA2 were changed from Silver-Russell syndrome 5, MONDO:0020795; Silver-Russell syndrome 5, OMIM:618908 to Silver-Russell syndrome 5, MIM# 618908; MONDO:0020795
Growth failure v0.44 HMGA2 Zornitza Stark Publications for gene: HMGA2 were set to 29655892
Growth failure v0.43 HMGA2 Zornitza Stark reviewed gene: HMGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25809938, 29453418, 29655892, 33482836; Phenotypes: Silver-Russell syndrome 5, MIM# 618908; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.43 FGFR3 Zornitza Stark Marked gene: FGFR3 as ready
Growth failure v0.43 FGFR3 Zornitza Stark Gene: fgfr3 has been classified as Green List (High Evidence).
Growth failure v0.43 FGFR3 Zornitza Stark Phenotypes for gene: FGFR3 were changed from Hypochondroplasia, 146000 to Hypochondroplasia, MIM#146000
Growth failure v0.42 FGFR3 Zornitza Stark Mode of inheritance for gene: FGFR3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.41 FGFR3 Zornitza Stark reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypochondroplasia, MIM# 146000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v0.41 FANCL Zornitza Stark Marked gene: FANCL as ready
Growth failure v0.41 FANCL Zornitza Stark Gene: fancl has been classified as Green List (High Evidence).
Growth failure v0.41 FANCL Zornitza Stark Phenotypes for gene: FANCL were changed from Fanconi anemia; 614083Fanconi anemia, complementation group L; Fanconi anemia, complementation group L, 614083; Fanconi Anemia to Fanconi anemia, complementation group L, MIM# 614083; MONDO:0013566
Growth failure v0.40 FANCL Zornitza Stark Publications for gene: FANCL were set to 25754594; 12724401; 19405097; 12973351; 16474160
Growth failure v0.39 FANCL Zornitza Stark changed review comment from: Established gene-disease association. Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer.; to: Established gene-disease association. Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Poor growth is a key feature.
Growth failure v0.39 FANCI Zornitza Stark Marked gene: FANCI as ready
Growth failure v0.39 FANCI Zornitza Stark Gene: fanci has been classified as Green List (High Evidence).
Growth failure v0.39 FANCI Zornitza Stark Phenotypes for gene: FANCI were changed from 609053 Fanconi anemia, complementation group I; Fanconi anemia; Fanconi anemia, complementation group I, 609053; Fanconi Anemia to Fanconi anemia, complementation group I, MIM# 609053; MONDO:0012186
Growth failure v0.38 FANCI Zornitza Stark changed review comment from: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer.; to: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Poor growth is a key feature.
Growth failure v0.38 FANCG Zornitza Stark Marked gene: FANCG as ready
Growth failure v0.38 FANCG Zornitza Stark Gene: fancg has been classified as Green List (High Evidence).
Growth failure v0.38 FANCG Zornitza Stark Phenotypes for gene: FANCG were changed from 614082 Fanconi anemia, complementation group G; hypogonadism and reduced fertility; Fanconi Anemia; bone marrow failure; a typical facial appearance with small head, eyes, and mouth; cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); hearing loss; Fanconi anemia; and susceptibility to cancer, predominantly acute myeloid leukemia.; Fanconi anemia, complementation group G, 614082; Fanconi anemia complementation group G; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); pre- and postnatal growth retardation to Fanconi anaemia, complementation group G, MIM# 614082; MONDO:0013565
Growth failure v0.37 FANCG Zornitza Stark Publications for gene: FANCG were set to 16493006; 9806548
Growth failure v0.36 FANCG Zornitza Stark changed review comment from: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer.; to: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Poor growth is a key feature.
Growth failure v0.36 FANCF Zornitza Stark Marked gene: FANCF as ready
Growth failure v0.36 FANCF Zornitza Stark Gene: fancf has been classified as Green List (High Evidence).
Growth failure v0.36 FANCF Zornitza Stark Phenotypes for gene: FANCF were changed from Fanconi anemia, complementation group F, 603467; Fanconi anemia; 603467 Fanconi anemia, complementation group F; Fanconi Anemia to Fanconi anaemia, complementation group F 603467; MONDO:0011325
Growth failure v0.35 FANCF Zornitza Stark Publications for gene: FANCF were set to 10615118
Growth failure v0.34 FANCF Zornitza Stark changed review comment from: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer.; to: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Poor growth is a key feature.
Growth failure v0.34 FANCE Zornitza Stark Marked gene: FANCE as ready
Growth failure v0.34 FANCE Zornitza Stark Gene: fance has been classified as Green List (High Evidence).
Growth failure v0.34 FANCE Zornitza Stark Phenotypes for gene: FANCE were changed from Fanconi anemia; Fanconi anemia, complementation group E, 600901; 600901 Fanconi anemia, complementation group E; Fanconi Anemia to Fanconi anaemia, complementation group E, MIM# 600901; MONDO:0010953
Growth failure v0.33 FANCE Zornitza Stark Publications for gene: FANCE were set to 7662964; 10205272; 9147877; 9382107
Growth failure v0.32 FANCE Zornitza Stark changed review comment from: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer.; to: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Poor growth is a key feature.
Growth failure v0.32 FANCD2 Zornitza Stark Marked gene: FANCD2 as ready
Growth failure v0.32 FANCD2 Zornitza Stark Gene: fancd2 has been classified as Green List (High Evidence).
Growth failure v0.32 FANCD2 Zornitza Stark Phenotypes for gene: FANCD2 were changed from Fanconi anemia; 227646 Fanconi anemia, complementation group D2; Fanconi anemia, complementation group D2, 227646; Fanconi Anemia to Fanconi anaemia, complementation group D2, MIM# 227646
Growth failure v0.31 FANCD2 Zornitza Stark changed review comment from: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer.; to: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Poor growth is a key feature.
Growth failure v0.31 FANCC Zornitza Stark Marked gene: FANCC as ready
Growth failure v0.31 FANCC Zornitza Stark Gene: fancc has been classified as Green List (High Evidence).
Growth failure v0.31 FANCC Zornitza Stark Phenotypes for gene: FANCC were changed from hypogonadism and reduced fertility; Fanconi Anemia; bone marrow failure; a typical facial appearance with small head, eyes, and mouth; Fanconi anemia, complementation group C, 227645; cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); hearing loss; Fanconi anemia; and susceptibility to cancer, predominantly acute myeloid leukemia.; 227645 Fanconi anemia, complementation group C; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); pre- and postnatal growth retardation to Fanconi anemia, complementation group C, MIM# 227645; MONDO:0009213
Growth failure v0.30 FANCC Zornitza Stark Publications for gene: FANCC were set to 16493006; 1574115
Growth failure v0.29 FANCC Zornitza Stark changed review comment from: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer.; to: Established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Poor growth is a key feature.
Growth failure v0.29 FANCB Zornitza Stark changed review comment from: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, and early-onset bone marrow failure. Poor growth is a key feature.; to: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, and early-onset bone marrow failure. Poor growth is a key feature.
Growth failure v0.29 FANCA Zornitza Stark Phenotypes for gene: FANCA were changed from Fanconi anaemia, complementation group A, MIM# 227650; MONDO:0009215 to Fanconi anaemia, complementation group A, MIM# 227650; MONDO:0009215
Growth failure v0.28 FANCB Zornitza Stark Marked gene: FANCB as ready
Growth failure v0.28 FANCB Zornitza Stark Gene: fancb has been classified as Green List (High Evidence).
Growth failure v0.28 FANCB Zornitza Stark Phenotypes for gene: FANCB were changed from Fanconi anemia, complementation group B, 300514; Falcon anemia; VACTERL Association with Hydrocephalus; Fanconi Anaemia; Fanconi Anemia Type B; 300514 Fanconi anemia, complementation group B; Fanconi anemia; Fanconi Anemia, X-Linked to Fanconi anaemia, complementation group B, MIM# 300514
Growth failure v0.27 FANCB Zornitza Stark Publications for gene: FANCB were set to
Growth failure v0.26 FANCB Zornitza Stark Mode of inheritance for gene: FANCB 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
Growth failure v0.25 FANCB Zornitza Stark changed review comment from: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, and early-onset bone marrow failure.; to: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, and early-onset bone marrow failure. Poor growth is a key feature.
Growth failure v0.25 FANCA Zornitza Stark Marked gene: FANCA as ready
Growth failure v0.25 FANCA Zornitza Stark Gene: fanca has been classified as Green List (High Evidence).
Growth failure v0.25 FANCA Zornitza Stark Phenotypes for gene: FANCA were changed from hypogonadism and reduced fertility; Fanconi Anemia; bone marrow failure; a typical facial appearance with small head, eyes, and mouth; 227650 Fanconi anemia complementation group A; cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); hearing loss; Fanconi anemia; and susceptibility to cancer, predominantly acute myeloid leukemia.; Fanconi anemia, complementation group A, 227650; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); pre- and postnatal growth retardation to Fanconi anaemia, complementation group A, MIM# 227650; MONDO:0009215
Growth failure v0.24 FANCA Zornitza Stark Publications for gene: FANCA were set to 16493006; 8896563
Growth failure v0.23 FANCA Zornitza Stark changed review comment from: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. ; to: Well established gene-disease association.

Fanconi anaemia causes genomic instability and is characterised by multiple congenital anomalies including radial ray abnormalities and microcephaly, early-onset bone marrow failure, and a predisposition to cancer. Growth failure is a key feature.
Growth failure v0.23 ERCC4 Zornitza Stark Marked gene: ERCC4 as ready
Growth failure v0.23 ERCC4 Zornitza Stark Gene: ercc4 has been classified as Green List (High Evidence).
Growth failure v0.23 ERCC4 Zornitza Stark Phenotypes for gene: ERCC4 were changed from 615272 Fanconi anemia, complementation group Q; Fanconi anemia, complementation group Q, 615272 to Fanconi anemia, complementation group Q, MIM# 615272; MONDO:0014108; XFE progeroid syndrome, MIM# 610965; MONDO:0012590
Growth failure v0.22 ERCC4 Zornitza Stark Publications for gene: ERCC4 were set to 23623386; 23623389; 24027083
Growth failure v0.21 ERCC4 Zornitza Stark changed review comment from: Excision repair defect resulting in a range of phenotypes. Growth failure is a key feature of FA.; to: Excision repair defect resulting in a range of phenotypes. Growth failure is a key feature of FA and of progeroid syndrome.
Growth failure v0.21 ERCC4 Zornitza Stark edited their review of gene: ERCC4: Changed phenotypes: Fanconi anemia, complementation group Q, MIM# 615272, MONDO:0014108, XFE progeroid syndrome, MIM# 610965, MONDO:0012590
Growth failure v0.21 ERCC4 Zornitza Stark changed review comment from: Excision repair defect resulting in a range of phenotypes.; to: Excision repair defect resulting in a range of phenotypes. Growth failure is a key feature of FA.
Renal Ciliopathies and Nephronophthisis v1.1 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from Bardet-Biedl syndrome; Short-rib thoracic dysplasia 10 with or without polydactyly, MIM# 615630 to Bardet-Biedl syndrome 20, MIM# 619471; Short-rib thoracic dysplasia 10 with or without polydactyly, MIM# 615630
Renal Ciliopathies and Nephronophthisis v1.0 IFT172 Zornitza Stark changed review comment from: Three families reported with a BBS phenotype, although this association is not listed in OMIM or MONDO. Gene is also associated with skeletal ciliopathy, with nephronophthisis reported.; to: Three families reported with a BBS phenotype. Gene is also associated with skeletal ciliopathy, with nephronophthisis reported.
Renal Ciliopathies and Nephronophthisis v1.0 IFT172 Zornitza Stark edited their review of gene: IFT172: Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 619471, Short-rib thoracic dysplasia 10 with or without polydactyly, MIM# 615630
Mendeliome v0.8663 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome to Retinitis pigmentosa 71 616394; Short-rib thoracic dysplasia 10 with or without polydactyly - 615630; Bardet-Biedl syndrome 20, MIM# 619471
Ciliopathies v1.7 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from Bardet-Biedl syndrome; Retinitis pigmentosa 71, MIM# 616394; Short-rib thoracic dysplasia 10 with or without polydactyly, MIM# 615630 to Bardet-Biedl syndrome 20, MIM# 619471; Retinitis pigmentosa 71, MIM# 616394; Short-rib thoracic dysplasia 10 with or without polydactyly, MIM# 615630
Ciliopathies v1.6 IFT172 Zornitza Stark changed review comment from: Three families reported with a BBS phenotype, although this association is not listed in OMIM or MONDO.
More than 10 families reported with skeletal ciliopathy and 3 with RP. Supportive zebrafish models.; to: Three families reported with a BBS phenotype.
More than 10 families reported with skeletal ciliopathy and 3 with RP. Supportive zebrafish models.
Ciliopathies v1.6 IFT172 Zornitza Stark edited their review of gene: IFT172: Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 619471, Retinitis pigmentosa 71, MIM# 616394, Short-rib thoracic dysplasia 10 with or without polydactyly, MIM# 615630
Bardet Biedl syndrome v1.10 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from Bardet-Biedl syndrome to Bardet-Biedl syndrome 20, MIM# 619471
Bardet Biedl syndrome v1.9 IFT172 Zornitza Stark changed review comment from: Three families reported with a BBS phenotype, although this association is not listed in OMIM or MONDO. Gene is associated with other ciliopathies as well.; to: Three families reported with a BBS phenotype. Gene is associated with other ciliopathies as well.
Bardet Biedl syndrome v1.9 IFT172 Zornitza Stark edited their review of gene: IFT172: Changed phenotypes: Bardet-Biedl syndrome 20, MIM# 619471
Intellectual disability syndromic and non-syndromic v0.4027 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from Intellectual disability; Seizures; FSGS to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428; Intellectual disability; Seizures; FSGS
Intellectual disability syndromic and non-syndromic v0.4026 TRIM8 Zornitza Stark edited their review of gene: TRIM8: Changed phenotypes: Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428, Intellectual disability, Seizures, FSGS
Genetic Epilepsy v0.1157 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from Intellectual disability; Seizures to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428; Intellectual disability; Seizures
Genetic Epilepsy v0.1156 TRIM8 Zornitza Stark edited their review of gene: TRIM8: Changed phenotypes: Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428, Intellectual disability, Seizures
Proteinuria v0.170 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from intellectual disability; epileptic encephalopathy; nephrotic syndrome; proteinuria to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428; Intellectual disability; Seizures; nephrotic syndrome; proteinuria
Proteinuria v0.169 TRIM8 Zornitza Stark reviewed gene: TRIM8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428, Intellectual disability, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8662 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from Intellectual disability; Seizures to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428; Intellectual disability; Seizures
Mendeliome v0.8661 TRIM8 Zornitza Stark edited their review of gene: TRIM8: Changed phenotypes: Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428, Intellectual disability, Seizures
Imprinting disorders v0.1 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Imprinting disorders v0.0 ZFP57 Zornitza Stark gene: ZFP57 was added
gene: ZFP57 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: ZFP57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFP57 were set to 18622393; 23150280; 25848000
Phenotypes for gene: ZFP57 were set to IUGR; Diabetes mellitus, transient neonatal 1 OMIM:601410; Multi Locus Imprinting Disturbance; diabetes mellitus, transient neonatal, 1MONDO:0011073
Imprinting disorders v0.0 UBE3A Zornitza Stark gene: UBE3A was added
gene: UBE3A was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: UBE3A was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: UBE3A were set to 12545427; 8988172; http://igc.otago.ac.nz/home.html; 18500341]; 8988171; 21974935; 2309780; PMID: 9887341; [7795645; 30794780
Phenotypes for gene: UBE3A were set to Affected tissue: brain; Phenotype resulting from under expression: Angelman Syndrome
Imprinting disorders v0.0 SGCE Zornitza Stark gene: SGCE was added
gene: SGCE was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: SGCE was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: SGCE were set to PMID: 25209853; 23237735; 23365103; http://igc.otago.ac.nz/home.html; 30794780
Phenotypes for gene: SGCE were set to Affected tissue: brain; Phenotype resulting from under expression: upper body myoclonus, dystonia
Imprinting disorders v0.0 PADI6 Zornitza Stark gene: PADI6 was added
gene: PADI6 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: PADI6 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: PADI6 were set to 27545678; 33221824; 32928291
Phenotypes for gene: PADI6 were set to Preimplantation embryonic lethality 2 OMIM:617234; preimplantation embryonic lethality 2 MONDO:0014978; Multi Locus Imprinting Disturbance; Beckwith-Wiedemann syndrome
Imprinting disorders v0.0 NLRP7 Zornitza Stark gene: NLRP7 was added
gene: NLRP7 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: NLRP7 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: NLRP7 were set to 19246479; 28916717; 31201414; 16462743; 29574422
Phenotypes for gene: NLRP7 were set to Affected tissue: all (incompatible with life); hydatidiform mole, recurrent, 1 MONDO:0009273; Phenotype resulting from under expression: Biparental complete hydatidiform mole; Multi Locus Imprinting Disturbance
Imprinting disorders v0.0 NLRP5 Zornitza Stark gene: NLRP5 was added
gene: NLRP5 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: NLRP5 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: NLRP5 were set to 26323243; 31201414; 31829238
Phenotypes for gene: NLRP5 were set to Phenotype resulting from under expression: Biparental complete hydatidiform mole, Beckwith-Wiedemann Syndrome, Multi-locus imprinting disorder; Affected tissue: all
Imprinting disorders v0.0 NLRP2 Zornitza Stark gene: NLRP2 was added
gene: NLRP2 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: NLRP2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: NLRP2 were set to 26323243; 29574422; 32169557; 28317850; 30221575; 30877238; 33090377; 19300480; 28422141
Phenotypes for gene: NLRP2 were set to Beckwith-Wiedemann syndrome due to imprinting defect of 11p15 MONDO:0016475
Mode of pathogenicity for gene: NLRP2 was set to Other
Imprinting disorders v0.0 MKRN3 Zornitza Stark gene: MKRN3 was added
gene: MKRN3 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: MKRN3 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: MKRN3 were set to PMID: 23738509; http://igc.otago.ac.nz/home.html; 30794780
Phenotypes for gene: MKRN3 were set to Phenotype resulting from under expression: Precocious Puberty Syndrome; Affected tissue: HPA axis
Imprinting disorders v0.0 L3MBTL1 Zornitza Stark gene: L3MBTL1 was added
gene: L3MBTL1 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: L3MBTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: L3MBTL1 were set to http://igc.otago.ac.nz/home.html; 23543057; PMID: 15123827; 30794780
Phenotypes for gene: L3MBTL1 were set to Affected tissue: myeloid lineages; Phenotype resulting from under expression: lymphoid malignancy
Imprinting disorders v0.0 KCNQ1OT1 Zornitza Stark gene: KCNQ1OT1 was added
gene: KCNQ1OT1 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: KCNQ1OT1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: KCNQ1OT1 were set to 22205991; 15372379; 10220444; http://igc.otago.ac.nz/home.html; 23511928; 30794780
Phenotypes for gene: KCNQ1OT1 were set to Beckwith-Wiedemann syndrome OMIM:130650
Imprinting disorders v0.0 KCNK9 Zornitza Stark gene: KCNK9 was added
gene: KCNK9 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: KCNK9 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: KCNK9 were set to http://igc.otago.ac.nz/home.html; PMID: 24667089; 18678320; 30794780
Phenotypes for gene: KCNK9 were set to Phenotype resulting from under expression: mental retardation, hypotonia, dysmprophism; Affected tissue: brain; Birk-Barel syndrome
Imprinting disorders v0.0 IGF2 Zornitza Stark gene: IGF2 was added
gene: IGF2 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: IGF2 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: IGF2 were set to http://igc.otago.ac.nz/home.html; PMID: 26154720; 30794780
Phenotypes for gene: IGF2 were set to Affected tissue: all; Phenotypes resulting from gene over expression: Beckwith-Wiedemann Syndrome (proven effects of dosage alteration rather than gene muation). Phenotype resulting from under expression: Silver-Russell Syndrome
Imprinting disorders v0.0 H19 Zornitza Stark gene: H19 was added
gene: H19 was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: H19 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: H19 were set to PMID: 20007505; 15743916; 23118352; [21863054; 21571108; 18245780]; 24916376; 25943194
Phenotypes for gene: H19 were set to Phenotypes resulting from gene over expression: Silver-Russell Syndrome (proven effects of dosage alteration rather than gene muation); Affected tissue: all; Phenotype resulting from under expression: Beckwith-Wiedemann Syndrome
Imprinting disorders v0.0 GNAS Zornitza Stark gene: GNAS was added
gene: GNAS was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: GNAS was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: GNAS were set to 10980525; [11406605; 12024005; 15800843]; 15181091; 9506752; 12024004; http://igc.otago.ac.nz/home.html; 15592469; [15592469; 11788646; 1944469; PMID: 2109828; 30794780
Phenotypes for gene: GNAS were set to Affected tissue: kidney, bone, brain; pseudopseudohypoparathyroidism; Phenotype resulting from under expression: Pseudohypoparathyroidism Type 1a
Imprinting disorders v0.0 CDKN1C Zornitza Stark gene: CDKN1C was added
gene: CDKN1C was added to Imprinting disorders. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: CDKN1C was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: CDKN1C were set to 10424811; PMID: 8841187; 22205991]; 20503313; 19843502; http://igc.otago.ac.nz/home.html; [15372379; 23511928; 30794780
Phenotypes for gene: CDKN1C were set to Affected tissue: all; Phenotype resulting from under expression: Beckwith-Wiedemann Syndrome; Phenotypes resulting from gene over expression: IMAGE syndrome; Silver-Russell Syndrome
Imprinting disorders v0.0 Zornitza Stark Added panel Imprinting disorders
Skeletal dysplasia v0.112 CUL7 Zornitza Stark Marked gene: CUL7 as ready
Skeletal dysplasia v0.112 CUL7 Zornitza Stark Gene: cul7 has been classified as Green List (High Evidence).
Skeletal dysplasia v0.112 CUL7 Zornitza Stark Phenotypes for gene: CUL7 were changed from 3-M syndrome 1 273750 to 3-M syndrome 1, MIM# 273750; Yakut short stature syndrome
Skeletal dysplasia v0.111 CUL7 Zornitza Stark Publications for gene: CUL7 were set to
Skeletal dysplasia v0.110 CUL7 Zornitza Stark reviewed gene: CUL7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16142236, 19225462, 17675530; Phenotypes: 3-M syndrome 1, MIM# 273750, Yakut short stature syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8661 CUL7 Zornitza Stark Marked gene: CUL7 as ready
Mendeliome v0.8661 CUL7 Zornitza Stark Gene: cul7 has been classified as Green List (High Evidence).
Mendeliome v0.8661 CUL7 Zornitza Stark Phenotypes for gene: CUL7 were changed from to 3-M syndrome 1, MIM# 273750; Yakut short stature syndrome
Mendeliome v0.8660 CUL7 Zornitza Stark Publications for gene: CUL7 were set to
Mendeliome v0.8659 CUL7 Zornitza Stark Mode of inheritance for gene: CUL7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8658 CUL7 Zornitza Stark reviewed gene: CUL7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16142236, 19225462, 17675530; Phenotypes: 3-M syndrome 1, MIM# 273750, Yakut short stature syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.21 CUL7 Zornitza Stark Marked gene: CUL7 as ready
Growth failure v0.21 CUL7 Zornitza Stark Gene: cul7 has been classified as Green List (High Evidence).
Growth failure v0.21 CUL7 Zornitza Stark Phenotypes for gene: CUL7 were changed from 3M; 3-M syndrome 1, 273750 to 3-M syndrome 1, MIM# 273750; Yakut short stature syndrome
Growth failure v0.20 CUL7 Zornitza Stark Publications for gene: CUL7 were set to
Growth failure v0.19 CUL7 Zornitza Stark reviewed gene: CUL7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16142236, 19225462, 17675530; Phenotypes: 3-M syndrome 1, MIM# 273750, Yakut short stature syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.19 CDKN1C Zornitza Stark edited their review of gene: CDKN1C: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Growth failure v0.19 CDKN1C Zornitza Stark Marked gene: CDKN1C as ready
Growth failure v0.19 CDKN1C Zornitza Stark Gene: cdkn1c has been classified as Green List (High Evidence).
Growth failure v0.19 CDKN1C Zornitza Stark Phenotypes for gene: CDKN1C were changed from Beckwith-Wiedemann syndrome, 130650; Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies; SRS/BWS to IMAGe syndrome, MIM# 614732; Silver-Russell syndrome
Growth failure v0.18 CDKN1C Zornitza Stark Publications for gene: CDKN1C were set to
Growth failure v0.17 CDKN1C Zornitza Stark Mode of pathogenicity for gene: CDKN1C was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Growth failure v0.16 CDKN1C Zornitza Stark edited their review of gene: CDKN1C: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Growth failure v0.16 CDKN1C Zornitza Stark changed review comment from: IMAGe syndrome is a rare multisystem disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. Patients with this condition may present shortly after birth with severe adrenal insufficiency, which can be life-threatening if not recognized early and steroid replacement therapy commenced. Other reported features in this condition include hypercalciuria and/or hypocalcemia, craniosynostosis, cleft palate, and scoliosis.

Reported variants are gain-of-function missense on the maternal allele, and are located in a highly-conserved "hot-spot" within the PCNA-binding domain of CDKN1C between codons 272-279. Note 3 families reported with RSS phenotype without other IMAGE features, all with missense changes at amino acid positions 279 and 281.; to: IMAGe syndrome is a rare multisystem disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. Patients with this condition may present shortly after birth with severe adrenal insufficiency, which can be life-threatening if not recognized early and steroid replacement therapy commenced. Other reported features in this condition include hypercalciuria and/or hypocalcemia, craniosynostosis, cleft palate, and scoliosis.

Reported variants are gain-of-function missense on the maternal allele, and are located in a highly-conserved "hot-spot" within the PCNA-binding domain of CDKN1C between codons 272-279. Note 3 families reported with RSS phenotype without other IMAGE features, all with missense changes at amino acid positions 279 and 281.

Note LoF variants in this gene cause overgrowth and BWS.
Growth failure v0.16 CDKN1C Zornitza Stark reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 22634751, 33076988, 31976094, 31497289; Phenotypes: IMAGe syndrome, MIM# 614732, Silver-Russell syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Anophthalmia_Microphthalmia_Coloboma v1.7 PACS1 Chris Richmond gene: PACS1 was added
gene: PACS1 was added to Anophthalmia_Microphthalmia_Coloboma. Sources: Literature
Mode of inheritance for gene: PACS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PACS1 were set to 32672908
Phenotypes for gene: PACS1 were set to 615009
Penetrance for gene: PACS1 were set to Complete
Review for gene: PACS1 was set to GREEN
gene: PACS1 was marked as current diagnostic
Added comment: Multiple papers reporting patients with colobomata - well described.
Sources: Literature
Growth failure v0.16 CCDC8 Zornitza Stark Marked gene: CCDC8 as ready
Growth failure v0.16 CCDC8 Zornitza Stark Gene: ccdc8 has been classified as Green List (High Evidence).
Growth failure v0.16 CCDC8 Zornitza Stark Phenotypes for gene: CCDC8 were changed from 3M; 3-M syndrome 3, 614205 to 3-M syndrome 3, MIM# 614205
Growth failure v0.15 CCDC8 Zornitza Stark Publications for gene: CCDC8 were set to 21737058
Growth failure v0.14 CCDC8 Zornitza Stark reviewed gene: CCDC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21737058, 22325252, 28675896, 28675896; Phenotypes: 3-M syndrome 3, MIM# 614205; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v0.14 CBL Zornitza Stark Marked gene: CBL as ready
Growth failure v0.14 CBL Zornitza Stark Gene: cbl has been classified as Green List (High Evidence).
Growth failure v0.14 CBL Zornitza Stark Phenotypes for gene: CBL were changed from Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia; NOONAN SYNDROME-LIKE DISORDER WITH OR WITHOUT JUVENILE MEYLOMONOCYTIC LEUKEMIA to Noonan syndrome-like disorder with or without juvenile myelomonocytic leukaemia, MIM# 613563; CBL-related disorder, MONDO:0013308
Growth failure v0.13 BRIP1 Zornitza Stark Marked gene: BRIP1 as ready
Growth failure v0.13 BRIP1 Zornitza Stark Gene: brip1 has been classified as Green List (High Evidence).
Growth failure v0.13 BRIP1 Zornitza Stark Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054; 609054 Fanconi anemia, complementation group J to Fanconi anaemia, complementation group J, MIM# 609054
Growth failure v0.12 BRIP1 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Prenatal and postnatal growth failure is a key feature of FA.
Growth failure v0.12 BRCA2 Zornitza Stark Marked gene: BRCA2 as ready
Growth failure v0.12 BRCA2 Zornitza Stark Gene: brca2 has been classified as Green List (High Evidence).
Growth failure v0.12 BRCA2 Zornitza Stark Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; 605724 Fanconi anemia, complementation group D1 to Fanconi anaemia, complementation group D1, MIM# 605724
Growth failure v0.11 BRCA2 Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Pre-natal and post-natal growth failure is a key feature.
Growth failure v0.11 BRAF Zornitza Stark Marked gene: BRAF as ready
Growth failure v0.11 BRAF Zornitza Stark Gene: braf has been classified as Green List (High Evidence).
Growth failure v0.11 BRAF Zornitza Stark Phenotypes for gene: BRAF were changed from Noonan Syndrome; LEOPARD Syndrome; Cardiofaciocutaneous Syndrome; Cardiofaciocutaneous syndrome; Cardio-facio-cutaneous syndrome; LEOPARD syndrome 3 to Noonan syndrome 7, MIM# 613706; Cardiofaciocutaneous syndrome, MIM# 115150
Growth failure v0.10 BRAF Zornitza Stark Publications for gene: BRAF were set to 16474404; 21396583; 16825433; 19206169
Growth failure v0.9 BRAF Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Growth failure, feeding difficulties, short stature are prominent early presenting features.
Growth failure v0.9 BLM Zornitza Stark Marked gene: BLM as ready
Growth failure v0.9 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Growth failure v0.9 BLM Zornitza Stark Phenotypes for gene: BLM were changed from Bloom syndrome, 210900; 210900 Bloom syndrome; Bloom to Bloom syndrome, MIM# 210900
Growth failure v0.8 BLM Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Proportionate pre- and postnatal growth deficiency is a key feature.
Growth failure v0.8 ANKRD11 Zornitza Stark Marked gene: ANKRD11 as ready
Growth failure v0.8 ANKRD11 Zornitza Stark Gene: ankrd11 has been classified as Green List (High Evidence).
Growth failure v0.8 ANKRD11 Zornitza Stark Phenotypes for gene: ANKRD11 were changed from KBG syndrome, 148050; KBG to KBG syndrome, MIM# 148050
Growth failure v0.7 ANKRD11 Zornitza Stark Publications for gene: ANKRD11 were set to 21782149
Growth failure v0.6 ANKRD11 Zornitza Stark reviewed gene: ANKRD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33955014, 32258089, 32124548, 31191201, 29565525, 28449295; Phenotypes: KBG syndrome, MIM# 148050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8658 ACAN Zornitza Stark Publications for gene: ACAN were set to
Mendeliome v0.8657 ACAN Zornitza Stark edited their review of gene: ACAN: Added comment: Patients with SSOAD exhibit a broad phenotypic spectrum involving short stature associated with advanced bone maturation and early-onset osteoarthritis (OA), as well as mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disc disease and osteochondritis dissecans, which is characterized by separation of articular cartilage and subchondral bone from the articular surface. Phenotypes are highly variable even among patients within the same family, and there are no apparent genotype-phenotype correlations.

Well established gene-disease association, multiple families reported.

Note fewer families reported with bi-allelic variants in this gene and extreme short stature.; Changed publications: 24762113, 27870580, 19110214, 30124491, 28331218, 20137779; Changed phenotypes: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800, Spondyloepimetaphyseal dysplasia, aggrecan type 612813
Growth failure v0.6 ACAN Zornitza Stark Marked gene: ACAN as ready
Growth failure v0.6 ACAN Zornitza Stark Gene: acan has been classified as Green List (High Evidence).
Growth failure v0.6 ACAN Zornitza Stark Phenotypes for gene: ACAN were changed from Spondyloepimetaphyseal dysplasia, aggrecan type (AR), 612813; ?Spondyloepiphyseal dysplasia, Kimberley type (AD), 608361; short stature, accelerated bone maturation, Spondyloepiphyseal dysplasia, early onset osteoarthritis; Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (AD), 165800 to Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, MIM# 165800; Spondyloepimetaphyseal dysplasia, aggrecan type, MIM# 612813
Growth failure v0.5 ACAN Zornitza Stark Publications for gene: ACAN were set to 24762113; 27870580
Growth failure v0.4 ACAN Zornitza Stark Mode of inheritance for gene: ACAN 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
Growth failure v0.3 ACAN Zornitza Stark reviewed gene: ACAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 28331218, 20137779, 24762113, 19110214, 30124491; Phenotypes: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, MIM# 165800, Spondyloepimetaphyseal dysplasia, aggrecan type, MIM# 612813; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Combined Immunodeficiency v0.289 NFKBIA Zornitza Stark Marked gene: NFKBIA as ready
Combined Immunodeficiency v0.289 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.289 NFKBIA Zornitza Stark Phenotypes for gene: NFKBIA were changed from to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132; Ectodermal dysplasia; TCR/ BCR activation impaired; low memory and isotype switched B cells; decreased IgG and IgA; elevated IgM; poor specific antibody responses; diarrhoea; agammaglobulinaemia; ectodermal dysplasia; recurrent respiratory and gastrointestinal infections; colitis; variable defects of skin, hair and teeth
Combined Immunodeficiency v0.288 NFKBIA Zornitza Stark Publications for gene: NFKBIA were set to
Combined Immunodeficiency v0.287 NFKBIA Zornitza Stark Mode of pathogenicity for gene: NFKBIA was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Combined Immunodeficiency v0.286 NFKBIA Zornitza Stark Mode of inheritance for gene: NFKBIA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8657 NFKBIA Zornitza Stark Marked gene: NFKBIA as ready
Mendeliome v0.8657 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
Mendeliome v0.8657 NFKBIA Zornitza Stark Phenotypes for gene: NFKBIA were changed from to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132; Ectodermal dysplasia; TCR/ BCR activation impaired; low memory and isotype switched B cells; decreased IgG and IgA; elevated IgM; poor specific antibody responses; diarrhoea; agammaglobulinaemia; ectodermal dysplasia; recurrent respiratory and gastrointestinal infections; colitis; variable defects of skin, hair and teeth
Mendeliome v0.8656 NFKBIA Zornitza Stark Mode of pathogenicity for gene: NFKBIA was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v0.8655 NFKBIA Zornitza Stark Mode of inheritance for gene: NFKBIA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Predominantly Antibody Deficiency v0.74 NFKB2 Zornitza Stark Marked gene: NFKB2 as ready
Predominantly Antibody Deficiency v0.74 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Predominantly Antibody Deficiency v0.74 NFKB2 Zornitza Stark Phenotypes for gene: NFKB2 were changed from to Immunodeficiency, common variable, 10 MIM# 615577; Low serum IgG, IgA, IgM; low B cell numbers; low switched memory B cells; Recurrent sinopulmonary infections, Alopecia; endocrinopathies; ACTH deficiency
Predominantly Antibody Deficiency v0.73 NFKB2 Zornitza Stark Publications for gene: NFKB2 were set to
Predominantly Antibody Deficiency v0.72 NFKB2 Zornitza Stark Mode of inheritance for gene: NFKB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Predominantly Antibody Deficiency v0.71 NFKB2 Zornitza Stark reviewed gene: NFKB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140114, 24888602, 25524009, 31417880; Phenotypes: Immunodeficiency, common variable, 10 MIM# 615577, Low serum IgG, IgA, IgM, low B cell numbers, low switched memory B cells, Recurrent sinopulmonary infections, Alopecia, endocrinopathies, ACTH deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.285 NFKB2 Zornitza Stark Marked gene: NFKB2 as ready
Combined Immunodeficiency v0.285 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Mendeliome v0.8654 NFKB2 Zornitza Stark Marked gene: NFKB2 as ready
Mendeliome v0.8654 NFKB2 Zornitza Stark Gene: nfkb2 has been classified as Green List (High Evidence).
Mendeliome v0.8654 NFKB2 Zornitza Stark Phenotypes for gene: NFKB2 were changed from to Immunodeficiency, common variable, 10 MIM# 615577; Low serum IgG, IgA, IgM; low B cell numbers; low switched memory B cells; Recurrent sinopulmonary infections, Alopecia; endocrinopathies; ACTH deficiency
Mendeliome v0.8653 NFKB2 Zornitza Stark Publications for gene: NFKB2 were set to
Mendeliome v0.8652 NFKB2 Zornitza Stark Mode of inheritance for gene: NFKB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.285 NFKB2 Zornitza Stark Phenotypes for gene: NFKB2 were changed from to Immunodeficiency, common variable, 10 MIM# 615577; Low serum IgG, IgA, IgM; low B cell numbers; low switched memory B cells; Recurrent sinopulmonary infections, Alopecia; endocrinopathies; ACTH deficiency
Combined Immunodeficiency v0.284 NFKB2 Zornitza Stark Publications for gene: NFKB2 were set to
Combined Immunodeficiency v0.283 NFKB2 Zornitza Stark Mode of inheritance for gene: NFKB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Predominantly Antibody Deficiency v0.71 NFKB1 Zornitza Stark Marked gene: NFKB1 as ready
Predominantly Antibody Deficiency v0.71 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Predominantly Antibody Deficiency v0.71 NFKB1 Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576; Normal-low IgG, IgA, IgM; low-normal B cells; low switched memory B cells; hypogammaglobulinaemia; recurrent respiratory and gastrointestinal infections; Chronic obstructive pulmonary disease COPD; EBV proliferation; autoimmunity; alopecia
Predominantly Antibody Deficiency v0.70 NFKB1 Zornitza Stark Publications for gene: NFKB1 were set to
Predominantly Antibody Deficiency v0.69 NFKB1 Zornitza Stark Mode of inheritance for gene: NFKB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Predominantly Antibody Deficiency v0.68 NFKB1 Zornitza Stark reviewed gene: NFKB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26279205, 32278790, 27022143, 7834752; Phenotypes: Immunodeficiency, common variable, 12 MIM# 616576, Normal-low IgG, IgA, IgM, low-normal B cells, low switched memory B cells, hypogammaglobulinaemia, recurrent respiratory and gastrointestinal infections, Chronic obstructive pulmonary disease COPD, EBV proliferation, autoimmunity, alopecia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8651 NFKB1 Zornitza Stark Marked gene: NFKB1 as ready
Mendeliome v0.8651 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Mendeliome v0.8651 NFKB1 Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576; Normal-low IgG, IgA, IgM; low-normal B cells; low switched memory B cells; hypogammaglobulinaemia; recurrent respiratory and gastrointestinal infections; Chronic obstructive pulmonary disease COPD; EBV proliferation; autoimmunity; alopecia
Mendeliome v0.8650 NFKB1 Zornitza Stark Publications for gene: NFKB1 were set to
Mendeliome v0.8649 NFKB1 Zornitza Stark Mode of inheritance for gene: NFKB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.282 NFKB1 Zornitza Stark Marked gene: NFKB1 as ready
Combined Immunodeficiency v0.282 NFKB1 Zornitza Stark Gene: nfkb1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.282 NFKB1 Zornitza Stark Phenotypes for gene: NFKB1 were changed from to Immunodeficiency, common variable, 12 MIM# 616576; Normal-low IgG, IgA, IgM; low-normal B cells; low switched memory B cells; hypogammaglobulinaemia; recurrent respiratory and gastrointestinal infections; Chronic obstructive pulmonary disease COPD; EBV proliferation; autoimmunity; alopecia
Combined Immunodeficiency v0.281 NFKB1 Zornitza Stark Publications for gene: NFKB1 were set to
Combined Immunodeficiency v0.280 NFKB1 Zornitza Stark Mode of inheritance for gene: NFKB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mackenzie's Mission_Reproductive Carrier Screening v0.102 MCM4 Zornitza Stark reviewed gene: MCM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 22354167, 22354170, 22499342; Phenotypes: Immunodeficiency 54, MIM# 609981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8648 MCM4 Zornitza Stark Marked gene: MCM4 as ready
Mendeliome v0.8648 MCM4 Zornitza Stark Gene: mcm4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8648 MCM4 Zornitza Stark Phenotypes for gene: MCM4 were changed from to Immunodeficiency 54 MIM# 609981; Decreased NK cell number and function; Viral infections (EBV, HSV, VZV); Short stature; B cell lymphoma; Adrenal failure; Failure to thrive; Microcephaly; Increased chromosomal breakage; Hyperpigmentation; Lymphadenopathy
Mendeliome v0.8647 MCM4 Zornitza Stark Publications for gene: MCM4 were set to
Mendeliome v0.8646 MCM4 Zornitza Stark Mode of inheritance for gene: MCM4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8645 MCM4 Zornitza Stark Classified gene: MCM4 as Amber List (moderate evidence)
Mendeliome v0.8645 MCM4 Zornitza Stark Gene: mcm4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8644 MCM4 Zornitza Stark Tag founder tag was added to gene: MCM4.
Mendeliome v0.8644 MCM4 Zornitza Stark reviewed gene: MCM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 22354167, 22354170, 22499342; Phenotypes: Immunodeficiency 54 MIM# 609981, Decreased NK cell number and function, Viral infections (EBV, HSV, VZV), Short stature, B cell lymphoma, Adrenal failure, Failure to thrive, Microcephaly, Increased chromosomal breakage, Hyperpigmentation, Lymphadenopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.279 MCM4 Zornitza Stark Tag founder tag was added to gene: MCM4.
Combined Immunodeficiency v0.279 MCM4 Zornitza Stark Marked gene: MCM4 as ready
Combined Immunodeficiency v0.279 MCM4 Zornitza Stark Gene: mcm4 has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v0.279 MCM4 Zornitza Stark Phenotypes for gene: MCM4 were changed from to Immunodeficiency 54 MIM# 609981; Decreased NK cell number and function; Viral infections (EBV, HSV, VZV); Short stature; B cell lymphoma; Adrenal failure; Failure to thrive; Microcephaly; Increased chromosomal breakage; Hyperpigmentation; Lymphadenopathy
Combined Immunodeficiency v0.278 MCM4 Zornitza Stark Publications for gene: MCM4 were set to
Combined Immunodeficiency v0.277 MCM4 Zornitza Stark Mode of inheritance for gene: MCM4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.276 MCM4 Zornitza Stark Classified gene: MCM4 as Amber List (moderate evidence)
Combined Immunodeficiency v0.276 MCM4 Zornitza Stark Gene: mcm4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8644 MAP3K14 Zornitza Stark Marked gene: MAP3K14 as ready
Mendeliome v0.8644 MAP3K14 Zornitza Stark Gene: map3k14 has been classified as Green List (High Evidence).
Mendeliome v0.8644 MAP3K14 Zornitza Stark Phenotypes for gene: MAP3K14 were changed from to NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels
Mendeliome v0.8643 MAP3K14 Zornitza Stark Publications for gene: MAP3K14 were set to
Mendeliome v0.8642 MAP3K14 Zornitza Stark Mode of inheritance for gene: MAP3K14 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8641 MAP3K14 Zornitza Stark reviewed gene: MAP3K14: Rating: GREEN; Mode of pathogenicity: None; Publications: 10319865, 11238593, 12352969; Phenotypes: NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.275 MAP3K14 Zornitza Stark Marked gene: MAP3K14 as ready
Combined Immunodeficiency v0.275 MAP3K14 Zornitza Stark Added comment: Comment when marking as ready: Extensive functional characterisation in mouse models, see also PMIDs 10319865; 11238593; 12352969, hence Green rating with two families reported only.
Combined Immunodeficiency v0.275 MAP3K14 Zornitza Stark Gene: map3k14 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.275 MAP3K14 Zornitza Stark Publications for gene: MAP3K14 were set to 25406581; 29230214; 11251123
Combined Immunodeficiency v0.274 MAP3K14 Zornitza Stark Phenotypes for gene: MAP3K14 were changed from to NIK deficiency; Poor T cell proliferation to antigen; Low B-cell numbers; Low NK number and function; recurrent bacterial/viral/ cryptosporidium infections; hypogammaglobulinaemia; decreased immunoglobulin levels
Combined Immunodeficiency v0.273 MAP3K14 Zornitza Stark Publications for gene: MAP3K14 were set to
Combined Immunodeficiency v0.272 MAP3K14 Zornitza Stark Mode of inheritance for gene: MAP3K14 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8641 LRBA Zornitza Stark Marked gene: LRBA as ready
Mendeliome v0.8641 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
Mendeliome v0.8641 LRBA Zornitza Stark Phenotypes for gene: LRBA were changed from to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700; Normal-decreased CD4 numbers; T cell dysregulation; Low-normal B cells; Reduced IgG and IgA; Recurrent infections; chronic diarrhoea; inflammatory bowel disease; hypogammaglobulinaemia; pneumonitis; autoimmune disorders; thrombocytopaenia
Mendeliome v0.8640 LRBA Zornitza Stark Publications for gene: LRBA were set to
Mendeliome v0.8639 LRBA Zornitza Stark Mode of inheritance for gene: LRBA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8638 LRBA Zornitza Stark reviewed gene: LRBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22608502, 22721650, 25468195, 26206937, 33155142; Phenotypes: Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700, Normal-decreased CD4 numbers, T cell dysregulation, Low-normal B cells, Reduced IgG and IgA, Recurrent infections, chronic diarrhoea, inflammatory bowel disease, hypogammaglobulinaemia, pneumonitis, autoimmune disorders, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.271 LRBA Zornitza Stark Marked gene: LRBA as ready
Combined Immunodeficiency v0.271 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.271 LRBA Zornitza Stark Phenotypes for gene: LRBA were changed from to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700; Normal-decreased CD4 numbers; T cell dysregulation; Low-normal B cells; Reduced IgG and IgA; Recurrent infections; chronic diarrhoea; inflammatory bowel disease; hypogammaglobulinaemia; pneumonitis; autoimmune disorders; thrombocytopaenia
Combined Immunodeficiency v0.270 LRBA Zornitza Stark Publications for gene: LRBA were set to
Combined Immunodeficiency v0.269 LRBA Zornitza Stark Mode of inheritance for gene: LRBA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8638 NFKBIA Danielle Ariti reviewed gene: NFKBIA: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 28597146, 23864385, 23708964; Phenotypes: Ectodermal dysplasia and immunodeficiency 2 MIM# 612132, Ectodermal dysplasia, TCR/ BCR activation impaired, low memory and isotype switched B cells, decreased IgG and IgA, elevated IgM, poor specific antibody responses, diarrhoea, agammaglobulinaemia, ectodermal dysplasia, recurrent respiratory and gastrointestinal infections, colitis, variable defects of skin, hair and teeth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8638 NFKB2 Danielle Ariti reviewed gene: NFKB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140114, 24888602, 25524009, 31417880; Phenotypes: Immunodeficiency, common variable, 10 MIM# 615577, Low serum IgG, IgA, IgM, low B cell numbers, low switched memory B cells, Recurrent sinopulmonary infections, Alopecia, endocrinopathies, ACTH deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8638 NFKB1 Danielle Ariti reviewed gene: NFKB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26279205, 32278790, 27022143, 7834752; Phenotypes: Immunodeficiency, common variable, 12 MIM# 616576, Normal-low IgG, IgA, IgM, low-normal B cells, low switched memory B cells, hypogammaglobulinaemia, recurrent respiratory and gastrointestinal infections, Chronic obstructive pulmonary disease COPD, EBV proliferation, autoimmunity, alopecia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.268 NFKBIA Danielle Ariti changed review comment from: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual).

Functional studies & two mouse models; demonstrate reported NFKBIA
gain-of-function variants resulting in impaired NFKB1 activity.

The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands).; to: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual).

Functional studies & two mouse models; demonstrate reported NFKBIA gain-of-function variants resulting in impaired NFKB1 activity.

The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands).
Combined Immunodeficiency v0.268 NFKBIA Danielle Ariti reviewed gene: NFKBIA: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 28597146, 23864385, 23708964; Phenotypes: Ectodermal dysplasia and immunodeficiency 2 MIM# 612132, Ectodermal dysplasia, TCR/ BCR activation impaired, low memory and isotype switched B cells, decreased IgG and IgA, elevated IgM, poor specific antibody responses, diarrhoea, agammaglobulinaemia, ectodermal dysplasia, recurrent respiratory and gastrointestinal infections, colitis, variable defects of skin, hair and teeth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.268 NFKB2 Danielle Ariti reviewed gene: NFKB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140114, 24888602, 25524009, 31417880; Phenotypes: Immunodeficiency, common variable, 10 MIM# 615577, Low serum IgG, IgA, IgM, low B cell numbers, low switched memory B cells, Recurrent sinopulmonary infections, Alopecia, endocrinopathies, ACTH deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.268 NFKB1 Danielle Ariti reviewed gene: NFKB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26279205, 32278790, 27022143, 7834752; Phenotypes: Immunodeficiency, common variable, 12 MIM# 616576, Normal-low IgG, IgA, IgM, low-normal B cells, low switched memory B cells, hypogammaglobulinaemia, recurrent respiratory and gastrointestinal infections, Chronic obstructive pulmonary disease COPD, EBV proliferation, autoimmunity, alopecia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.268 MCM4 Danielle Ariti reviewed gene: MCM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 22354167, 22354170, 22499342; Phenotypes: Immunodeficiency 54 MIM# 609981, Decreased NK cell number and function, Viral infections (EBV, HSV, VZV), Short stature, B cell lymphoma, Adrenal failure, Failure to thrive, Microcephaly, Increased chromosomal breakage, Hyperpigmentation, Lymphadenopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertension and Aldosterone disorders v1.4 WNK1 Zornitza Stark Phenotypes for gene: WNK1 were changed from to Pseudohypoaldosteronism 2C (PHA2C), MIM#614492
Hypertension and Aldosterone disorders v1.3 WNK1 Zornitza Stark Publications for gene: WNK1 were set to
Hypertension and Aldosterone disorders v1.2 WNK1 Zornitza Stark Mode of pathogenicity for gene: WNK1 was changed from to Other
Hypertension and Aldosterone disorders v1.1 WNK1 Zornitza Stark Mode of inheritance for gene: WNK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.268 MAP3K14 Danielle Ariti reviewed gene: MAP3K14: Rating: AMBER; Mode of pathogenicity: None; Publications: 25406581, 29230214, 11251123; Phenotypes: NIK deficiency, Poor T cell proliferation to antigen, Low B-cell numbers, Low NK number and function, recurrent bacterial/viral/ cryptosporidium infections, hypogammaglobulinaemia, decreased immunoglobulin levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.268 LRBA Danielle Ariti changed review comment from: Over 10 unrelated individuals with LRBA variants displaying immunodeficiency phenotype; one mouse model.

Reported homozygous truncating variants (missense/ nonsense).

Most reported individuals displayed reduced IgG and IgA, autoimmune disorders, hypogammaglobulinemia and recurrent infections.; to: Over 10 unrelated individuals with LRBA variants displaying immunodeficiency phenotype; one mouse model.

Reported homozygous truncating variants (missense/ nonsense).

Most reported individuals displayed reduced IgG and IgA, autoimmune disorders, hypogammaglobulinaemia and recurrent infections.
Combined Immunodeficiency v0.268 LRBA Danielle Ariti reviewed gene: LRBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22608502, 22721650, 25468195, 26206937, 33155142; Phenotypes: Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700, Normal-decreased CD4 numbers, T cell dysregulation, Low-normal B cells, Reduced IgG and IgA, Recurrent infections, chronic diarrhoea, inflammatory bowel disease, hypogammaglobulinaemia, pneumonitis, autoimmune disorders, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertension and Aldosterone disorders v1.0 WNK1 Chirag Patel reviewed gene: WNK1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 11498583, 11498583; Phenotypes: Pseudohypoaldosteronism 2C (PHA2C); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.8638 AQP2 Zornitza Stark Marked gene: AQP2 as ready
Mendeliome v0.8638 AQP2 Zornitza Stark Gene: aqp2 has been classified as Green List (High Evidence).
Mendeliome v0.8638 AQP2 Zornitza Stark Phenotypes for gene: AQP2 were changed from to Diabetes insipidus, nephrogenic, MIM#125800
Mendeliome v0.8637 AQP2 Zornitza Stark Publications for gene: AQP2 were set to
Mendeliome v0.8636 AQP2 Zornitza Stark Mode of inheritance for gene: AQP2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8635 AQP2 Zornitza Stark reviewed gene: AQP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7537761, 11536078; Phenotypes: Diabetes insipidus, nephrogenic, MIM#125800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4026 RNF2 Zornitza Stark Phenotypes for gene: RNF2 were changed from epilepsy; intellectual disability; intrauterine growth retardation to Lou-Schoch-Yamamoto syndrome , MIM#619460; epilepsy; intellectual disability; intrauterine growth retardation
Intellectual disability syndromic and non-syndromic v0.4025 RNF2 Zornitza Stark edited their review of gene: RNF2: Changed phenotypes: Lou-Schoch-Yamamoto syndrome , MIM#619460, epilepsy, intellectual disability, intrauterine growth retardation
Genetic Epilepsy v0.1156 RNF2 Zornitza Stark Phenotypes for gene: RNF2 were changed from epilepsy; intellectual disability; intrauterine growth retardation to Lou-Schoch-Yamamoto syndrome , MIM#619460; epilepsy; intellectual disability; intrauterine growth retardation
Genetic Epilepsy v0.1155 RNF2 Zornitza Stark edited their review of gene: RNF2: Changed phenotypes: Lou-Schoch-Yamamoto syndrome , MIM#619460, epilepsy, intellectual disability, intrauterine growth retardation
Mendeliome v0.8635 RNF2 Zornitza Stark Phenotypes for gene: RNF2 were changed from epilepsy; intellectual disability; intrauterine growth retardation to Lou-Schoch-Yamamoto syndrome , MIM#619460; epilepsy; intellectual disability; intrauterine growth retardation
Mendeliome v0.8634 RNF2 Zornitza Stark reviewed gene: RNF2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Lou-Schoch-Yamamoto syndrome , MIM#619460; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.4025 USP7 Zornitza Stark Phenotypes for gene: USP7 were changed from Hao-Fountain syndrome, MIM# 616863; ID; Autism to Hao-Fountain syndrome, MIM# 616863; MONDO:0014805; Intellectual disability; Autism
Intellectual disability syndromic and non-syndromic v0.4024 USP7 Zornitza Stark edited their review of gene: USP7: Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, MONDO:0014805, Intellectual disability, Autism
Mendeliome v0.8634 USP7 Zornitza Stark Phenotypes for gene: USP7 were changed from Hao-Fountain syndrome, MIM# 616863; Intellectual disability; Autism to Hao-Fountain syndrome, MIM# 616863; MONDO:0014805; Intellectual disability; Autism
Mendeliome v0.8633 USP7 Zornitza Stark edited their review of gene: USP7: Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, MONDO:0014805, Intellectual disability, Autism
Autism v0.167 USP7 Zornitza Stark Phenotypes for gene: USP7 were changed from Hao-Fountain syndrome, MIM# 616863; Intellectual disability; Autism to Hao-Fountain syndrome, MIM# 616863; MONDO:0014805; Intellectual disability; Autism
Autism v0.166 USP7 Zornitza Stark edited their review of gene: USP7: Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, MONDO:0014805, Intellectual disability, Autism
Bone Marrow Failure v1.6 GIMAP5 Zornitza Stark Marked gene: GIMAP5 as ready
Bone Marrow Failure v1.6 GIMAP5 Zornitza Stark Gene: gimap5 has been classified as Green List (High Evidence).
Bone Marrow Failure v1.6 GIMAP5 Zornitza Stark Classified gene: GIMAP5 as Green List (high evidence)
Bone Marrow Failure v1.6 GIMAP5 Zornitza Stark Gene: gimap5 has been classified as Green List (High Evidence).
Bone Marrow Failure v1.5 GIMAP5 Zornitza Stark gene: GIMAP5 was added
gene: GIMAP5 was added to Bone Marrow Failure. Sources: Expert list
Mode of inheritance for gene: GIMAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP5 were set to 33956074
Phenotypes for gene: GIMAP5 were set to Portal hypertension, noncirrhotic, 2, MIM# 619463
Review for gene: GIMAP5 was set to GREEN
Added comment: 8 individuals from 4 unrelated families reported with onset of disease in the first decade of life. Clinical features included jaundice, hyperbilirubinaemia, pancytopaenia, including neutropaenia, lymphopaenia, and thrombocytopaenia, hepatosplenomegaly, and oesophageal varices. Some individuals had recurrent infections or features suggestive of an immunodeficiency. Liver biopsy was notable for the absence of cirrhosis and the presence of nodular regeneration.
Sources: Expert list
Mendeliome v0.8633 GIMAP5 Zornitza Stark Marked gene: GIMAP5 as ready
Mendeliome v0.8633 GIMAP5 Zornitza Stark Gene: gimap5 has been classified as Green List (High Evidence).
Mendeliome v0.8633 GIMAP5 Zornitza Stark Classified gene: GIMAP5 as Green List (high evidence)
Mendeliome v0.8633 GIMAP5 Zornitza Stark Gene: gimap5 has been classified as Green List (High Evidence).
Mendeliome v0.8632 GIMAP5 Zornitza Stark gene: GIMAP5 was added
gene: GIMAP5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GIMAP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP5 were set to 33956074
Phenotypes for gene: GIMAP5 were set to Portal hypertension, noncirrhotic, 2, MIM# 619463
Review for gene: GIMAP5 was set to GREEN
Added comment: 8 individuals from 4 unrelated families reported with onset of disease in the first decade of life. Clinical features included jaundice, hyperbilirubinaemia, pancytopaenia, including neutropaenia, lymphopaenia, and thrombocytopaenia, hepatosplenomegaly, and oesophageal varices. Some individuals had recurrent infections or features suggestive of an immunodeficiency. Liver biopsy was notable for the absence of cirrhosis and the presence of nodular regeneration.
Sources: Expert list
Mendeliome v0.8631 ERBB2 Zornitza Stark Phenotypes for gene: ERBB2 were changed from to Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465
Gastrointestinal neuromuscular disease v1.15 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Complex neurocristinopathy to Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180; Complex neurocristinopathy
Gastrointestinal neuromuscular disease v1.14 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Changed phenotypes: Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180, Complex neurocristinopathy
Mendeliome v0.8630 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Complex neurocristinopathy to Lethal congenital contractural syndrome 2, MIM# 607598; Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180; Hirschsprung disease; Arthrogryposis; Complex neurocristinopathy
Mendeliome v0.8629 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Changed phenotypes: Lethal congenital contractural syndrome 2, MIM# 607598, Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180, Complex neurocristinopathy
Hirschsprung disease v0.18 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Complex neurocristinopathy to Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180; Complex neurocristinopathy
Hirschsprung disease v0.17 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Changed phenotypes: Visceral neuropathy, familial, 1, autosomal recessive, MIM# 243180, Complex neurocristinopathy
Mendeliome v0.8629 IL7R Zornitza Stark Marked gene: IL7R as ready
Mendeliome v0.8629 IL7R Zornitza Stark Gene: il7r has been classified as Green List (High Evidence).
Mendeliome v0.8629 IL7R Zornitza Stark Phenotypes for gene: IL7R were changed from to Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971; fever; rash; failure to thrive; recurrent respiratory and gastric infections; diarrhoea; lymphadenopathy; pneumonitis; Pancytopaenia; low T-cell numbers; decreased immunoglobulins; normal-high B/NK-cell numbers.
Mendeliome v0.8628 IL7R Zornitza Stark Publications for gene: IL7R were set to
Mendeliome v0.8627 IL7R Zornitza Stark Mode of inheritance for gene: IL7R was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.268 ITK Zornitza Stark Marked gene: ITK as ready
Combined Immunodeficiency v0.268 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.268 ITK Zornitza Stark Phenotypes for gene: ITK were changed from to Lymphoproliferative syndrome 1 MIM# 613011; Lymphadenopathy; Recurrent infections; Hypogammaglobulinaemia; Evidence of EBV infection; EBV associated B cell Lymphoproliferation; High EBV viral load; Normal-low serum Ig; Depleted CD4+ T cells; Anaemia; Thrombocytopaenia; Hepatosplenomegaly
Combined Immunodeficiency v0.267 ITK Zornitza Stark Publications for gene: ITK were set to
Combined Immunodeficiency v0.266 ITK Zornitza Stark Mode of inheritance for gene: ITK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8626 MALT1 Zornitza Stark Marked gene: MALT1 as ready
Mendeliome v0.8626 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
Mendeliome v0.8626 MALT1 Zornitza Stark Phenotypes for gene: MALT1 were changed from to Immunodeficiency 12 MIM# 615468; poor T-cell proliferation; normal T/B cell numbers; poor specific antibody response; recurrent bacterial/fungal/viral infections; bronchiectasis; failure to thrive
Mendeliome v0.8625 MALT1 Zornitza Stark Publications for gene: MALT1 were set to
Mendeliome v0.8624 MALT1 Zornitza Stark Mode of inheritance for gene: MALT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Severe Combined Immunodeficiency v0.28 IL2RG Zornitza Stark Marked gene: IL2RG as ready
Severe Combined Immunodeficiency v0.28 IL2RG Zornitza Stark Gene: il2rg has been classified as Green List (High Evidence).
Severe Combined Immunodeficiency v0.28 IL2RG Zornitza Stark Phenotypes for gene: IL2RG were changed from to Combined immunodeficiency, X-linked, moderate MIM# 312863; Severe combined immunodeficiency, X-linked MIM# 300400; recurrent viral/fungal/bacterial infections; Low T/NK cells; Low Ig levels; lymphocytopaenia; hypogammaglobulinaemia; failure to thrive; diarrhoea; Pneumonia; Thymic hypoplasia
Severe Combined Immunodeficiency v0.27 IL2RG Zornitza Stark Publications for gene: IL2RG were set to
Severe Combined Immunodeficiency v0.26 IL2RG Zornitza Stark Mode of inheritance for gene: IL2RG was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Severe Combined Immunodeficiency v0.25 IL2RG Zornitza Stark reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301584, 8462096, 8401490, 7883965, 9399950; Phenotypes: Combined immunodeficiency, X-linked, moderate MIM# 312863, Severe combined immunodeficiency, X-linked MIM# 300400, recurrent viral/fungal/bacterial infections, Low T/NK cells, Low Ig levels, lymphocytopaenia, hypogammaglobulinaemia, failure to thrive, diarrhoea, Pneumonia, Thymic hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8623 IL2RG Zornitza Stark Marked gene: IL2RG as ready
Mendeliome v0.8623 IL2RG Zornitza Stark Gene: il2rg has been classified as Green List (High Evidence).
Mendeliome v0.8623 IL2RG Zornitza Stark Phenotypes for gene: IL2RG were changed from to Combined immunodeficiency, X-linked, moderate MIM# 312863; Severe combined immunodeficiency, X-linked MIM# 300400; recurrent viral/fungal/bacterial infections; Low T/NK cells; Low Ig levels; lymphocytopaenia; hypogammaglobulinaemia; failure to thrive; diarrhoea; Pneumonia; Thymic hypoplasia
Mendeliome v0.8622 IL2RG Zornitza Stark Publications for gene: IL2RG were set to
Mendeliome v0.8621 IL2RG Zornitza Stark Mode of inheritance for gene: IL2RG was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8620 IL2RG Zornitza Stark reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301584, 8462096, 8401490, 7883965, 9399950; Phenotypes: Combined immunodeficiency, X-linked, moderate MIM# 312863, Severe combined immunodeficiency, X-linked MIM# 300400, recurrent viral/fungal/bacterial infections, Low T/NK cells, Low Ig levels, lymphocytopaenia, hypogammaglobulinaemia, failure to thrive, diarrhoea, Pneumonia, Thymic hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8620 IKZF1 Zornitza Stark Marked gene: IKZF1 as ready
Mendeliome v0.8620 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
Mendeliome v0.8620 IKZF1 Zornitza Stark Phenotypes for gene: IKZF1 were changed from 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
Mendeliome v0.8619 IKZF1 Zornitza Stark Publications for gene: IKZF1 were set to
Mendeliome v0.8618 IKZF1 Zornitza Stark Mode of inheritance for gene: IKZF1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8617 IKZF1 Zornitza Stark reviewed gene: IKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317; Phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.265 LIG4 Zornitza Stark Marked gene: LIG4 as ready
Combined Immunodeficiency v0.265 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.265 LIG4 Zornitza Stark Phenotypes for gene: LIG4 were changed from to LIG4 syndrome MIM# 606593; T-/B- lymphocytopaenia; Normal NK, radiation sensitivity; Microcephaly; low B/C cells; low Ig; raised IgM; failure to thrive; bacterial/viral/fungal infections; hypogammaglobulinaemia; neurodevelopmental delay; microcephaly; pancytopaenia
Combined Immunodeficiency v0.264 LIG4 Zornitza Stark Publications for gene: LIG4 were set to
Combined Immunodeficiency v0.263 LIG4 Zornitza Stark Mode of inheritance for gene: LIG4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8617 ITK Zornitza Stark Marked gene: ITK as ready
Mendeliome v0.8617 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.262 IL7R Zornitza Stark Marked gene: IL7R as ready
Combined Immunodeficiency v0.262 IL7R Zornitza Stark Gene: il7r has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.262 IL7R Zornitza Stark Phenotypes for gene: IL7R were changed from to Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971; fever; rash; failure to thrive; recurrent respiratory and gastric infections; diarrhoea; lymphadenopathy; pneumonitis; Pancytopaenia; low T-cell numbers; decreased immunoglobulins; normal-high B/NK-cell numbers.
Combined Immunodeficiency v0.261 IL7R Zornitza Stark Publications for gene: IL7R were set to
Mendeliome v0.8617 ITK Zornitza Stark Phenotypes for gene: ITK were changed from to Lymphoproliferative syndrome 1 MIM# 613011; Lymphadenopathy; Recurrent infections; Hypogammaglobulinaemia; Evidence of EBV infection; EBV associated B cell Lymphoproliferation; High EBV viral load; Normal-low serum Ig; Depleted CD4+ T cells; Anaemia; Thrombocytopaenia; Hepatosplenomegaly
Combined Immunodeficiency v0.260 IL7R Zornitza Stark Mode of inheritance for gene: IL7R was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8616 ITK Zornitza Stark Publications for gene: ITK were set to
Mendeliome v0.8615 ITK Zornitza Stark Mode of inheritance for gene: ITK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.259 MALT1 Danielle Ariti Deleted their comment
Combined Immunodeficiency v0.259 MALT1 Danielle Ariti edited their review of gene: MALT1: Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency.

Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains.

All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation.; Changed rating: GREEN
Combined Immunodeficiency v0.259 MALT1 Zornitza Stark Phenotypes for gene: MALT1 were changed from Immunodeficiency 12 MIM# 615468; poor T-cell proliferation; normal T/B cell numbers; poor specific antibody response; recurrent bacterial/fungal/viral infections; bronchiectasis; failure to thrive to Immunodeficiency 12 MIM# 615468; poor T-cell proliferation; normal T/B cell numbers; poor specific antibody response; recurrent bacterial/fungal/viral infections; bronchiectasis; failure to thrive
Combined Immunodeficiency v0.259 MALT1 Zornitza Stark Marked gene: MALT1 as ready
Combined Immunodeficiency v0.259 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.259 MALT1 Zornitza Stark Phenotypes for gene: MALT1 were changed from to Immunodeficiency 12 MIM# 615468; poor T-cell proliferation; normal T/B cell numbers; poor specific antibody response; recurrent bacterial/fungal/viral infections; bronchiectasis; failure to thrive
Mendeliome v0.8614 MALT1 Danielle Ariti Deleted their comment
Combined Immunodeficiency v0.258 IL2RG Zornitza Stark Marked gene: IL2RG as ready
Combined Immunodeficiency v0.258 IL2RG Zornitza Stark Gene: il2rg has been classified as Green List (High Evidence).
Mendeliome v0.8614 MALT1 Danielle Ariti edited their review of gene: MALT1: Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency.

Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains.

All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation.; Changed rating: GREEN
Combined Immunodeficiency v0.258 MALT1 Zornitza Stark Publications for gene: MALT1 were set to
Combined Immunodeficiency v0.257 MALT1 Zornitza Stark Mode of inheritance for gene: MALT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.256 IL2RG Zornitza Stark Phenotypes for gene: IL2RG were changed from to Combined immunodeficiency, X-linked, moderate MIM# 312863; Severe combined immunodeficiency, X-linked MIM# 300400; recurrent viral/fungal/bacterial infections; Low T/NK cells; Low Ig levels; lymphocytopaenia; hypogammaglobulinaemia; failure to thrive; diarrhoea; Pneumonia; Thymic hypoplasia
Combined Immunodeficiency v0.255 IL2RG Zornitza Stark Publications for gene: IL2RG were set to 20301584; 8462096; 8401490; 7883965; 9399950
Combined Immunodeficiency v0.255 IKZF1 Zornitza Stark Marked gene: IKZF1 as ready
Combined Immunodeficiency v0.255 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.255 IKZF1 Zornitza Stark Phenotypes for gene: IKZF1 were changed from 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
Combined Immunodeficiency v0.254 IL2RG Zornitza Stark Publications for gene: IL2RG were set to
Combined Immunodeficiency v0.254 IKZF1 Zornitza Stark Publications for gene: IKZF1 were set to 21548011; 26981933; 29889099; 31057532; 7923373; 11805317
Combined Immunodeficiency v0.253 IL2RG Zornitza Stark Mode of inheritance for gene: IL2RG was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Combined Immunodeficiency v0.253 IKZF1 Zornitza Stark Publications for gene: IKZF1 were set to
Combined Immunodeficiency v0.253 IL2RG Zornitza Stark Mode of inheritance for gene: IL2RG was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Combined Immunodeficiency v0.252 IKZF1 Zornitza Stark Mode of inheritance for gene: IKZF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Combined Immunodeficiency v0.252 IKZF1 Zornitza Stark Mode of inheritance for gene: IKZF1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Marked gene: AP1G1 as ready
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Classified gene: AP1G1 as Green List (high evidence)
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Marked gene: AP1G1 as ready
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Marked gene: AP1G1 as ready
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Classified gene: AP1G1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4024 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4023 AP1G1 Zornitza Stark changed review comment from: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

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

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

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature; to: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

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

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

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.

GREEN for mono-allelic, AMBER for bi-allelic.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4023 AP1G1 Zornitza Stark gene: AP1G1 was added
gene: AP1G1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Review for gene: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

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

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

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Genetic Epilepsy v0.1154 AP1G1 Danielle Ariti gene: AP1G1 was added
gene: AP1G1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Review for gene: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

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

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

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Combined Immunodeficiency v0.251 LIG4 Danielle Ariti reviewed gene: LIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27717373, 10911993; Phenotypes: LIG4 syndrome MIM# 606593, T-/B- lymphocytopaenia, Normal NK, radiation sensitivity, Microcephaly, low B/C cells, low Ig, raised IgM, failure to thrive, bacterial/viral/fungal infections, hypogammaglobulinaemia, neurodevelopmental delay, microcephaly, pancytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8614 IL7R Danielle Ariti reviewed gene: IL7R: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843216, 19890784, 26123418, 11023514, 7964471; Phenotypes: Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971, fever, rash, failure to thrive, recurrent respiratory and gastric infections, diarrhoea, lymphadenopathy, pneumonitis, Pancytopaenia, low T-cell numbers, decreased immunoglobulins, normal-high B/NK-cell numbers.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.251 IL7R Danielle Ariti changed review comment from: 6 unrelated individuals with 9 unique variants (missense, splicing, nonsense, and frameshift) have been reported).

Two IL7R null mice models demonstrating a phenotype consistent with T cell Lymphopaenia

Typical patient immunological phenotype consisted of Low B-cells, decreased immunoglobulins with normal-high B/NK cell numbers.; to: 6 unrelated individuals with 9 unique variants (missense, splicing, nonsense, and frameshift) have been reported.

Two IL7R null mice models demonstrating a phenotype consistent with T cell Lymphopaenia

Typical patient immunological phenotype consisted of Low B-cells, decreased immunoglobulins with normal-high B/NK cell numbers.
Combined Immunodeficiency v0.251 IL7R Danielle Ariti reviewed gene: IL7R: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843216, 19890784, 26123418, 11023514, 7964471; Phenotypes: Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971, fever, rash, failure to thrive, recurrent respiratory and gastric infections, diarrhoea, lymphadenopathy, pneumonitis, Pancytopaenia, low T-cell numbers, decreased immunoglobulins, normal-high B/NK-cell numbers.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8614 ITK Danielle Ariti reviewed gene: ITK: Rating: GREEN; Mode of pathogenicity: None; Publications: 19425169, 22289921, 25061172, 26056787, 9311799, 10213685; Phenotypes: Lymphoproliferative syndrome 1 MIM# 613011, Lymphadenopathy, Recurrent infections, Hypogammaglobulinaemia, Evidence of EBV infection, EBV associated B cell Lymphoproliferation, High EBV viral load, Normal-low serum Ig, Depleted CD4+ T cells, Anaemia, Thrombocytopaenia, Hepatosplenomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8614 MALT1 Danielle Ariti reviewed gene: MALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23727036, 24332264, 14576442, 31037583; Phenotypes: Immunodeficiency 12 MIM# 615468, poor T-cell proliferation, normal T/B cell numbers, poor specific antibody response, recurrent bacterial/fungal/viral infections, bronchiectasis, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.251 ITK Danielle Ariti reviewed gene: ITK: Rating: GREEN; Mode of pathogenicity: None; Publications: 19425169, 22289921, 25061172, 26056787, 9311799, 10213685; Phenotypes: Lymphoproliferative syndrome 1 MIM# 613011, Lymphadenopathy, Recurrent infections, Hypogammaglobulinaemia, Evidence of EBV infection, EBV associated B cell Lymphoproliferation, High EBV viral load, Normal-low serum Ig, Depleted CD4+ T cells, Anaemia, Thrombocytopaenia, Hepatosplenomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.251 MALT1 Danielle Ariti reviewed gene: MALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23727036, 24332264, 14576442, 31037583; Phenotypes: Immunodeficiency 12 MIM# 615468, poor T-cell proliferation, normal T/B cell numbers, poor specific antibody response, recurrent bacterial/fungal/viral infections, bronchiectasis, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.251 IL2RG Danielle Ariti reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301584, 8462096, 8401490, 7883965, 9399950; Phenotypes: Combined immunodeficiency, X-linked, moderate MIM# 312863, Severe combined immunodeficiency, X-linked MIM# 300400, recurrent viral/fungal/bacterial infections, Low T/NK cells, Low Ig levels, lymphocytopaenia, hypogammaglobulinaemia, failure to thrive, diarrhoea, Pneumonia, Thymic hypoplasia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Combined Immunodeficiency v0.251 IKZF1 Danielle Ariti reviewed gene: IKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21548011, 26981933, 29889099, 31057532, 7923373, 11805317; Phenotypes: Immunodeficiency, common variable, 13 MIM# 616873, recurrent bacterial respiratory infections, Thrombocytopaenia, immunodeficiency, Hypogammaglobulinaemia, decrease B-cells, decrease B-cell differentiation, decrease memory B/T cells, Low Ig, pneumocystis early CID onset; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pierre Robin Sequence v0.38 PLCB4 Zornitza Stark Marked gene: PLCB4 as ready
Pierre Robin Sequence v0.38 PLCB4 Zornitza Stark Gene: plcb4 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.38 PLCB4 Zornitza Stark Phenotypes for gene: PLCB4 were changed from to Auriculocondylar syndrome 2, MIM# 614669
Pierre Robin Sequence v0.37 PLCB4 Zornitza Stark Publications for gene: PLCB4 were set to
Pierre Robin Sequence v0.36 PLCB4 Zornitza Stark Mode of inheritance for gene: PLCB4 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pierre Robin Sequence v0.35 PLCB4 Zornitza Stark reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8614 PLCB4 Zornitza Stark Marked gene: PLCB4 as ready
Mendeliome v0.8614 PLCB4 Zornitza Stark Gene: plcb4 has been classified as Green List (High Evidence).
Mendeliome v0.8614 PLCB4 Zornitza Stark Phenotypes for gene: PLCB4 were changed from to Auriculocondylar syndrome 2, MIM# 614669
Mendeliome v0.8613 PLCB4 Zornitza Stark Publications for gene: PLCB4 were set to
Mendeliome v0.8612 PLCB4 Zornitza Stark Mode of inheritance for gene: PLCB4 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8611 PLCB4 Zornitza Stark reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.57 PLCB4 Zornitza Stark Marked gene: PLCB4 as ready
Mandibulofacial Acrofacial dysostosis v0.57 PLCB4 Zornitza Stark Gene: plcb4 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.57 PLCB4 Zornitza Stark Phenotypes for gene: PLCB4 were changed from to Auriculocondylar syndrome 2, MIM# 614669
Mandibulofacial Acrofacial dysostosis v0.56 PLCB4 Zornitza Stark Publications for gene: PLCB4 were set to
Mandibulofacial Acrofacial dysostosis v0.55 PLCB4 Zornitza Stark Mode of pathogenicity for gene: PLCB4 was changed from to Other
Mandibulofacial Acrofacial dysostosis v0.54 PLCB4 Zornitza Stark Mode of inheritance for gene: PLCB4 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.53 PLCB4 Zornitza Stark reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8611 PBX1 Zornitza Stark Marked gene: PBX1 as ready
Mendeliome v0.8611 PBX1 Zornitza Stark Gene: pbx1 has been classified as Green List (High Evidence).
Mendeliome v0.8611 PBX1 Zornitza Stark Phenotypes for gene: PBX1 were changed from to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641
Mendeliome v0.8610 PBX1 Zornitza Stark Publications for gene: PBX1 were set to
Mendeliome v0.8609 PBX1 Zornitza Stark Mode of inheritance for gene: PBX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8608 PBX1 Zornitza Stark reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28566479, 29036646; Phenotypes: Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.53 PBX1 Zornitza Stark Marked gene: PBX1 as ready
Mandibulofacial Acrofacial dysostosis v0.53 PBX1 Zornitza Stark Gene: pbx1 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.53 PBX1 Zornitza Stark Phenotypes for gene: PBX1 were changed from to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641
Mandibulofacial Acrofacial dysostosis v0.52 PBX1 Zornitza Stark Publications for gene: PBX1 were set to
Mandibulofacial Acrofacial dysostosis v0.51 PBX1 Zornitza Stark Mode of inheritance for gene: PBX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.50 PBX1 Zornitza Stark reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28566479, 29036646; Phenotypes: Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Marked gene: SPTBN1 as ready
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Classified gene: SPTBN1 as Green List (high evidence)
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Marked gene: SPTBN1 as ready
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Classified gene: SPTBN1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4022 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Polydactyly v0.236 HMGB1 Zornitza Stark Marked gene: HMGB1 as ready
Polydactyly v0.236 HMGB1 Zornitza Stark Gene: hmgb1 has been classified as Red List (Low Evidence).
Polydactyly v0.236 HMGB1 Zornitza Stark Classified gene: HMGB1 as Red List (low evidence)
Polydactyly v0.236 HMGB1 Zornitza Stark Gene: hmgb1 has been classified as Red List (Low Evidence).
Skeletal dysplasia v0.110 UBA2 Zornitza Stark Classified gene: UBA2 as Green List (high evidence)
Skeletal dysplasia v0.110 UBA2 Zornitza Stark Gene: uba2 has been classified as Green List (High Evidence).
Mendeliome v0.8608 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A, MIM# 607596; SMA to Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia
Mendeliome v0.8607 VRK1 Zornitza Stark Publications for gene: VRK1 were set to 19646678; 21937992; 25609612; 24126608; 27281532
Mendeliome v0.8606 VRK1 Zornitza Stark changed review comment from: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia.; to: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia.

Further delineation of phenotype 2021:
PMID 34169149: expanding spectrum of neurologic disorders associated with VRK1. Two Hispanic individuals, one homozygous (R321C: VUS and LP/P in ClinVar) and one cHet (R321C+V236M, latter P and more recently VUS in ClinVar), with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy WITHOUT pontocerebellar atrophy. No hom in gnomAD and both have been reported in cHet individuals with other features: R321C in association with adult-onset amyotrophic lateral sclerosis and V236M with rapidly progressive sensorimotor polyneuropathy and microcephaly. Authors suggest PMID 26583493 and 31837156 have similar reports. PMID 26583493 reports a 32yo Hispanic individual, cHet H119R+R321C, with early-onset amyotrophic lateral sclerosis, 5 years progressive weakness. PMID 31837156 reports two patients with adult-onset length-dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent, both hom for R387H.
Mendeliome v0.8606 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed publications: 19646678, 21937992, 25609612, 24126608, 27281532, 34169149, 26583493; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia
Motor Neurone Disease v0.126 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from Distal hereditary motor neuropathy; dHMN/dSMA to Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia; Distal hereditary motor neuropathy; dHMN/dSMA
Motor Neurone Disease v0.125 VRK1 Zornitza Stark Publications for gene: VRK1 were set to 31560180; 32242460; 31178479; 31837156; 30847374
Motor Neurone Disease v0.124 VRK1 Zornitza Stark Classified gene: VRK1 as Amber List (moderate evidence)
Motor Neurone Disease v0.124 VRK1 Zornitza Stark Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Marked gene: CLCN3 as ready
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Classified gene: CLCN3 as Green List (high evidence)
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Callosome v0.309 CLCN3 Zornitza Stark Marked gene: CLCN3 as ready
Callosome v0.309 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Callosome v0.309 CLCN3 Zornitza Stark Classified gene: CLCN3 as Green List (high evidence)
Callosome v0.309 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1152 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

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

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

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

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Callosome v0.308 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Callosome. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

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

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

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

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Marked gene: CLCN3 as ready
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Classified gene: CLCN3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4021 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4020 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

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

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

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

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Mendeliome v0.8606 CLCN3 Zornitza Stark Marked gene: CLCN3 as ready
Mendeliome v0.8606 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Mendeliome v0.8606 CLCN3 Zornitza Stark Mode of inheritance for gene: CLCN3 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 v0.8605 CLCN3 Zornitza Stark Classified gene: CLCN3 as Green List (high evidence)
Mendeliome v0.8605 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Microcephaly v1.37 TNPO2 Zornitza Stark Marked gene: TNPO2 as ready
Microcephaly v1.37 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Microcephaly v1.37 TNPO2 Zornitza Stark Classified gene: TNPO2 as Green List (high evidence)
Microcephaly v1.37 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Microcephaly v1.36 TNPO2 Zornitza Stark gene: TNPO2 was added
gene: TNPO2 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability, neurologic deficits and dysmorphic features
Mode of pathogenicity for gene: TNPO2 was set to Other
Review for gene: TNPO2 was set to GREEN
Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia). Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF. gnomAD: minimal PTCs present
Sources: Literature
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Marked gene: TNPO2 as ready
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Classified gene: TNPO2 as Green List (high evidence)
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1150 TNPO2 Zornitza Stark gene: TNPO2 was added
gene: TNPO2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability, neurologic deficits and dysmorphic features
Mode of pathogenicity for gene: TNPO2 was set to Other
Review for gene: TNPO2 was set to GREEN
Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia). Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF. gnomAD: minimal PTCs present.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4019 TNPO2 Zornitza Stark Marked gene: TNPO2 as ready
Intellectual disability syndromic and non-syndromic v0.4019 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4019 TNPO2 Zornitza Stark Phenotypes for gene: TNPO2 were changed from Developmental delays, neurologic deficits and dysmorphic features to Intellectual disability, neurologic deficits and dysmorphic features
Intellectual disability syndromic and non-syndromic v0.4018 TNPO2 Zornitza Stark Classified gene: TNPO2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4018 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Mendeliome v0.8604 TNPO2 Zornitza Stark Marked gene: TNPO2 as ready
Mendeliome v0.8604 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Mendeliome v0.8604 TNPO2 Zornitza Stark Phenotypes for gene: TNPO2 were changed from Developmental delays, neurologic deficits and dysmorphic features to Intellectual disability, neurologic deficits and dysmorphic features
Mendeliome v0.8603 TNPO2 Zornitza Stark Classified gene: TNPO2 as Green List (high evidence)
Mendeliome v0.8603 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Mendeliome v0.8602 ZDHHC15 Daniel Flanagan reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8602 DNAH10 Zornitza Stark Marked gene: DNAH10 as ready
Mendeliome v0.8602 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Mendeliome v0.8602 DNAH10 Zornitza Stark Classified gene: DNAH10 as Green List (high evidence)
Mendeliome v0.8602 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Motor Neurone Disease v0.123 VRK1 Michelle Torres reviewed gene: VRK1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34169149, 26583493, 31837156; Phenotypes: Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8601 CLCN3 Kristin Rigbye gene: CLCN3 was added
gene: CLCN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to PMID: 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

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

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

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

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Motor Neurone Disease v0.123 VRK1 Michelle Torres Deleted their review
Motor Neurone Disease v0.123 VRK1 Michelle Torres commented on gene: VRK1
Intellectual disability syndromic and non-syndromic v0.4017 TNPO2 Elena Savva gene: TNPO2 was added
gene: TNPO2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to PMID: 34314705
Phenotypes for gene: TNPO2 were set to Developmental delays, neurologic deficits and dysmorphic features
Mode of pathogenicity for gene: TNPO2 was set to Other
Review for gene: TNPO2 was set to GREEN
Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia).

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

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

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

gnomAD: minimal PTCs present
Sources: Literature
Mendeliome v0.8601 SPTBN4 Melanie Marty Deleted their review
Mendeliome v0.8601 DNAH10 Ain Roesley gene: DNAH10 was added
gene: DNAH10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH10 were set to 34237282
Phenotypes for gene: DNAH10 were set to primary male infertility with asthenoteratozoospermia
Penetrance for gene: DNAH10 were set to unknown
Review for gene: DNAH10 was set to GREEN
Added comment: 4x families with 5 affecteds (chets and homs - 4 missense and 2 fs). Knockout mouse models were infertile and showed significant reduction in count and motility compared to heterozygous mice
Sources: Literature
Lissencephaly and Band Heterotopia v1.3 TP73 Seb Lunke Marked gene: TP73 as ready
Lissencephaly and Band Heterotopia v1.3 TP73 Seb Lunke Gene: tp73 has been classified as Green List (High Evidence).
Lissencephaly and Band Heterotopia v1.3 TP73 Seb Lunke Phenotypes for gene: TP73 were changed from chronic airway disease; brain malformation; lissencephaly to brain malformation; lissencephaly
Lissencephaly and Band Heterotopia v1.2 TP73 Seb Lunke Classified gene: TP73 as Green List (high evidence)
Lissencephaly and Band Heterotopia v1.2 TP73 Seb Lunke Gene: tp73 has been classified as Green List (High Evidence).
Mendeliome v0.8601 AP1G1 Zornitza Stark Marked gene: AP1G1 as ready
Mendeliome v0.8601 AP1G1 Zornitza Stark Added comment: Comment when marking as ready: Good evidence for association between mono-allelic variants and NDD, moderate evidence for bi-allelic variants causing disease.
Mendeliome v0.8601 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Mendeliome v0.8601 ALDH1A2 Seb Lunke commented on gene: ALDH1A2
Lissencephaly and Band Heterotopia v1.1 TP73 Ee Ming Wong gene: TP73 was added
gene: TP73 was added to Lissencephaly and Band Heterotopia. Sources: Literature
Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP73 were set to 34077761
Phenotypes for gene: TP73 were set to chronic airway disease; brain malformation; lissencephaly
Review for gene: TP73 was set to GREEN
gene: TP73 was marked as current diagnostic
Added comment: - Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants)
- In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls
Sources: Literature
Mendeliome v0.8601 AP1G1 Zornitza Stark Classified gene: AP1G1 as Green List (high evidence)
Mendeliome v0.8601 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Mendeliome v0.8600 SEMA3D Ain Roesley edited their review of gene: SEMA3D: Added comment: Reported as a common susceptibility loci. No reported evidence for an association with Mendelian disease. Sema3d null heterozygote and homozygote mouse model had normal intestinal innervation.; Changed publications: 28334784, 25839327; Changed phenotypes: Hirschsprung disease
Mendeliome v0.8600 AP1G1 Danielle Ariti gene: AP1G1 was added
gene: AP1G1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Mode of pathogenicity for gene: AP1G1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

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

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

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Mendeliome v0.8600 SEMA3D Zornitza Stark Marked gene: SEMA3D as ready
Mendeliome v0.8600 SEMA3D Zornitza Stark Gene: sema3d has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4017 TP73 Seb Lunke Publications for gene: TP73 were set to 31130284
Mendeliome v0.8600 SEMA3D Zornitza Stark Phenotypes for gene: SEMA3D were changed from to Hand and foot malformations
Mendeliome v0.8599 SEMA3D Zornitza Stark Classified gene: SEMA3D as Red List (low evidence)
Mendeliome v0.8599 SEMA3D Zornitza Stark Gene: sema3d has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4016 SPTBN1 Belinda Chong changed review comment from: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

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

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4016 TP73 Seb Lunke Classified gene: TP73 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4016 TP73 Seb Lunke Gene: tp73 has been classified as Green List (High Evidence).
Mendeliome v0.8598 SPTBN1 Belinda Chong changed review comment from: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

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

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Mendeliome v0.8598 SPTBN4 Zornitza Stark Marked gene: SPTBN4 as ready
Mendeliome v0.8598 SPTBN4 Zornitza Stark Gene: sptbn4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1149 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179 PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures (9/29) ; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Sources: Literature
Mendeliome v0.8598 SPTBN4 Zornitza Stark Phenotypes for gene: SPTBN4 were changed from to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM #617519)
Mendeliome v0.8597 TP73 Seb Lunke Classified gene: TP73 as Green List (high evidence)
Mendeliome v0.8597 TP73 Seb Lunke Gene: tp73 has been classified as Green List (High Evidence).
Mendeliome v0.8597 SPTBN4 Zornitza Stark Publications for gene: SPTBN4 were set to
Mendeliome v0.8596 SPTBN4 Zornitza Stark Mode of inheritance for gene: SPTBN4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8595 TP73 Seb Lunke Publications for gene: TP73 were set to PMID: 31130284
Intellectual disability syndromic and non-syndromic v0.4015 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179 PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Sources: Literature
Polydactyly v0.235 HMGB1 Ain Roesley gene: HMGB1 was added
gene: HMGB1 was added to Polydactyly. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HMGB1 were set to 34159400
Phenotypes for gene: HMGB1 were set to Mirror image foot polydactyly
Penetrance for gene: HMGB1 were set to unknown
Review for gene: HMGB1 was set to RED
Added comment: 1x de novo fs in a proband with severe mirror image foot polydactyly. No functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4015 EDEM3 Seb Lunke Marked gene: EDEM3 as ready
Intellectual disability syndromic and non-syndromic v0.4015 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Congenital Disorders of Glycosylation v1.16 EDEM3 Seb Lunke Phenotypes for gene: EDEM3 were changed from EDEM3-congenital disorder of glycosylation to Congenital disorder of glycosylation; Developmental delay
Congenital Disorders of Glycosylation v1.15 EDEM3 Seb Lunke Marked gene: EDEM3 as ready
Congenital Disorders of Glycosylation v1.15 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4015 EDEM3 Seb Lunke Phenotypes for gene: EDEM3 were changed from EDEM3-congenital disorder of glycosylation to Congenital disorder of glycosylation; Developmental delay
Mendeliome v0.8594 HMGB1 Zornitza Stark Marked gene: HMGB1 as ready
Mendeliome v0.8594 HMGB1 Zornitza Stark Gene: hmgb1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.4014 EDEM3 Seb Lunke Classified gene: EDEM3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4014 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Mendeliome v0.8594 HMGB1 Zornitza Stark Classified gene: HMGB1 as Red List (low evidence)
Mendeliome v0.8594 HMGB1 Zornitza Stark Gene: hmgb1 has been classified as Red List (Low Evidence).
Congenital Disorders of Glycosylation v1.15 EDEM3 Seb Lunke Classified gene: EDEM3 as Green List (high evidence)
Congenital Disorders of Glycosylation v1.15 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Mendeliome v0.8593 SPTBN1 Zornitza Stark Marked gene: SPTBN1 as ready
Mendeliome v0.8593 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Mendeliome v0.8593 SPTBN1 Zornitza Stark Phenotypes for gene: SPTBN1 were changed from Neurodevelopmental Syndrome to Neurodevelopmental Syndrome; Intellectual disability; Seizures
Mendeliome v0.8592 EDEM3 Seb Lunke Marked gene: EDEM3 as ready
Mendeliome v0.8592 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Mendeliome v0.8592 EDEM3 Seb Lunke Phenotypes for gene: EDEM3 were changed from EDEM3-congenital disorder of glycosylation to Congenital disorder of glycosylation; Developmental delay
Skeletal dysplasia v0.109 UBA2 Ain Roesley reviewed gene: UBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34159400; Phenotypes: isolated split hand malformation; Mode of inheritance: None
Mendeliome v0.8591 UBA2 Ain Roesley changed review comment from: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available)

1x proband with unilateral split-hand malformation. Her daughter and grandson reported to have ectrofactyly but were unavailable for testing; to: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available)

1x proband with unilateral split-hand malformation (missense). Her daughter and grandson reported to have ectrofactyly but were unavailable for testing
Mendeliome v0.8591 SPTBN1 Zornitza Stark Classified gene: SPTBN1 as Green List (high evidence)
Mendeliome v0.8591 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Mendeliome v0.8590 EDEM3 Seb Lunke Classified gene: EDEM3 as Green List (high evidence)
Mendeliome v0.8590 EDEM3 Seb Lunke Gene: edem3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4013 EDEM3 Michelle Torres gene: EDEM3 was added
gene: EDEM3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to EDEM3-congenital disorder of glycosylation
Review for gene: EDEM3 was set to GREEN
Added comment: PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional show LoF of EDEM3 enzymatic activity.
Sources: Literature
Mendeliome v0.8589 UBA2 Zornitza Stark Publications for gene: UBA2 were set to PMID: 31332306; 31587267
Mendeliome v0.8588 UBA2 Zornitza Stark Classified gene: UBA2 as Green List (high evidence)
Mendeliome v0.8588 UBA2 Zornitza Stark Gene: uba2 has been classified as Green List (High Evidence).
Mendeliome v0.8587 ALDH1A2 Ain Roesley reviewed gene: ALDH1A2: Rating: RED; Mode of pathogenicity: None; Publications: 34159400; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.8587 GCNA Zornitza Stark Marked gene: GCNA as ready
Mendeliome v0.8587 GCNA Zornitza Stark Gene: gcna has been classified as Green List (High Evidence).
Mendeliome v0.8587 GCNA Zornitza Stark Classified gene: GCNA as Green List (high evidence)
Mendeliome v0.8587 GCNA Zornitza Stark Gene: gcna has been classified as Green List (High Evidence).
Mendeliome v0.8586 SEMA3D Ain Roesley gene: SEMA3D was added
gene: SEMA3D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEMA3D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEMA3D were set to 34159400
Penetrance for gene: SEMA3D were set to unknown
Review for gene: SEMA3D was set to RED
Added comment: 1x de novo missense in a proband with short stature, absent distal phalanges of the 5th fingers and toes, and dysplastic middle phalanges of the toes.

However, there is 4 hets in gnomAD v2
Sources: Literature
Mendeliome v0.8586 SPTBN4 Melanie Marty reviewed gene: SPTBN4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33772159; Phenotypes: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM #617519); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8586 TP73 Ee Ming Wong changed review comment from: - Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants)
- Epithelial cells from TP73 variant carriers showed reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls; to: - Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants)
- In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls
Mendeliome v0.8586 TP73 Ee Ming Wong reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34077761; Phenotypes: chronic airway disease, brain malformation, lissencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.8586 HMGB1 Ain Roesley changed review comment from: 1x de novo fs, no functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development
Sources: Literature; to: 1x de novo fs in a proband with severe mirror image foot polydactyly. No functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development
Sources: Literature
Mendeliome v0.8586 HMGB1 Ain Roesley gene: HMGB1 was added
gene: HMGB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HMGB1 were set to 34159400
Phenotypes for gene: HMGB1 were set to Mirror image foot polydactyly
Penetrance for gene: HMGB1 were set to unknown
Review for gene: HMGB1 was set to RED
Added comment: 1x de novo fs, no functional studies done but cited Itou 2011 - mouse and zebrafish studies demonstrated the role of HMGB1 in regulating digit number during embryonic limb development
Sources: Literature
Mendeliome v0.8586 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179; PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Mendeliome v0.8586 UBA2 Ain Roesley reviewed gene: UBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34159400; Phenotypes: isolated split hand malformation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Disorders of Glycosylation v1.14 EDEM3 Michelle Torres gene: EDEM3 was added
gene: EDEM3 was added to Congenital Disorders of Glycosylation. Sources: Literature
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to EDEM3-congenital disorder of glycosylation
Review for gene: EDEM3 was set to GREEN
Added comment: PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional show LoF of EDEM3 enzymatic activity.
Sources: Literature
Sources: Literature
Mendeliome v0.8586 EDEM3 Michelle Torres gene: EDEM3 was added
gene: EDEM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to EDEM3-congenital disorder of glycosylation
Review for gene: EDEM3 was set to GREEN
Added comment: PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional show LoF of EDEM3 enzymatic activity.
Sources: Literature
Mendeliome v0.8586 GCNA Ain Roesley gene: GCNA was added
gene: GCNA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GCNA was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GCNA were set to 33963445
Phenotypes for gene: GCNA were set to primary spermatogenic failure
Penetrance for gene: GCNA were set to unknown
Review for gene: GCNA was set to GREEN
Added comment: 7x probands all missense except 1 fs. Variants had <0.0005 MAF in gnomad v2 male cohort and absent in 5784 Dutch control cohort
no functional studies were done except for histology of Ser659Trp, revealing a Sertoli-cell only
Sources: Literature
Additional findings_Paediatric v0.253 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from Long QT syndrome to Complex neurodevelopmental disorder, MONDO:0100038
Additional findings_Paediatric v0.252 ANK2 Zornitza Stark Classified gene: ANK2 as Green List (high evidence)
Additional findings_Paediatric v0.252 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Additional findings_Paediatric v0.251 ANK2 Zornitza Stark reviewed gene: ANK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491, 33004838, 33057194; Phenotypes: Complex neurodevelopmental disorder, MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Long QT Syndrome v0.60 ANK2 Zornitza Stark Mode of inheritance for gene: ANK2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8586 ANK2 Zornitza Stark Marked gene: ANK2 as ready
Mendeliome v0.8586 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Mendeliome v0.8586 ANK2 Zornitza Stark Classified gene: ANK2 as Green List (high evidence)
Mendeliome v0.8586 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Mendeliome v0.8585 ANK2 Zornitza Stark gene: ANK2 was added
gene: ANK2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 31983240; 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Phenotypes for gene: ANK2 were set to Long QT syndrome 4, MIM# 600919; Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: ANK2 was set to GREEN
Added comment: Link with cardiac abnormalities such as LongQT is DISPUTED. More than 10 unrelated individuals reported with neurodevelopmental phenotype, comprising autism/ID and de novo truncating variants, in addition to many other individuals as part of large NDD cohorts. This association has been assessed as DEFINITIVE by ClinGen.
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4013 ANK2 Zornitza Stark Marked gene: ANK2 as ready
Intellectual disability syndromic and non-syndromic v0.4013 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Incidentalome v0.75 ANK2 Zornitza Stark Marked gene: ANK2 as ready
Incidentalome v0.75 ANK2 Zornitza Stark Gene: ank2 has been classified as Red List (Low Evidence).
Incidentalome v0.75 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from to Long QT syndrome 4, MIM# 600919
Incidentalome v0.74 ANK2 Zornitza Stark Publications for gene: ANK2 were set to
Incidentalome v0.73 ANK2 Zornitza Stark Mode of inheritance for gene: ANK2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.72 ANK2 Zornitza Stark Classified gene: ANK2 as Red List (low evidence)
Incidentalome v0.72 ANK2 Zornitza Stark Gene: ank2 has been classified as Red List (Low Evidence).
Incidentalome v0.71 ANK2 Zornitza Stark reviewed gene: ANK2: Rating: RED; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Long QT syndrome 4, MIM# 600919; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autism v0.166 ANK2 Zornitza Stark Marked gene: ANK2 as ready
Autism v0.166 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Autism v0.166 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from to Complex neurodevelopmental disorder, MONDO:0100038
Autism v0.165 ANK2 Zornitza Stark Publications for gene: ANK2 were set to
Autism v0.164 ANK2 Zornitza Stark Mode of inheritance for gene: ANK2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autism v0.163 ANK2 Zornitza Stark reviewed gene: ANK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491, 33004838, 33057194; Phenotypes: Complex neurodevelopmental disorder, MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.4013 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from Complex neurodevelopmental disorder, MONDO:0100038 to Complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability syndromic and non-syndromic v0.4012 ANK2 Zornitza Stark Publications for gene: ANK2 were set to 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Intellectual disability syndromic and non-syndromic v0.4011 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from intellectual disability to Complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability syndromic and non-syndromic v0.4010 ANK2 Zornitza Stark Publications for gene: ANK2 were set to 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491
Intellectual disability syndromic and non-syndromic v0.4010 ANK2 Zornitza Stark Classified gene: ANK2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4010 ANK2 Zornitza Stark Gene: ank2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Zornitza Stark reviewed gene: ANK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491, 33004838, 33057194; Phenotypes: Complex neurodevelopmental disorder, MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia v0.289 PRDX3 Zornitza Stark Marked gene: PRDX3 as ready
Ataxia v0.289 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Ataxia v0.289 PRDX3 Zornitza Stark Classified gene: PRDX3 as Green List (high evidence)
Ataxia v0.289 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Ataxia v0.288 PRDX3 Zornitza Stark gene: PRDX3 was added
gene: PRDX3 was added to Ataxia - paediatric. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDX3 were set to 33889951
Phenotypes for gene: PRDX3 were set to Cerebellar ataxia (early onset, mild to moderate, progressive)
Review for gene: PRDX3 was set to GREEN
Added comment: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.

Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.

The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.

The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.

Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.

PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.

Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.

In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mitochondrial disease v0.645 PRDX3 Zornitza Stark Marked gene: PRDX3 as ready
Mitochondrial disease v0.645 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Mitochondrial disease v0.645 PRDX3 Zornitza Stark Classified gene: PRDX3 as Green List (high evidence)
Mitochondrial disease v0.645 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Mitochondrial disease v0.644 PRDX3 Zornitza Stark gene: PRDX3 was added
gene: PRDX3 was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDX3 were set to 33889951
Phenotypes for gene: PRDX3 were set to Cerebellar ataxia (early onset, mild to moderate, progressive)
Review for gene: PRDX3 was set to GREEN
Added comment: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.

Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.

The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.

The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.

Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.

PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.

Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.

In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Anna Le Fevre commented on gene: ANK2: Publications largely cover autism risk and discovery in large cohorts. ClinGen review mentions ID, seizures and microcephaly but phenotype and penetrance appear incompletely described.
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Anna Le Fevre edited their review of gene: ANK2: Changed phenotypes: intellectual disability, autism
Intellectual disability syndromic and non-syndromic v0.4009 ANK2 Anna Le Fevre gene: ANK2 was added
gene: ANK2 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491
Phenotypes for gene: ANK2 were set to intellectual disability
Penetrance for gene: ANK2 were set to unknown
Added comment: Curated by ClinGen 2020 as definitively associated
? consider taking gene off incidentalome gene list
Sources: Other
Mendeliome v0.8584 PRDX3 Zornitza Stark Marked gene: PRDX3 as ready
Mendeliome v0.8584 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Mendeliome v0.8584 PRDX3 Zornitza Stark Classified gene: PRDX3 as Green List (high evidence)
Mendeliome v0.8584 PRDX3 Zornitza Stark Gene: prdx3 has been classified as Green List (High Evidence).
Mendeliome v0.8583 PRDX3 Hazel Phillimore changed review comment from: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature; to: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mendeliome v0.8583 PRDX3 Hazel Phillimore gene: PRDX3 was added
gene: PRDX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDX3 were set to PMID: 33889951
Phenotypes for gene: PRDX3 were set to cerebellar ataxia (early onset, mild to moderate, progressive)
Penetrance for gene: PRDX3 were set to unknown
Review for gene: PRDX3 was set to GREEN
Added comment: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex.
Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres.
The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote of a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism.
The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense.
Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity.
PRXD3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated.
Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species.
In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress.
Sources: Literature
Mandibulofacial Acrofacial dysostosis v0.49 EDN1 Zornitza Stark Marked gene: EDN1 as ready
Mandibulofacial Acrofacial dysostosis v0.49 EDN1 Zornitza Stark Gene: edn1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v0.109 GSC Zornitza Stark Marked gene: GSC as ready
Skeletal dysplasia v0.109 GSC Zornitza Stark Gene: gsc has been classified as Green List (High Evidence).
Skeletal dysplasia v0.109 GSC Zornitza Stark Phenotypes for gene: GSC were changed from Foundation Trust) Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities 602471; Foundation Trust) Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities 602471 to Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471
Skeletal dysplasia v0.108 GSC Zornitza Stark Publications for gene: GSC were set to
Skeletal dysplasia v0.107 GSC Zornitza Stark reviewed gene: GSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 24290375; Phenotypes: Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8583 GSC Zornitza Stark Marked gene: GSC as ready
Mendeliome v0.8583 GSC Zornitza Stark Gene: gsc has been classified as Green List (High Evidence).
Mendeliome v0.8583 GSC Zornitza Stark Phenotypes for gene: GSC were changed from to Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471
Mendeliome v0.8582 GSC Zornitza Stark Publications for gene: GSC were set to
Mendeliome v0.8581 GSC Zornitza Stark Mode of inheritance for gene: GSC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8580 GSC Zornitza Stark reviewed gene: GSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 24290375; Phenotypes: Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.49 GSC Zornitza Stark Marked gene: GSC as ready
Mandibulofacial Acrofacial dysostosis v0.49 GSC Zornitza Stark Gene: gsc has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.49 GSC Zornitza Stark Phenotypes for gene: GSC were changed from to Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471
Mandibulofacial Acrofacial dysostosis v0.48 GSC Zornitza Stark Publications for gene: GSC were set to
Mandibulofacial Acrofacial dysostosis v0.47 GSC Zornitza Stark Mode of inheritance for gene: GSC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.46 GSC Zornitza Stark reviewed gene: GSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 24290375; Phenotypes: Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8580 GNAI3 Zornitza Stark Marked gene: GNAI3 as ready
Mendeliome v0.8580 GNAI3 Zornitza Stark Gene: gnai3 has been classified as Green List (High Evidence).
Mendeliome v0.8580 GNAI3 Zornitza Stark Phenotypes for gene: GNAI3 were changed from to Auriculocondylar syndrome 1, OMIM #602483
Mendeliome v0.8579 GNAI3 Zornitza Stark Publications for gene: GNAI3 were set to
Mendeliome v0.8578 GNAI3 Zornitza Stark Mode of inheritance for gene: GNAI3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8577 GNAI3 Zornitza Stark reviewed gene: GNAI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091; Phenotypes: Auriculocondylar syndrome 1, OMIM #602483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.46 GNAI3 Zornitza Stark Marked gene: GNAI3 as ready
Mandibulofacial Acrofacial dysostosis v0.46 GNAI3 Zornitza Stark Gene: gnai3 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.46 GNAI3 Zornitza Stark Phenotypes for gene: GNAI3 were changed from to Auriculocondylar syndrome 1, OMIM #602483
Mandibulofacial Acrofacial dysostosis v0.45 GNAI3 Zornitza Stark Publications for gene: GNAI3 were set to
Mandibulofacial Acrofacial dysostosis v0.44 GNAI3 Zornitza Stark Mode of inheritance for gene: GNAI3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mandibulofacial Acrofacial dysostosis v0.43 GNAI3 Zornitza Stark reviewed gene: GNAI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091; Phenotypes: Auriculocondylar syndrome 1, OMIM #602483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Clefting disorders v0.134 EIF4A3 Zornitza Stark Marked gene: EIF4A3 as ready
Clefting disorders v0.134 EIF4A3 Zornitza Stark Gene: eif4a3 has been classified as Green List (High Evidence).
Clefting disorders v0.134 EIF4A3 Zornitza Stark Publications for gene: EIF4A3 were set to 10594883; 29112243; 29922329
Clefting disorders v0.133 EIF4A3 Zornitza Stark reviewed gene: EIF4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360810; Phenotypes: Robin sequence with cleft mandible and limb anomalies, MIM# 268305, Richieri-Costa-Pereira syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4009 EIF4A3 Zornitza Stark Marked gene: EIF4A3 as ready
Intellectual disability syndromic and non-syndromic v0.4009 EIF4A3 Zornitza Stark Gene: eif4a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4009 EIF4A3 Zornitza Stark Phenotypes for gene: EIF4A3 were changed from to Robin sequence with cleft mandible and limb anomalies, MIM# 268305; Richieri-Costa-Pereira syndrome
Intellectual disability syndromic and non-syndromic v0.4008 EIF4A3 Zornitza Stark Publications for gene: EIF4A3 were set to
Intellectual disability syndromic and non-syndromic v0.4007 EIF4A3 Zornitza Stark Mode of inheritance for gene: EIF4A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4006 EIF4A3 Zornitza Stark reviewed gene: EIF4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360810; Phenotypes: Robin sequence with cleft mandible and limb anomalies, MIM# 268305, Richieri-Costa-Pereira syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pierre Robin Sequence v0.35 EIF4A3 Zornitza Stark Marked gene: EIF4A3 as ready
Pierre Robin Sequence v0.35 EIF4A3 Zornitza Stark Gene: eif4a3 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.35 EIF4A3 Zornitza Stark Phenotypes for gene: EIF4A3 were changed from to Robin sequence with cleft mandible and limb anomalies, MIM# 268305; Richieri-Costa-Pereira syndrome
Pierre Robin Sequence v0.34 EIF4A3 Zornitza Stark Publications for gene: EIF4A3 were set to
Pierre Robin Sequence v0.33 EIF4A3 Zornitza Stark Mode of inheritance for gene: EIF4A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Pierre Robin Sequence v0.32 EIF4A3 Zornitza Stark reviewed gene: EIF4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360810; Phenotypes: Robin sequence with cleft mandible and limb anomalies, MIM# 268305, Richieri-Costa-Pereira syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8577 EIF4A3 Zornitza Stark Marked gene: EIF4A3 as ready
Mendeliome v0.8577 EIF4A3 Zornitza Stark Gene: eif4a3 has been classified as Green List (High Evidence).
Mendeliome v0.8577 EIF4A3 Zornitza Stark Phenotypes for gene: EIF4A3 were changed from to Robin sequence with cleft mandible and limb anomalies, MIM# 268305; Richieri-Costa-Pereira syndrome
Mendeliome v0.8576 EIF4A3 Zornitza Stark Publications for gene: EIF4A3 were set to
Mendeliome v0.8575 EIF4A3 Zornitza Stark Mode of inheritance for gene: EIF4A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8574 EIF4A3 Zornitza Stark reviewed gene: EIF4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360810; Phenotypes: Robin sequence with cleft mandible and limb anomalies, MIM# 268305, Richieri-Costa-Pereira syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.43 EIF4A3 Zornitza Stark Marked gene: EIF4A3 as ready
Mandibulofacial Acrofacial dysostosis v0.43 EIF4A3 Zornitza Stark Gene: eif4a3 has been classified as Green List (High Evidence).
Mandibulofacial Acrofacial dysostosis v0.43 EIF4A3 Zornitza Stark Phenotypes for gene: EIF4A3 were changed from to Robin sequence with cleft mandible and limb anomalies, MIM# 268305; Richieri-Costa-Pereira syndrome
Mandibulofacial Acrofacial dysostosis v0.42 EIF4A3 Zornitza Stark Publications for gene: EIF4A3 were set to
Mandibulofacial Acrofacial dysostosis v0.41 EIF4A3 Zornitza Stark Mode of inheritance for gene: EIF4A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mandibulofacial Acrofacial dysostosis v0.40 EIF4A3 Zornitza Stark reviewed gene: EIF4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360810; Phenotypes: Robin sequence with cleft mandible and limb anomalies, MIM# 268305, Richieri-Costa-Pereira syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gastrointestinal neuromuscular disease v1.12 SCN11A Zornitza Stark Marked gene: SCN11A as ready
Gastrointestinal neuromuscular disease v1.12 SCN11A Zornitza Stark Gene: scn11a has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.12 SCN11A Zornitza Stark Classified gene: SCN11A as Green List (high evidence)
Gastrointestinal neuromuscular disease v1.12 SCN11A Zornitza Stark Gene: scn11a has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.11 SCN11A Zornitza Stark gene: SCN11A was added
gene: SCN11A was added to Gastrointestinal neuromuscular disease. Sources: Expert list
Mode of inheritance for gene: SCN11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN11A were set to 27503742; 25118027
Phenotypes for gene: SCN11A were set to Neuropathy, hereditary sensory and autonomic, type VII, MIM# 615548
Review for gene: SCN11A was set to GREEN
Added comment: Gastrointestinal dysmotility reported.
Sources: Expert list
Gastrointestinal neuromuscular disease v1.10 SAMD9 Zornitza Stark Marked gene: SAMD9 as ready
Gastrointestinal neuromuscular disease v1.10 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.10 SAMD9 Zornitza Stark Classified gene: SAMD9 as Green List (high evidence)
Gastrointestinal neuromuscular disease v1.10 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.9 SAMD9 Zornitza Stark gene: SAMD9 was added
gene: SAMD9 was added to Gastrointestinal neuromuscular disease. Sources: Expert list
Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9 were set to 27182967
Phenotypes for gene: SAMD9 were set to MIRAGE syndrome, MIM# 617053
Review for gene: SAMD9 was set to GREEN
Added comment: Chronic diarrhoea and colonic dilatation reported.
Sources: Expert list
Gastrointestinal neuromuscular disease v1.8 IDS Zornitza Stark Classified gene: IDS as Green List (high evidence)
Gastrointestinal neuromuscular disease v1.8 IDS Zornitza Stark Gene: ids has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.7 IDS Zornitza Stark gene: IDS was added
gene: IDS was added to Gastrointestinal neuromuscular disease. Sources: Expert list
Mode of inheritance for gene: IDS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: IDS were set to Mucopolysaccharidosis II, MIM# 309900
Review for gene: IDS was set to GREEN
Added comment: Intestinal pseudo-obstruction reported.
Sources: Expert list
Gastrointestinal neuromuscular disease v1.6 DMD Zornitza Stark Marked gene: DMD as ready
Gastrointestinal neuromuscular disease v1.6 DMD Zornitza Stark Gene: dmd has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.6 DMD Zornitza Stark Classified gene: DMD as Green List (high evidence)
Gastrointestinal neuromuscular disease v1.6 DMD Zornitza Stark Gene: dmd has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.5 DMD Zornitza Stark Tag SV/CNV tag was added to gene: DMD.
Gastrointestinal neuromuscular disease v1.5 DMD Zornitza Stark gene: DMD was added
gene: DMD was added to Gastrointestinal neuromuscular disease. Sources: Expert list
Mode of inheritance for gene: DMD was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DMD were set to 3380114
Phenotypes for gene: DMD were set to Duchenne muscular dystrophy, MIM# 310200
Review for gene: DMD was set to GREEN
Added comment: Can rarely present with gut dysmotility.
Sources: Expert list
Gastrointestinal neuromuscular disease v1.4 DES Zornitza Stark Marked gene: DES as ready
Gastrointestinal neuromuscular disease v1.4 DES Zornitza Stark Gene: des has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.4 DES Zornitza Stark Classified gene: DES as Green List (high evidence)
Gastrointestinal neuromuscular disease v1.4 DES Zornitza Stark Gene: des has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.3 DES Zornitza Stark gene: DES was added
gene: DES was added to Gastrointestinal neuromuscular disease. Sources: Expert list
Mode of inheritance for gene: DES was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DES were set to Myopathy, myofibrillar, 1 , MIM#601419
Review for gene: DES was set to GREEN
Added comment: Well established gene-disease association. Primarily skeletal and cardiac involvement but gut involvement with constipation/diarrhoea reported.
Sources: Expert list
Gastrointestinal neuromuscular disease v1.2 CLMP Zornitza Stark Marked gene: CLMP as ready
Gastrointestinal neuromuscular disease v1.2 CLMP Zornitza Stark Gene: clmp has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.2 CLMP Zornitza Stark Classified gene: CLMP as Green List (high evidence)
Gastrointestinal neuromuscular disease v1.2 CLMP Zornitza Stark Gene: clmp has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v1.1 CLMP Zornitza Stark gene: CLMP was added
gene: CLMP was added to Gastrointestinal neuromuscular disease. Sources: Expert list
Mode of inheritance for gene: CLMP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLMP were set to 22155368
Phenotypes for gene: CLMP were set to Congenital short bowel syndrome , MIM#615237
Review for gene: CLMP was set to GREEN
Added comment: Well established gene-disease association, phenotypic overlap.
Sources: Expert list
Gastrointestinal neuromuscular disease v1.0 Zornitza Stark promoted panel to version 1.0
Hirschsprung disease v0.17 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Hirschsprung disease; Arthrogryposis to Complex neurocristinopathy
Hirschsprung disease v0.16 ERBB3 Zornitza Stark Publications for gene: ERBB3 were set to 33720042
Hirschsprung disease v0.15 ERBB3 Zornitza Stark reviewed gene: ERBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33497358; Phenotypes: Complex neurocristinopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gastrointestinal neuromuscular disease v0.69 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Neurodevelopmental disorder with gut dysmotility to Complex neurocristinopathy
Gastrointestinal neuromuscular disease v0.68 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Changed phenotypes: Complex neurocristinopathy
Mendeliome v0.8574 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Changed phenotypes: Lethal congenital contractural syndrome 2, MIM# 607598, Complex neurocristinopathy
Mendeliome v0.8574 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Changed phenotypes: Complex neurocristinopathy
Mendeliome v0.8574 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Neurodevelopmental disorder with gut dysmotility to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Complex neurocristinopathy
Mendeliome v0.8573 ERBB3 Zornitza Stark changed review comment from: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.; to: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and other features of neurocristinopathy including short-segment HSCR, progressive axonal peripheral neuropathy, dysautonomia, hypopigmentation, deafness. Note variants in this gene have also recently been linked to Hirschsprung's disease.
Gastrointestinal neuromuscular disease v0.68 ERBB3 Zornitza Stark changed review comment from: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.
Sources: Literature; to: 6 individuals from 4 unrelated families reported with severe gut dysmotility and other features of neurocristinopathy including short-segment HSCR, progressive axonal peripheral neuropathy, dysautonomia, hypopigmentation, deafness. Note variants in this gene have also recently been linked to Hirschsprung's disease.
Sources: Literature
Mendeliome v0.8573 ERBB3 Zornitza Stark Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease; Arthrogryposis; Neurodevelopmental disorder with gut dysmotility
Mendeliome v0.8572 ERBB3 Zornitza Stark Publications for gene: ERBB3 were set to 17701904; 31752936; 33720042
Mendeliome v0.8571 ERBB3 Zornitza Stark changed review comment from: Two families reported with contractures, positional approach used in gene discovery (2007). Another family reported more recently with a multi-system disorder but without contractures.; to: Lethal congenital contractual syndrome: Two families reported with contractures, positional approach used in gene discovery (2007). Another family reported more recently with a multi-system disorder but without contractures.
Mendeliome v0.8571 ERBB3 Zornitza Stark edited their review of gene: ERBB3: Added comment: PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.; Changed rating: GREEN; Changed publications: 17701904, 31752936, 33497358; Changed phenotypes: Lethal congenital contractural syndrome 2, MIM# 607598, Neurodevelopmental disorder with gut dysmotility
Gastrointestinal neuromuscular disease v0.68 ERBB3 Zornitza Stark Marked gene: ERBB3 as ready
Gastrointestinal neuromuscular disease v0.68 ERBB3 Zornitza Stark Gene: erbb3 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.68 ERBB3 Zornitza Stark Classified gene: ERBB3 as Green List (high evidence)
Gastrointestinal neuromuscular disease v0.68 ERBB3 Zornitza Stark Gene: erbb3 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.67 ERBB3 Zornitza Stark gene: ERBB3 was added
gene: ERBB3 was added to Gastrointestinal neuromuscular disease. Sources: Literature
Mode of inheritance for gene: ERBB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERBB3 were set to 33497358
Phenotypes for gene: ERBB3 were set to Neurodevelopmental disorder with gut dysmotility
Review for gene: ERBB3 was set to GREEN
Added comment: 6 individuals from 4 unrelated families reported with severe gut dysmotility and neurodevelopmental disorder. Note variants in this gene have also recently been linked to Hirschsprung's disease.
Sources: Literature
Pulmonary Fibrosis_Interstitial Lung Disease v0.31 FLNA Zornitza Stark Marked gene: FLNA as ready
Pulmonary Fibrosis_Interstitial Lung Disease v0.31 FLNA Zornitza Stark Gene: flna has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.66 POLG Zornitza Stark Marked gene: POLG as ready
Gastrointestinal neuromuscular disease v0.66 POLG Zornitza Stark Gene: polg has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.66 POLG Zornitza Stark Phenotypes for gene: POLG were changed from Mitochondrial DNA depletion syndrome 4B (MNGIE type), 613662 to Mitochondrial DNA depletion syndrome 4A (Alpers type), MIM# 203700
Gastrointestinal neuromuscular disease v0.65 POLG Zornitza Stark Publications for gene: POLG were set to
Gastrointestinal neuromuscular disease v0.64 POLG Zornitza Stark reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 22006280; Phenotypes: Mitochondrial DNA depletion syndrome 4A (Alpers type), MIM# 203700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gastrointestinal neuromuscular disease v0.64 FLNA Zornitza Stark Publications for gene: FLNA were set to 17357080; 23037936; 33464596
Gastrointestinal neuromuscular disease v0.63 FLNA Zornitza Stark changed review comment from: Variants in FLNA cause a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, and intellectual disability.

At least 4 families reported with predominantly intestinal phenotype with dysmotility and obstruction +/- short bowel.; to: Variants in FLNA cause a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, and intellectual disability.

At least 6 families reported with predominantly intestinal phenotype with dysmotility and obstruction +/- short bowel.
Gastrointestinal neuromuscular disease v0.63 FLNA Zornitza Stark edited their review of gene: FLNA: Changed publications: 17357080, 23037936, 33464596, 20871226
Pulmonary Fibrosis_Interstitial Lung Disease v0.31 FLNA Zornitza Stark Classified gene: FLNA as Green List (high evidence)
Pulmonary Fibrosis_Interstitial Lung Disease v0.31 FLNA Zornitza Stark Gene: flna has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.30 FLNA Zornitza Stark gene: FLNA was added
gene: FLNA was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Literature
Mode of inheritance for gene: FLNA was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FLNA were set to 30547349
Phenotypes for gene: FLNA were set to Interstitial lung disease
Review for gene: FLNA was set to GREEN
Added comment: Variants in FLNA cause a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, and intellectual disability.

PMID 30547349 reviews 18 individuals with significant interstitial lung disease +/- other cardiac/neurological features.
Sources: Literature
Gastrointestinal neuromuscular disease v0.63 FLNA Zornitza Stark Marked gene: FLNA as ready
Gastrointestinal neuromuscular disease v0.63 FLNA Zornitza Stark Gene: flna has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.63 FLNA Zornitza Stark Phenotypes for gene: FLNA were changed from Periventricular heterotopia in males, seizures in females to Intestinal pseudoobstruction, neuronal, MIM# 300048; Congenital short bowel syndrome, MIM# 300048
Gastrointestinal neuromuscular disease v0.62 FLNA Zornitza Stark Publications for gene: FLNA were set to
Gastrointestinal neuromuscular disease v0.61 FLNA Zornitza Stark reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 17357080, 23037936, 33464596; Phenotypes: Intestinal pseudoobstruction, neuronal, MIM# 300048, Congenital short bowel syndrome, MIM# 300048; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Gastrointestinal neuromuscular disease v0.61 EDNRB Zornitza Stark Marked gene: EDNRB as ready
Gastrointestinal neuromuscular disease v0.61 EDNRB Zornitza Stark Gene: ednrb has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.61 EDNRB Zornitza Stark Phenotypes for gene: EDNRB were changed from Waardenburg syndrome w/pigmentary abnormalities to Waardenburg syndrome, type 4A, MIM# 277580
Gastrointestinal neuromuscular disease v0.60 EDNRB Zornitza Stark reviewed gene: EDNRB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Waardenburg syndrome, type 4A, MIM# 277580; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.8571 PDCL3 Zornitza Stark Marked gene: PDCL3 as ready
Mendeliome v0.8571 PDCL3 Zornitza Stark Gene: pdcl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8571 PDCL3 Zornitza Stark Classified gene: PDCL3 as Amber List (moderate evidence)
Mendeliome v0.8571 PDCL3 Zornitza Stark Gene: pdcl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8570 PDCL3 Zornitza Stark gene: PDCL3 was added
gene: PDCL3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PDCL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCL3 were set to 32621347
Phenotypes for gene: PDCL3 were set to Megacystis-microcolon
Review for gene: PDCL3 was set to AMBER
Added comment: Single publication (PMID 32621347): one family with two affected fetuses - one with megacystis and microcolon, and the other with megacystisis and bilateral diaphragmatic hernia (prune-belly phenotype). Compound het LOF variants in PDCL3 (one frameshift and one missense). Complete absence of PDLC3 expression demonstrated in one of the affected fetuses. No homozygous LOF PDCL3 variants in gnomAD. PCDL3 negatively modulates actin folding and is strongly expressed in smooth muscle of bladder and colon.
Sources: Expert Review
Gastrointestinal neuromuscular disease v0.60 PDCL3 Zornitza Stark Marked gene: PDCL3 as ready
Gastrointestinal neuromuscular disease v0.60 PDCL3 Zornitza Stark Gene: pdcl3 has been classified as Amber List (Moderate Evidence).
Gastrointestinal neuromuscular disease v0.60 PDCL3 Zornitza Stark Classified gene: PDCL3 as Amber List (moderate evidence)
Gastrointestinal neuromuscular disease v0.60 PDCL3 Zornitza Stark Gene: pdcl3 has been classified as Amber List (Moderate Evidence).
Gastrointestinal neuromuscular disease v0.59 RET Zornitza Stark Marked gene: RET as ready
Gastrointestinal neuromuscular disease v0.59 RET Zornitza Stark Gene: ret has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.59 RET Zornitza Stark Phenotypes for gene: RET were changed from {Hirschsprung disease, susceptibility to, 1}, 142623 to Central hypoventilation syndrome, congenital, MIM# 209880; Multiple endocrine neoplasia IIA, MIM# 171400; Multiple endocrine neoplasia IIB, MIM# 162300
Gastrointestinal neuromuscular disease v0.58 RET Zornitza Stark Mode of inheritance for gene: RET was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gastrointestinal neuromuscular disease v0.57 RET Zornitza Stark reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Central hypoventilation syndrome, congenital, MIM# 209880, Multiple endocrine neoplasia IIA, MIM# 171400, Multiple endocrine neoplasia IIB, MIM# 162300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8569 SGO1 Zornitza Stark Marked gene: SGO1 as ready
Mendeliome v0.8569 SGO1 Zornitza Stark Gene: sgo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8569 SGO1 Zornitza Stark Phenotypes for gene: SGO1 were changed from to Chronic atrial and intestinal dysrhythmia, MIM# 616201
Mendeliome v0.8568 SGO1 Zornitza Stark Publications for gene: SGO1 were set to
Mendeliome v0.8567 SGO1 Zornitza Stark Mode of inheritance for gene: SGO1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8566 SGO1 Zornitza Stark Classified gene: SGO1 as Amber List (moderate evidence)
Mendeliome v0.8566 SGO1 Zornitza Stark Gene: sgo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8565 SGO1 Zornitza Stark reviewed gene: SGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25282101; Phenotypes: Chronic atrial and intestinal dysrhythmia, MIM# 616201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mackenzie's Mission_Reproductive Carrier Screening v0.102 SGO1 Zornitza Stark reviewed gene: SGO1: Rating: RED; Mode of pathogenicity: None; Publications: 25282101; Phenotypes: Chronic atrial and intestinal dysrhythmia, MIM# 616201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gastrointestinal neuromuscular disease v0.57 SGO1 Zornitza Stark Marked gene: SGO1 as ready
Gastrointestinal neuromuscular disease v0.57 SGO1 Zornitza Stark Gene: sgo1 has been classified as Amber List (Moderate Evidence).
Gastrointestinal neuromuscular disease v0.57 SGO1 Zornitza Stark Phenotypes for gene: SGO1 were changed from Chronic atrial and intestinal dysrhythmia, 616201 to Chronic atrial and intestinal dysrhythmia, MIM# 616201
Gastrointestinal neuromuscular disease v0.56 SGO1 Zornitza Stark Publications for gene: SGO1 were set to
Gastrointestinal neuromuscular disease v0.55 SGO1 Zornitza Stark Classified gene: SGO1 as Amber List (moderate evidence)
Gastrointestinal neuromuscular disease v0.55 SGO1 Zornitza Stark Gene: sgo1 has been classified as Amber List (Moderate Evidence).
Gastrointestinal neuromuscular disease v0.54 SGO1 Zornitza Stark Tag founder tag was added to gene: SGO1.
Gastrointestinal neuromuscular disease v0.54 SGO1 Zornitza Stark changed review comment from: Single homozygous missense identified in 3 families, founder effect demonstrated by haplotype analysis. Functional data supports gene-disease association.; to: Single homozygous missense identified in 15 individuals, founder effect demonstrated by haplotype analysis. Functional data supports gene-disease association.
Gastrointestinal neuromuscular disease v0.54 SGO1 Zornitza Stark reviewed gene: SGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25282101; Phenotypes: Chronic atrial and intestinal dysrhythmia, MIM# 616201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gastrointestinal neuromuscular disease v0.54 SOX10 Zornitza Stark Marked gene: SOX10 as ready
Gastrointestinal neuromuscular disease v0.54 SOX10 Zornitza Stark Gene: sox10 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.54 SOX10 Zornitza Stark Mode of inheritance for gene: SOX10 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gastrointestinal neuromuscular disease v0.53 SOX10 Zornitza Stark Phenotypes for gene: SOX10 were changed from Waardenburg syndrome w/pigmentary abnormalities to PCWH syndrome, MIM# 609136
Gastrointestinal neuromuscular disease v0.52 SOX10 Zornitza Stark Publications for gene: SOX10 were set to
Gastrointestinal neuromuscular disease v0.51 SOX10 Zornitza Stark reviewed gene: SOX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 10762540, 10482261, 15004559; Phenotypes: PCWH syndrome, MIM# 609136; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8565 TYMP Zornitza Stark Marked gene: TYMP as ready
Mendeliome v0.8565 TYMP Zornitza Stark Gene: tymp has been classified as Green List (High Evidence).
Mendeliome v0.8565 TYMP Zornitza Stark Phenotypes for gene: TYMP were changed from to Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041; MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy
Mendeliome v0.8564 TYMP Zornitza Stark Publications for gene: TYMP were set to
Mendeliome v0.8563 TYMP Zornitza Stark Mode of inheritance for gene: TYMP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8562 TYMP Zornitza Stark reviewed gene: TYMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9924029, 14757860; Phenotypes: Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041, MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gastrointestinal neuromuscular disease v0.51 TYMP Zornitza Stark Marked gene: TYMP as ready
Gastrointestinal neuromuscular disease v0.51 TYMP Zornitza Stark Gene: tymp has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disease v0.51 TYMP Zornitza Stark Phenotypes for gene: TYMP were changed from MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy to Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041; MNGIE: ptosis, ophthalmoplegia & ophthalmoparesis, hearing loss, neuropathy
Gastrointestinal neuromuscular disease v0.50 TYMP Zornitza Stark Publications for gene: TYMP were set to
Gastrointestinal neuromuscular disease v0.49 TYMP Zornitza Stark reviewed gene: TYMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9924029, 14757860; Phenotypes: Mitochondrial DNA depletion syndrome 1 (MNGIE type), MIM# 603041; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8562 ZNF687 Zornitza Stark Marked gene: ZNF687 as ready
Mendeliome v0.8562 ZNF687 Zornitza Stark Gene: znf687 has been classified as Green List (High Evidence).
Mendeliome v0.8562 ZNF687 Zornitza Stark Phenotypes for gene: ZNF687 were changed from to Paget disease of bone 6, MIM#616833
Mendeliome v0.8561 ZNF687 Zornitza Stark Publications for gene: ZNF687 were set to
Mendeliome v0.8560 ZNF687 Zornitza Stark Mode of inheritance for gene: ZNF687 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8559 ZNF687 Zornitza Stark Tag founder tag was added to gene: ZNF687.
Mendeliome v0.8559 ZNF687 Zornitza Stark reviewed gene: ZNF687: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Paget disease of bone 6, MIM#616833; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8559 GRHPR Zornitza Stark Marked gene: GRHPR as ready
Mendeliome v0.8559 GRHPR Zornitza Stark Gene: grhpr has been classified as Green List (High Evidence).
Mendeliome v0.8559 GRHPR Zornitza Stark Phenotypes for gene: GRHPR were changed from to Hyperoxaluria, primary, type II, MIM# 260000; MONDO:0009824
Mendeliome v0.8558 GRHPR Zornitza Stark Publications for gene: GRHPR were set to
Mendeliome v0.8557 GRHPR Zornitza Stark Mode of inheritance for gene: GRHPR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8556 GRHPR Zornitza Stark reviewed gene: GRHPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 10484776, 11030416, 24116921; Phenotypes: Hyperoxaluria, primary, type II, MIM# 260000, MONDO:0009824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8556 AGXT Zornitza Stark Marked gene: AGXT as ready
Mendeliome v0.8556 AGXT Zornitza Stark Gene: agxt has been classified as Green List (High Evidence).
Mendeliome v0.8556 AGXT Zornitza Stark Phenotypes for gene: AGXT were changed from to Hyperoxaluria, primary, type 1, MIM# 259900; MONDO:0009823
Mendeliome v0.8555 AGXT Zornitza Stark Publications for gene: AGXT were set to
Mendeliome v0.8554 AGXT Zornitza Stark Mode of inheritance for gene: AGXT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8553 AGXT Zornitza Stark reviewed gene: AGXT: Rating: GREEN; Mode of pathogenicity: None; Publications: 2039493, 19479957; Phenotypes: Hyperoxaluria, primary, type 1, MIM# 259900, MONDO:0009823; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8553 HOGA1 Zornitza Stark Marked gene: HOGA1 as ready
Mendeliome v0.8553 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
Mendeliome v0.8553 HOGA1 Zornitza Stark Phenotypes for gene: HOGA1 were changed from to Hyperoxaluria, primary, type III MIM#613616
Mendeliome v0.8552 HOGA1 Zornitza Stark Publications for gene: HOGA1 were set to
Mendeliome v0.8551 HOGA1 Zornitza Stark Mode of inheritance for gene: HOGA1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8550 ZNF687 Ain Roesley reviewed gene: ZNF687: Rating: AMBER; Mode of pathogenicity: None; Publications: 26849110, 29493781, 32106343; Phenotypes: Paget disease of bone 6, MIM#616833; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.8550 HOGA1 Paul De Fazio reviewed gene: HOGA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20797690, 21896830, 22391140; Phenotypes: Hyperoxaluria, primary, type III MIM#613616; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Desmosomal disorders v0.8 DSC2 Zornitza Stark Marked gene: DSC2 as ready
Desmosomal disorders v0.8 DSC2 Zornitza Stark Gene: dsc2 has been classified as Green List (High Evidence).
Desmosomal disorders v0.8 DSC2 Zornitza Stark Phenotypes for gene: DSC2 were changed from to Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair, MIM# 610476
Desmosomal disorders v0.7 DSC2 Zornitza Stark Publications for gene: DSC2 were set to
Desmosomal disorders v0.6 DSC2 Zornitza Stark Mode of inheritance for gene: DSC2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Desmosomal disorders v0.5 DSC2 Zornitza Stark reviewed gene: DSC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18957847, 23863954; Phenotypes: Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair, MIM# 610476; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phagocyte Defects v1.0 Zornitza Stark promoted panel to version 1.0
Phagocyte Defects v0.136 SEC61A1 Zornitza Stark Marked gene: SEC61A1 as ready
Phagocyte Defects v0.136 SEC61A1 Zornitza Stark Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v0.136 MKL1 Zornitza Stark Marked gene: MKL1 as ready
Phagocyte Defects v0.136 MKL1 Zornitza Stark Gene: mkl1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v0.136 CXCR4 Zornitza Stark Marked gene: CXCR4 as ready
Phagocyte Defects v0.136 CXCR4 Zornitza Stark Gene: cxcr4 has been classified as Green List (High Evidence).
Phagocyte Defects v0.136 CXCR4 Zornitza Stark Phenotypes for gene: CXCR4 were changed from to WHIM syndrome 1, MIM# 193670
Phagocyte Defects v0.135 CXCR4 Zornitza Stark Publications for gene: CXCR4 were set to
Phagocyte Defects v0.134 CXCR4 Zornitza Stark Mode of inheritance for gene: CXCR4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phagocyte Defects v0.133 CXCR4 Zornitza Stark reviewed gene: CXCR4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12692554, 15536153, 23009155; Phenotypes: WHIM syndrome 1, MIM# 193670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phagocyte Defects v0.133 WAS Zornitza Stark Marked gene: WAS as ready
Phagocyte Defects v0.133 WAS Zornitza Stark Gene: was has been classified as Green List (High Evidence).
Phagocyte Defects v0.133 WAS Zornitza Stark Phenotypes for gene: WAS were changed from to Neutropaenia, severe congenital, X-linked, MIM# 300299
Phagocyte Defects v0.132 WAS Zornitza Stark Publications for gene: WAS were set to
Phagocyte Defects v0.131 WAS Zornitza Stark Mode of inheritance for gene: WAS was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phagocyte Defects v0.130 WAS Zornitza Stark reviewed gene: WAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 11242115, 16804117, 19006568; Phenotypes: Neutropaenia, severe congenital, X-linked, MIM# 300299; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phagocyte Defects v0.130 WIPF1 Zornitza Stark changed review comment from: Neutropaenia is not a prominent feature. Mostly experimental data linking to macrophage defects.; to: Neutropaenia is not a prominent feature. Mostly experimental data linking to macrophage defects. Gene is on multiple other, more appropriate immunology panels.
Phagocyte Defects v0.130 WIPF1 Zornitza Stark Marked gene: WIPF1 as ready
Phagocyte Defects v0.130 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v0.130 WIPF1 Zornitza Stark Phenotypes for gene: WIPF1 were changed from to Wiskott-Aldrich syndrome 2, MIM# 614493
Phagocyte Defects v0.129 WIPF1 Zornitza Stark Publications for gene: WIPF1 were set to
Phagocyte Defects v0.128 WIPF1 Zornitza Stark Mode of inheritance for gene: WIPF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.127 WIPF1 Zornitza Stark Classified gene: WIPF1 as Amber List (moderate evidence)
Phagocyte Defects v0.127 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v0.126 WIPF1 Zornitza Stark reviewed gene: WIPF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 17312144, 17890224; Phenotypes: Wiskott-Aldrich syndrome 2, MIM# 614493; Mode of inheritance: None
Mendeliome v0.8550 VPS45 Zornitza Stark Marked gene: VPS45 as ready
Mendeliome v0.8550 VPS45 Zornitza Stark Gene: vps45 has been classified as Green List (High Evidence).
Mendeliome v0.8550 VPS45 Zornitza Stark Phenotypes for gene: VPS45 were changed from to Neutropaenia, severe congenital, 5, autosomal recessive, MIM# 615285
Mendeliome v0.8549 VPS45 Zornitza Stark Publications for gene: VPS45 were set to
Mendeliome v0.8548 VPS45 Zornitza Stark Mode of inheritance for gene: VPS45 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8547 VPS45 Zornitza Stark reviewed gene: VPS45: Rating: GREEN; Mode of pathogenicity: None; Publications: 23738510, 23599270, 33623350, 32037586, 30294941; Phenotypes: Neutropaenia, severe congenital, 5, autosomal recessive, MIM# 615285; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.126 VPS45 Zornitza Stark Marked gene: VPS45 as ready
Phagocyte Defects v0.126 VPS45 Zornitza Stark Gene: vps45 has been classified as Green List (High Evidence).
Phagocyte Defects v0.126 VPS45 Zornitza Stark Phenotypes for gene: VPS45 were changed from to Neutropaenia, severe congenital, 5, autosomal recessive, MIM# 615285
Phagocyte Defects v0.125 VPS45 Zornitza Stark Publications for gene: VPS45 were set to
Phagocyte Defects v0.124 VPS45 Zornitza Stark Mode of inheritance for gene: VPS45 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.123 VPS45 Zornitza Stark reviewed gene: VPS45: Rating: GREEN; Mode of pathogenicity: None; Publications: 23738510, 23599270, 33623350, 32037586, 30294941; Phenotypes: Neutropaenia, severe congenital, 5, autosomal recessive, MIM# 615285; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.123 VPS13B Zornitza Stark Marked gene: VPS13B as ready
Phagocyte Defects v0.123 VPS13B Zornitza Stark Gene: vps13b has been classified as Green List (High Evidence).
Phagocyte Defects v0.123 VPS13B Zornitza Stark Phenotypes for gene: VPS13B were changed from to Cohen syndrome, MIM# 216550
Phagocyte Defects v0.122 VPS13B Zornitza Stark Mode of inheritance for gene: VPS13B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.121 VPS13B Zornitza Stark reviewed gene: VPS13B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cohen syndrome, MIM# 216550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.121 TAZ Zornitza Stark Marked gene: TAZ as ready
Phagocyte Defects v0.121 TAZ Zornitza Stark Gene: taz has been classified as Green List (High Evidence).
Phagocyte Defects v0.121 TAZ Zornitza Stark Phenotypes for gene: TAZ were changed from to Barth syndrome, MIM# 302060
Phagocyte Defects v0.120 TAZ Zornitza Stark Mode of inheritance for gene: TAZ was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phagocyte Defects v0.119 TAZ Zornitza Stark reviewed gene: TAZ: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Barth syndrome, MIM# 302060; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phagocyte Defects v0.119 SLC37A4 Zornitza Stark Marked gene: SLC37A4 as ready
Phagocyte Defects v0.119 SLC37A4 Zornitza Stark Gene: slc37a4 has been classified as Green List (High Evidence).
Phagocyte Defects v0.119 SLC37A4 Zornitza Stark Phenotypes for gene: SLC37A4 were changed from to Glycogen storage disease Ib, MIM# 232220
Phagocyte Defects v0.118 SLC37A4 Zornitza Stark Mode of inheritance for gene: SLC37A4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.117 SLC37A4 Zornitza Stark reviewed gene: SLC37A4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycogen storage disease Ib, MIM# 232220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.117 NCF4 Zornitza Stark Marked gene: NCF4 as ready
Phagocyte Defects v0.117 NCF4 Zornitza Stark Gene: ncf4 has been classified as Green List (High Evidence).
Phagocyte Defects v0.117 NCF4 Zornitza Stark Phenotypes for gene: NCF4 were changed from to Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type III MIM#613960
Phagocyte Defects v0.116 NCF4 Zornitza Stark Publications for gene: NCF4 were set to
Phagocyte Defects v0.115 NCF4 Zornitza Stark Mode of inheritance for gene: NCF4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.114 NCF2 Zornitza Stark Marked gene: NCF2 as ready
Phagocyte Defects v0.114 NCF2 Zornitza Stark Gene: ncf2 has been classified as Green List (High Evidence).
Phagocyte Defects v0.114 NCF2 Zornitza Stark Phenotypes for gene: NCF2 were changed from to Chronic granulomatous disease 2, autosomal recessive, MIM# 233710
Phagocyte Defects v0.113 NCF2 Zornitza Stark Publications for gene: NCF2 were set to
Phagocyte Defects v0.112 NCF2 Zornitza Stark Mode of inheritance for gene: NCF2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.111 SLC35C1 Zornitza Stark Marked gene: SLC35C1 as ready
Phagocyte Defects v0.111 SLC35C1 Zornitza Stark Gene: slc35c1 has been classified as Green List (High Evidence).
Phagocyte Defects v0.111 SLC35C1 Zornitza Stark Phenotypes for gene: SLC35C1 were changed from to Congenital disorder of glycosylation, type IIc, MIM# 266265, MONDO:0009953
Phagocyte Defects v0.110 SLC35C1 Zornitza Stark Publications for gene: SLC35C1 were set to
Phagocyte Defects v0.109 SLC35C1 Zornitza Stark Mode of inheritance for gene: SLC35C1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.108 SBDS Zornitza Stark Marked gene: SBDS as ready
Phagocyte Defects v0.108 SBDS Zornitza Stark Gene: sbds has been classified as Green List (High Evidence).
Phagocyte Defects v0.108 SBDS Zornitza Stark Phenotypes for gene: SBDS were changed from to Shwachman-Diamond syndrome, MIM# 260400
Phagocyte Defects v0.107 SBDS Zornitza Stark Mode of inheritance for gene: SBDS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.106 SBDS Zornitza Stark reviewed gene: SBDS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Shwachman-Diamond syndrome, MIM# 260400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8547 LAMTOR2 Zornitza Stark Marked gene: LAMTOR2 as ready
Mendeliome v0.8547 LAMTOR2 Zornitza Stark Gene: lamtor2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8547 LAMTOR2 Zornitza Stark Phenotypes for gene: LAMTOR2 were changed from to Immunodeficiency due to defect in MAPBP-interacting protein, MIM# 610798
Mendeliome v0.8546 LAMTOR2 Zornitza Stark Publications for gene: LAMTOR2 were set to
Mendeliome v0.8545 LAMTOR2 Zornitza Stark Mode of inheritance for gene: LAMTOR2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8544 LAMTOR2 Zornitza Stark Classified gene: LAMTOR2 as Amber List (moderate evidence)
Mendeliome v0.8544 LAMTOR2 Zornitza Stark Gene: lamtor2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8543 LAMTOR2 Zornitza Stark reviewed gene: LAMTOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 17195838, 24092934; Phenotypes: Immunodeficiency due to defect in MAPBP-interacting protein, MIM# 610798; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.106 LAMTOR2 Zornitza Stark Marked gene: LAMTOR2 as ready
Phagocyte Defects v0.106 LAMTOR2 Zornitza Stark Gene: lamtor2 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v0.106 LAMTOR2 Zornitza Stark Phenotypes for gene: LAMTOR2 were changed from to Immunodeficiency due to defect in MAPBP-interacting protein, MIM# 610798
Phagocyte Defects v0.105 LAMTOR2 Zornitza Stark Publications for gene: LAMTOR2 were set to
Phagocyte Defects v0.104 LAMTOR2 Zornitza Stark Mode of inheritance for gene: LAMTOR2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.103 LAMTOR2 Zornitza Stark Classified gene: LAMTOR2 as Amber List (moderate evidence)
Phagocyte Defects v0.103 LAMTOR2 Zornitza Stark Gene: lamtor2 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v0.102 LAMTOR2 Zornitza Stark reviewed gene: LAMTOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 17195838, 24092934; Phenotypes: Immunodeficiency due to defect in MAPBP-interacting protein, MIM# 610798; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8543 IKZF3 Zornitza Stark Marked gene: IKZF3 as ready
Mendeliome v0.8543 IKZF3 Zornitza Stark Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8543 IKZF3 Zornitza Stark Classified gene: IKZF3 as Amber List (moderate evidence)
Mendeliome v0.8543 IKZF3 Zornitza Stark Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v0.251 IKZF3 Zornitza Stark Marked gene: IKZF3 as ready
Combined Immunodeficiency v0.251 IKZF3 Zornitza Stark Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8542 IKZF3 Zornitza Stark gene: IKZF3 was added
gene: IKZF3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IKZF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKZF3 were set to 34155405
Phenotypes for gene: IKZF3 were set to Immunodeficiency 84, MIM# 619437
Review for gene: IKZF3 was set to AMBER
Added comment: Single family reported where heterozygous missense variant in this gene segregated with immunodeficiency in a mother and two children. Findings included low levels of B cells and impaired early B-cell development, variable T-cell abnormalities, hypogammaglobulinaemia, increased susceptibility to infection with Epstein-Barr virus (EBV). One individual developed lymphoma in adulthood. Mouse model recapitulated phenotype.
Sources: Expert Review
Combined Immunodeficiency v0.251 IKZF3 Zornitza Stark Classified gene: IKZF3 as Amber List (moderate evidence)
Combined Immunodeficiency v0.251 IKZF3 Zornitza Stark Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v0.250 IKZF3 Zornitza Stark Classified gene: IKZF3 as Amber List (moderate evidence)
Combined Immunodeficiency v0.250 IKZF3 Zornitza Stark Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v0.249 IKZF3 Zornitza Stark gene: IKZF3 was added
gene: IKZF3 was added to Combined Immunodeficiency. Sources: Literature
Mode of inheritance for gene: IKZF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKZF3 were set to 34155405
Phenotypes for gene: IKZF3 were set to Immunodeficiency 84, MIM# 619437
Review for gene: IKZF3 was set to AMBER
Added comment: Single family reported where heterozygous missense variant in this gene segregated with immunodeficiency in a mother and two children. Findings included low levels of B cells and impaired early B-cell development, variable T-cell abnormalities, hypogammaglobulinaemia, increased susceptibility to infection with Epstein-Barr virus (EBV). One individual developed lymphoma in adulthood.

Mouse model recapitulated phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4006 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Intellectual disability syndromic and non-syndromic v0.4006 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4006 HSD17B4 Zornitza Stark Phenotypes for gene: HSD17B4 were changed from to D-bifunctional protein deficiency, AR (MIM#261515); Perrault syndrome 1, AR (MIM#233400)
Intellectual disability syndromic and non-syndromic v0.4005 HSD17B4 Zornitza Stark Publications for gene: HSD17B4 were set to
Intellectual disability syndromic and non-syndromic v0.4004 HSD17B4 Zornitza Stark Mode of inheritance for gene: HSD17B4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4003 HSD17B4 Zornitza Stark reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27790638; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Peroxisomal Disorders v0.23 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Peroxisomal Disorders v0.23 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Peroxisomal Disorders v0.23 HSD17B4 Zornitza Stark Phenotypes for gene: HSD17B4 were changed from to D-bifunctional protein deficiency, AR (MIM#261515); Perrault syndrome 1, AR (MIM#233400)
Peroxisomal Disorders v0.22 HSD17B4 Zornitza Stark Publications for gene: HSD17B4 were set to
Peroxisomal Disorders v0.21 HSD17B4 Zornitza Stark Mode of inheritance for gene: HSD17B4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Peroxisomal Disorders v0.20 HSD17B4 Zornitza Stark reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27790638; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8541 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Mendeliome v0.8541 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Mendeliome v0.8541 HSD17B4 Zornitza Stark Phenotypes for gene: HSD17B4 were changed from to D-bifunctional protein deficiency, AR (MIM#261515); Perrault syndrome 1, AR (MIM#233400)
Mendeliome v0.8540 HSD17B4 Zornitza Stark Publications for gene: HSD17B4 were set to
Mendeliome v0.8539 HSD17B4 Zornitza Stark Mode of inheritance for gene: HSD17B4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8538 HSD17B4 Zornitza Stark reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8538 HSD17B4 Michelle Torres reviewed gene: HSD17B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27790638; Phenotypes: D-bifunctional protein deficiency, AR (MIM#261515), Perrault syndrome 1, AR (MIM#233400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8538 LCK Zornitza Stark Marked gene: LCK as ready
Mendeliome v0.8538 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v0.248 ICOS Zornitza Stark Marked gene: ICOS as ready
Combined Immunodeficiency v0.248 ICOS Zornitza Stark Gene: icos has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.248 ICOS Zornitza Stark Phenotypes for gene: ICOS were changed from to Immunodeficiency, common variable, 1 MIM# 607594; recurrent bacterial respiratory/gastrointestinal infections; autoimmunity; gastroenteritis; low IgG/IgA; normal-low IgM; hypogammaglobulinaemia; low-normal B-cells; normal T-cells; Bronchitis; Lymphadenopathy; Hepatomegaly; Diarrhoea
Combined Immunodeficiency v0.247 ICOS Zornitza Stark Publications for gene: ICOS were set to
Combined Immunodeficiency v0.246 ICOS Zornitza Stark Mode of inheritance for gene: ICOS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.245 ICOS Zornitza Stark Tag SV/CNV tag was added to gene: ICOS.
Mendeliome v0.8538 LCK Zornitza Stark Phenotypes for gene: LCK were changed from to Immunodeficiency 22 MIM# 615758; Recurrent infections; Immune dysregulation; autoimmunity; Low CD4+; low CD8+; restricted T cell repertoire; poor TCR signaling; Normal IgG/IgA; high IgM; failure to thrive; diarrhoea; lymphopaenia; hypogammaglobulinaemia; anaemia; thrombocytopaenia; CD4+ T-cell lymphopaenia
Mendeliome v0.8537 LCK Zornitza Stark Publications for gene: LCK were set to
Mendeliome v0.8536 LCK Zornitza Stark Mode of inheritance for gene: LCK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8535 LCK Zornitza Stark Classified gene: LCK as Amber List (moderate evidence)
Mendeliome v0.8535 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8534 LCK Zornitza Stark Classified gene: LCK as Amber List (moderate evidence)
Mendeliome v0.8534 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v0.245 LCK Zornitza Stark Marked gene: LCK as ready
Combined Immunodeficiency v0.245 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8533 LCK Zornitza Stark reviewed gene: LCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22985903, 1579166, 11021796; Phenotypes: Immunodeficiency 22 MIM# 615758, Recurrent infections, Immune dysregulation, autoimmunity, Low CD4+, low CD8+, restricted T cell repertoire, poor TCR signaling, Normal IgG/IgA, high IgM, failure to thrive, diarrhoea, lymphopenia, hypogammaglobulinemia, anaemia, thrombocytopaenia, CD4+ T-cell lymphopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.245 LCK Zornitza Stark Phenotypes for gene: LCK were changed from to Immunodeficiency 22 MIM# 615758; Recurrent infections; Immune dysregulation; autoimmunity; Low CD4+; low CD8+; restricted T cell repertoire; poor TCR signaling; Normal IgG/IgA; high IgM; failure to thrive; diarrhoea; lymphopenia; hypogammaglobulinemia; anaemia; thrombocytopaenia; CD4+ T-cell lymphopenia
Combined Immunodeficiency v0.244 LCK Zornitza Stark Publications for gene: LCK were set to
Combined Immunodeficiency v0.243 LCK Zornitza Stark Mode of inheritance for gene: LCK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8533 DOCK8 Zornitza Stark Marked gene: DOCK8 as ready
Mendeliome v0.8533 DOCK8 Zornitza Stark Gene: dock8 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.242 LCK Zornitza Stark Classified gene: LCK as Amber List (moderate evidence)
Combined Immunodeficiency v0.242 LCK Zornitza Stark Gene: lck has been classified as Amber List (Moderate Evidence).
Mendeliome v0.8533 DOCK8 Zornitza Stark Phenotypes for gene: DOCK8 were changed from to Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700; T cell Lymphopaenia; decraese T/B/NK cells; Eosinophilia; low IgM; elevated IgE; recurrent cutaneous/ viral/ bacterial/ fungal/ infections; severe atopy/allergic disease; autoimmune haemolytic anaemia; eczema; cancer diathesis
Mendeliome v0.8532 DOCK8 Zornitza Stark Publications for gene: DOCK8 were set to
Combined Immunodeficiency v0.241 DOCK8 Zornitza Stark Marked gene: DOCK8 as ready
Combined Immunodeficiency v0.241 DOCK8 Zornitza Stark Gene: dock8 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.241 DOCK8 Zornitza Stark Phenotypes for gene: DOCK8 were changed from to Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700; T cell Lymphopaenia; decraese T/B/NK cells; Eosinophilia; low IgM; elevated IgE; recurrent cutaneous/ viral/ bacterial/ fungal/ infections; severe atopy/allergic disease; autoimmune haemolytic anaemia; eczema; cancer diathesis
Mendeliome v0.8531 DOCK8 Zornitza Stark Mode of inheritance for gene: DOCK8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.240 DOCK8 Zornitza Stark Publications for gene: DOCK8 were set to
Mendeliome v0.8530 DOCK2 Zornitza Stark Marked gene: DOCK2 as ready
Mendeliome v0.8530 DOCK2 Zornitza Stark Gene: dock2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.239 DOCK8 Zornitza Stark Mode of inheritance for gene: DOCK8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8530 DOCK2 Zornitza Stark Phenotypes for gene: DOCK2 were changed from to Immunodeficiency 40 MIM# 616433; T/B-cell lymphopaenia; early-onset invasive herpes/viral/bacterial Infections; function defects in T/B/NK cells; immunodeficiency; defective IFN-mediated immunity; elevated IgM; normal IgG/IgA levels
Mendeliome v0.8529 DOCK2 Zornitza Stark Publications for gene: DOCK2 were set to
Mendeliome v0.8528 DOCK2 Zornitza Stark Mode of inheritance for gene: DOCK2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8527 DOCK2 Zornitza Stark reviewed gene: DOCK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26083206, 29204803, 33928462, 30826364, 30838481, 11518968; Phenotypes: Immunodeficiency 40 MIM# 616433, T/B-cell lymphopaenia, early-onset invasive herpes/viral/bacterial Infections, function defects in T/B/NK cells, immunodeficiency, defective IFN-mediated immunity, elevated IgM, normal IgG/IgA levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8527 DOCK8 Danielle Ariti reviewed gene: DOCK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 19776401, 20622910, 21931011, 26659092, 19898472, 25422492; Phenotypes: Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700, T cell Lymphopaenia, decraese T/B/NK cells, Eosinophilia, low IgM, elevated IgE, recurrent cutaneous/ viral/ bacterial/ fungal/ infections, severe atopy/allergic disease, autoimmune haemolytic anaemia, eczema, cancer diathesisc; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.238 DOCK2 Zornitza Stark Marked gene: DOCK2 as ready
Combined Immunodeficiency v0.238 DOCK2 Zornitza Stark Gene: dock2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.238 DOCK2 Zornitza Stark Phenotypes for gene: DOCK2 were changed from to Immunodeficiency 40 MIM# 616433; T/B-cell lymphopaenia; early-onset invasive herpes/viral/bacterial Infections; function defects in T/B/NK cells; immunodeficiency; defective IFN-mediated immunity; elevated IgM; normal IgG/IgA levels
Combined Immunodeficiency v0.237 DOCK2 Zornitza Stark Publications for gene: DOCK2 were set to
Combined Immunodeficiency v0.236 DOCK2 Zornitza Stark Mode of inheritance for gene: DOCK2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8527 DNMT3B Zornitza Stark Marked gene: DNMT3B as ready
Mendeliome v0.8527 DNMT3B Zornitza Stark Gene: dnmt3b has been classified as Green List (High Evidence).
Mendeliome v0.8527 DNMT3B Zornitza Stark Phenotypes for gene: DNMT3B were changed from to Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860; facial dysmorphic features; flat nasal bridge; developmental delay; macroglossia; bacterial/opportunistic infections (recurrent); malabsorption; cytopaenia; malignancies; multiradial configurations of chromosomes 1, 9, 16; Hypogammaglobulinaemia; agammaglobulinaemia; variable antibody deficiency; decreased immunoglobulin production; low T/B/NK cells
Predominantly Antibody Deficiency v0.68 DNMT3B Danielle Ariti reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: mmunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8526 DNMT3B Zornitza Stark Publications for gene: DNMT3B were set to
Mendeliome v0.8525 DNMT3B Zornitza Stark Mode of inheritance for gene: DNMT3B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8524 DNMT3B Zornitza Stark reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.235 DNMT3B Zornitza Stark Marked gene: DNMT3B as ready
Combined Immunodeficiency v0.235 DNMT3B Zornitza Stark Gene: dnmt3b has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.235 DNMT3B Zornitza Stark Phenotypes for gene: DNMT3B were changed from to Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860; facial dysmorphic features; flat nasal bridge; developmental delay; macroglossia; bacterial/opportunistic infections (recurrent); malabsorption; cytopaenia; malignancies; multiradial configurations of chromosomes 1, 9, 16; Hypogammaglobulinaemia; agammaglobulinaemia; variable antibody deficiency; decreased immunoglobulin production; low T/B/NK cells
Combined Immunodeficiency v0.234 DNMT3B Zornitza Stark Publications for gene: DNMT3B were set to
Combined Immunodeficiency v0.233 DNMT3B Zornitza Stark Mode of inheritance for gene: DNMT3B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.232 ICOS Danielle Ariti changed review comment from: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models.

Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion.

Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA. However, phenotypic expression is highly variable, with some individuals only displaying immunological phenotypes.; to: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models.

Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion.

Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA. However, phenotypic expression is highly variable, with some individuals only displaying immunological phenotypes.
Combined Immunodeficiency v0.232 ICOS Danielle Ariti reviewed gene: ICOS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12577056, 15507387, 19380800, 28861081, 31858365, 11343122, 16982935; Phenotypes: Immunodeficiency, common variable, 1 MIM# 607594, recurrent bacterial respiratory/gastrointestinal infections, autoimmunity, gastroenteritis, low IgG/IgA, normal-low IgM, hypogammaglobulinaemia, low-normal B-cells, normal T-cells, Bronchitis, Lymphadenopathy, Hepatomegaly, Diarrhoea; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.232 LCK Danielle Ariti reviewed gene: LCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22985903, 1579166, 11021796; Phenotypes: Immunodeficiency 22 MIM# 615758, Recurrent infections, Immune dysregulation, autoimmunity, Low CD4+, low CD8+, restricted T cell repertoire, poor TCR signaling, Normal IgG/IgA, high IgM, failure to thrive, diarrhoea, lymphopenia, hypogammaglobulinemia, anaemia, thrombocytopaenia, CD4+ T-cell lymphopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.232 DOCK8 Danielle Ariti reviewed gene: DOCK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 19776401, 20622910, 21931011, 26659092, 19898472, 25422492; Phenotypes: Hyper-IgE recurrent infection syndrome, autosomal recessive MIM# 243700, T cell Lymphopaenia, decraese T/B/NK cells, Eosinophilia, low IgM, elevated IgE, recurrent cutaneous/ viral/ bacterial/ fungal/ infections, severe atopy/allergic disease, autoimmune haemolytic anaemia, eczema, cancer diathesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.232 DOCK2 Danielle Ariti reviewed gene: DOCK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26083206, 29204803, 33928462, 30826364, 30838481, 11518968; Phenotypes: Immunodeficiency 40 MIM# 616433, T/B-cell lymphopaenia, early-onset invasive herpes/viral/bacterial Infections, function defects in T/B/NK cells, immunodeficiency, defective IFN-mediated immunity, elevated IgM, normal IgG/IgA levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8524 TMPO Bryony Thompson Marked gene: TMPO as ready
Mendeliome v0.8524 TMPO Bryony Thompson Gene: tmpo has been classified as Red List (Low Evidence).
Mendeliome v0.8524 TMPO Bryony Thompson Classified gene: TMPO as Red List (low evidence)
Mendeliome v0.8524 TMPO Bryony Thompson Gene: tmpo has been classified as Red List (Low Evidence).
Mendeliome v0.8523 TMPO Bryony Thompson reviewed gene: TMPO: Rating: RED; Mode of pathogenicity: None; Publications: 16247757; Phenotypes: Hypertrophic cardiomyopathy, dilated cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8523 SYNCRIP Zornitza Stark Marked gene: SYNCRIP as ready
Mendeliome v0.8523 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Mendeliome v0.8523 SYNCRIP Zornitza Stark Classified gene: SYNCRIP as Green List (high evidence)
Mendeliome v0.8523 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Mendeliome v0.8522 SYNCRIP Zornitza Stark gene: SYNCRIP was added
gene: SYNCRIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to GREEN
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

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

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

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

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

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

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

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

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

There are no additional studies performed.

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

Animal models are not discussed.

There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Marked gene: SYNCRIP as ready
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Classified gene: SYNCRIP as Amber List (moderate evidence)
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Marked gene: SYNCRIP as ready
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Added comment: Comment when marking as ready: Sufficient cases for Green rating on ID panel.
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Classified gene: SYNCRIP as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4003 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Green List (High Evidence).
Combined Immunodeficiency v0.232 DNMT3B Danielle Ariti reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v0.232 CD3G Danielle Ariti changed review comment from: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models.

All individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features, whilst other CD3G-deficient individuals were in healthy condition decades into life. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins.; to: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models.

All individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features, whilst other CD3G- deficient individuals only display immunological phenotype and no other features. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins.
Combined Immunodeficiency v0.232 CD27 Danielle Ariti changed review comment from: 17 affected individuals from 9 unrelated families; homozygous (missense) and compound heterozygous (missense/ nonsense) variants identified in CD27; one mouse model

Affected individuals present with varied phenotypes (even within the same families); most commonly with lymphadenopathy, fever, hepatosplenomegaly, EBV-related infections, and immunodeficiency associated with hypogammaglobulinaemia. However, some CD27-deficient individuals are asymptomatic or display borderline-low hypogammaglobulinaemia.; to: 17 affected individuals from 9 unrelated families; homozygous (missense) and compound heterozygous (missense/ nonsense) variants identified in CD27; one mouse model

Affected individuals present with varied phenotypes (even within the same families); most commonly with lymphadenopathy, fever, hepatosplenomegaly, EBV-related infections, and immunodeficiency associated with hypogammaglobulinaemia. However, some CD27-deficient individuals are asymptomatic-borderline low hypogammaglobulinaemia.
Intellectual disability syndromic and non-syndromic v0.4002 SYNCRIP Konstantinos Varvagiannis gene: SYNCRIP was added
gene: SYNCRIP was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to AMBER
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

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

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

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

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

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

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

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

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

There are no additional studies performed.

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

Animal models are not discussed.

There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Genetic Epilepsy v0.1148 SYNCRIP Konstantinos Varvagiannis gene: SYNCRIP was added
gene: SYNCRIP was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to AMBER
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

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

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

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

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

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

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

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

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

There are no additional studies performed.

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

Animal models are not discussed.

There is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Phagocyte Defects v0.102 NCF1 Zornitza Stark Marked gene: NCF1 as ready
Phagocyte Defects v0.102 NCF1 Zornitza Stark Gene: ncf1 has been classified as Green List (High Evidence).
Phagocyte Defects v0.102 NCF1 Zornitza Stark Phenotypes for gene: NCF1 were changed from to Chronic granulomatous disease 1, autosomal recessive, MIM# 233700
Phagocyte Defects v0.101 NCF1 Zornitza Stark Publications for gene: NCF1 were set to
Phagocyte Defects v0.100 NCF1 Zornitza Stark Mode of inheritance for gene: NCF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8521 MSN Zornitza Stark Marked gene: MSN as ready
Mendeliome v0.8521 MSN Zornitza Stark Gene: msn has been classified as Green List (High Evidence).
Mendeliome v0.8521 MSN Zornitza Stark Phenotypes for gene: MSN were changed from to Immunodeficiency 50, MIM# 300988
Mendeliome v0.8520 MSN Zornitza Stark Publications for gene: MSN were set to
Mendeliome v0.8519 MSN Zornitza Stark Mode of inheritance for gene: MSN was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8518 MSN Zornitza Stark reviewed gene: MSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 27405666; Phenotypes: Immunodeficiency 50, MIM# 300988; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phagocyte Defects v0.99 MSN Zornitza Stark Marked gene: MSN as ready
Phagocyte Defects v0.99 MSN Zornitza Stark Gene: msn has been classified as Green List (High Evidence).
Phagocyte Defects v0.99 MSN Zornitza Stark changed review comment from: Seven males from five unrelated families reported.
Sources: Expert list; to: Seven males from five unrelated families reported. Profound lymphopaenia, fluctuating neutropaenia.
Sources: Expert list
Mendeliome v0.8518 JAGN1 Zornitza Stark Marked gene: JAGN1 as ready
Mendeliome v0.8518 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
Mendeliome v0.8518 JAGN1 Zornitza Stark Phenotypes for gene: JAGN1 were changed from to Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022
Mendeliome v0.8517 JAGN1 Zornitza Stark Publications for gene: JAGN1 were set to
Mendeliome v0.8516 JAGN1 Zornitza Stark Mode of inheritance for gene: JAGN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8515 JAGN1 Zornitza Stark reviewed gene: JAGN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25129144; Phenotypes: Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.99 JAGN1 Zornitza Stark Marked gene: JAGN1 as ready
Phagocyte Defects v0.99 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
Phagocyte Defects v0.99 JAGN1 Zornitza Stark Phenotypes for gene: JAGN1 were changed from to Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022
Phagocyte Defects v0.98 JAGN1 Zornitza Stark Publications for gene: JAGN1 were set to
Phagocyte Defects v0.97 JAGN1 Zornitza Stark Mode of inheritance for gene: JAGN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.96 JAGN1 Zornitza Stark reviewed gene: JAGN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25129144; Phenotypes: Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8515 ITGB2 Zornitza Stark Marked gene: ITGB2 as ready
Mendeliome v0.8515 ITGB2 Zornitza Stark Gene: itgb2 has been classified as Green List (High Evidence).
Mendeliome v0.8515 ITGB2 Zornitza Stark Phenotypes for gene: ITGB2 were changed from to Leukocyte adhesion deficiency, MIM# 116920
Mendeliome v0.8514 ITGB2 Zornitza Stark Publications for gene: ITGB2 were set to
Mendeliome v0.8513 ITGB2 Zornitza Stark Mode of inheritance for gene: ITGB2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8512 ITGB2 Zornitza Stark reviewed gene: ITGB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1968911, 1694220, 33957747, 32279896, 31374327; Phenotypes: Leukocyte adhesion deficiency, MIM# 116920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.96 ITGB2 Zornitza Stark Marked gene: ITGB2 as ready
Phagocyte Defects v0.96 ITGB2 Zornitza Stark Gene: itgb2 has been classified as Green List (High Evidence).
Phagocyte Defects v0.96 ITGB2 Zornitza Stark Phenotypes for gene: ITGB2 were changed from to Leukocyte adhesion deficiency, MIM# 116920
Phagocyte Defects v0.95 ITGB2 Zornitza Stark Publications for gene: ITGB2 were set to
Phagocyte Defects v0.94 ITGB2 Zornitza Stark Mode of inheritance for gene: ITGB2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.93 ITGB2 Zornitza Stark reviewed gene: ITGB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1968911, 1694220, 33957747, 32279896, 31374327; Phenotypes: Leukocyte adhesion deficiency, MIM# 116920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8512 NLRP2 Melanie Marty commented on gene: NLRP2
Phagocyte Defects v0.93 GATA2 Zornitza Stark Marked gene: GATA2 as ready
Phagocyte Defects v0.93 GATA2 Zornitza Stark Gene: gata2 has been classified as Green List (High Evidence).
Phagocyte Defects v0.93 GATA2 Zornitza Stark Phenotypes for gene: GATA2 were changed from to Emberger syndrome, MIM# 614038
Phagocyte Defects v0.92 GATA2 Zornitza Stark Publications for gene: GATA2 were set to
Phagocyte Defects v0.91 GATA2 Zornitza Stark Mode of inheritance for gene: GATA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phagocyte Defects v0.90 GATA2 Zornitza Stark edited their review of gene: GATA2: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phagocyte Defects v0.90 GATA2 Zornitza Stark reviewed gene: GATA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26710799; Phenotypes: Emberger syndrome, MIM# 614038; Mode of inheritance: None
Dystonia and Chorea v0.188 CAMK4 Zornitza Stark edited their review of gene: CAMK4: Changed phenotypes: Intellectual disability, Autism, Behavioral abnormality, Abnormality of movement, Dystonia, Ataxia, Chorea, Myoclonus
Dystonia and Chorea v0.188 CAMK4 Zornitza Stark Marked gene: CAMK4 as ready
Dystonia and Chorea v0.188 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Dystonia and Chorea v0.188 CAMK4 Zornitza Stark Phenotypes for gene: CAMK4 were changed from 30262571; 33098801; 33211350 to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Dystonia and Chorea v0.187 CAMK4 Zornitza Stark Classified gene: CAMK4 as Green List (high evidence)
Dystonia and Chorea v0.187 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Dystonia and Chorea v0.186 CAMK4 Zornitza Stark gene: CAMK4 was added
gene: CAMK4 was added to Dystonia - complex. Sources: Expert Review
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to 30262571; 33098801; 33211350
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

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

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

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

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

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

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

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

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

---

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

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

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

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

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

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

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

----

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

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).
Sources: Expert Review
Mendeliome v0.8512 CAMK4 Zornitza Stark Marked gene: CAMK4 as ready
Mendeliome v0.8512 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Mendeliome v0.8512 CAMK4 Zornitza Stark Classified gene: CAMK4 as Green List (high evidence)
Mendeliome v0.8512 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Mendeliome v0.8511 CAMK4 Zornitza Stark gene: CAMK4 was added
gene: CAMK4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

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

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

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

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

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

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

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

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

---

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

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

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

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

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

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

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

----

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

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Marked gene: CAMK4 as ready
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Classified gene: CAMK4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4002 CAMK4 Zornitza Stark Gene: camk4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4001 CAMK4 Konstantinos Varvagiannis gene: CAMK4 was added
gene: CAMK4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature,Other
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Penetrance for gene: CAMK4 were set to Complete
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

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

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

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

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

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

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

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

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

---

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

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

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

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

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

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

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

----

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

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).

----

There is no associated phenotype in OMIM, G2P.

In SysID CAMK4 is listed among the current primary ID genes.

----

Please consider inclusion in other relevant panels.
Sources: Literature, Other
Mendeliome v0.8510 FERMT3 Zornitza Stark Marked gene: FERMT3 as ready
Mendeliome v0.8510 FERMT3 Zornitza Stark Gene: fermt3 has been classified as Green List (High Evidence).
Mendeliome v0.8510 FERMT3 Zornitza Stark Phenotypes for gene: FERMT3 were changed from to Leukocyte adhesion deficiency, type III, MIM# 612840
Mendeliome v0.8509 FERMT3 Zornitza Stark Publications for gene: FERMT3 were set to
Mendeliome v0.8508 FERMT3 Zornitza Stark Mode of inheritance for gene: FERMT3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8507 FERMT3 Zornitza Stark reviewed gene: FERMT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234460, 19064721; Phenotypes: Leukocyte adhesion deficiency, type III, MIM# 612840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.90 FERMT3 Zornitza Stark Marked gene: FERMT3 as ready
Phagocyte Defects v0.90 FERMT3 Zornitza Stark Gene: fermt3 has been classified as Green List (High Evidence).
Phagocyte Defects v0.90 FERMT3 Zornitza Stark Phenotypes for gene: FERMT3 were changed from to Leukocyte adhesion deficiency, type III, MIM# 612840
Phagocyte Defects v0.89 FERMT3 Zornitza Stark Publications for gene: FERMT3 were set to
Phagocyte Defects v0.88 FERMT3 Zornitza Stark Mode of inheritance for gene: FERMT3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.87 FERMT3 Zornitza Stark reviewed gene: FERMT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234460, 19064721; Phenotypes: Leukocyte adhesion deficiency, type III, MIM# 612840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8507 ELANE Zornitza Stark Phenotypes for gene: ELANE were changed from Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700 to Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700; Neutropaenia, cyclic, MIM# 162800
Mendeliome v0.8506 ELANE Zornitza Stark edited their review of gene: ELANE: Changed phenotypes: Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700, Neutropaenia, cyclic, MIM# 162800
Phagocyte Defects v0.87 ELANE Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association.

Severe congenital neutropaenia is a heterogeneous disorder of haematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations.
Phagocyte Defects v0.87 ELANE Zornitza Stark Marked gene: ELANE as ready
Phagocyte Defects v0.87 ELANE Zornitza Stark Gene: elane has been classified as Green List (High Evidence).
Phagocyte Defects v0.87 ELANE Zornitza Stark Phenotypes for gene: ELANE were changed from to Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700; Neutropaenia, cyclic, MIM# 162800
Phagocyte Defects v0.86 ELANE Zornitza Stark Publications for gene: ELANE were set to
Phagocyte Defects v0.85 ELANE Zornitza Stark Mode of inheritance for gene: ELANE was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phagocyte Defects v0.84 ELANE Zornitza Stark reviewed gene: ELANE: Rating: GREEN; Mode of pathogenicity: None; Publications: 10581030, 11001877; Phenotypes: Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700, Neutropaenia, cyclic, MIM# 162800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.8506 CYBB Zornitza Stark Marked gene: CYBB as ready
Mendeliome v0.8506 CYBB Zornitza Stark Gene: cybb has been classified as Green List (High Evidence).
Mendeliome v0.8506 CYBB Zornitza Stark Phenotypes for gene: CYBB were changed from to Chronic granulomatous disease, X-linked, MIM# 306400
Mendeliome v0.8505 CYBB Zornitza Stark Publications for gene: CYBB were set to
Mendeliome v0.8504 CYBB Zornitza Stark Mode of inheritance for gene: CYBB was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.8503 CYBB Zornitza Stark reviewed gene: CYBB: Rating: GREEN; Mode of pathogenicity: None; Publications: 2556453, 1710153, 9585602; Phenotypes: Chronic granulomatous disease, X-linked, MIM# 306400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phagocyte Defects v0.84 CYBB Zornitza Stark Marked gene: CYBB as ready
Phagocyte Defects v0.84 CYBB Zornitza Stark Gene: cybb has been classified as Green List (High Evidence).
Phagocyte Defects v0.84 CYBB Zornitza Stark Phenotypes for gene: CYBB were changed from to Chronic granulomatous disease, X-linked, MIM# 306400
Phagocyte Defects v0.83 CYBB Zornitza Stark Publications for gene: CYBB were set to
Phagocyte Defects v0.82 CYBB Zornitza Stark Mode of inheritance for gene: CYBB was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phagocyte Defects v0.81 CTSC Zornitza Stark Marked gene: CTSC as ready
Phagocyte Defects v0.81 CTSC Zornitza Stark Gene: ctsc has been classified as Green List (High Evidence).
Phagocyte Defects v0.81 CTSC Zornitza Stark Phenotypes for gene: CTSC were changed from to Papillon-Lefevre syndrome, MIM# 245000
Phagocyte Defects v0.80 CTSC Zornitza Stark Publications for gene: CTSC were set to
Phagocyte Defects v0.79 CTSC Zornitza Stark Mode of inheritance for gene: CTSC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.78 CTSC Zornitza Stark reviewed gene: CTSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 25244098; Phenotypes: Papillon-Lefevre syndrome, MIM# 245000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bone Marrow Failure v1.4 CSF3R Zornitza Stark Phenotypes for gene: CSF3R were changed from Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014 to Neutropaenia, severe congenital, 7, autosomal recessive, MIM# 617014
Mendeliome v0.8503 CSF3R Zornitza Stark Marked gene: CSF3R as ready
Mendeliome v0.8503 CSF3R Zornitza Stark Gene: csf3r has been classified as Green List (High Evidence).
Mendeliome v0.8503 CSF3R Zornitza Stark Phenotypes for gene: CSF3R were changed from Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014 to Neutropaenia, severe congenital, 7, autosomal recessive, MIM# 617014
Bone Marrow Failure v1.3 CSF3R Zornitza Stark Publications for gene: CSF3R were set to 24753537; 26324699
Mendeliome v0.8502 CSF3R Zornitza Stark Phenotypes for gene: CSF3R were changed from to Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014
Bone Marrow Failure v1.2 CSF3R Zornitza Stark edited their review of gene: CSF3R: Changed publications: 24753537, 26324699, 33511998, 32966608; Changed phenotypes: Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014
Mendeliome v0.8501 CSF3R Zornitza Stark Publications for gene: CSF3R were set to
Mendeliome v0.8500 CSF3R Zornitza Stark Mode of inheritance for gene: CSF3R was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8499 CSF3R Zornitza Stark changed review comment from: More than 5 unrelated families reported.; to: More than 5 unrelated families reported. Some reports of progression to myelodysplasia.
Mendeliome v0.8499 CSF3R Zornitza Stark reviewed gene: CSF3R: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753537, 26324699, 33511998, 32966608; Phenotypes: Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bone Marrow Failure v1.2 CSF3R Zornitza Stark changed review comment from: Three unrelated families reported.
Sources: Expert list; to: At least 5 unrelated families reported. Some reports of progression to myelodysplasia.
Sources: Expert list
Phagocyte Defects v0.78 CSF3R Zornitza Stark Marked gene: CSF3R as ready
Phagocyte Defects v0.78 CSF3R Zornitza Stark Gene: csf3r has been classified as Green List (High Evidence).
Phagocyte Defects v0.78 CSF3R Zornitza Stark Phenotypes for gene: CSF3R were changed from to Neutropaenia, severe congenital, 7, autosomal recessive, MIM# 617014
Phagocyte Defects v0.77 CSF3R Zornitza Stark Publications for gene: CSF3R were set to
Phagocyte Defects v0.76 CSF3R Zornitza Stark Mode of inheritance for gene: CSF3R was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.75 CSF3R Zornitza Stark reviewed gene: CSF3R: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753537, 26324699, 33511998, 32966608; Phenotypes: Neutropenia, severe congenital, 7, autosomal recessive, MIM# 617014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8499 NUAK2 Zornitza Stark Phenotypes for gene: NUAK2 were changed from Anencephaly to Anencephaly 2, MIM# 619452
Mendeliome v0.8498 NUAK2 Zornitza Stark Deleted their comment
Mendeliome v0.8498 NUAK2 Zornitza Stark edited their review of gene: NUAK2: Changed phenotypes: Anencephaly 2, MIM# 619452
Susceptibility to Viral Infections v0.77 DBR1 Zornitza Stark Phenotypes for gene: DBR1 were changed from Viral infections of the brainstem to {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem
Susceptibility to Viral Infections v0.76 DBR1 Zornitza Stark edited their review of gene: DBR1: Changed phenotypes: {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441, Viral infections of the brainstem
Mendeliome v0.8498 DBR1 Zornitza Stark Phenotypes for gene: DBR1 were changed from Viral infections of the brainstem to {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem
Mendeliome v0.8497 DBR1 Zornitza Stark edited their review of gene: DBR1: Changed phenotypes: {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441, Viral infections of the brainstem
Intellectual disability syndromic and non-syndromic v0.4001 DPYSL5 Zornitza Stark Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, MIM# 619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Intellectual disability syndromic and non-syndromic v0.4000 DPYSL5 Zornitza Stark edited their review of gene: DPYSL5: Changed phenotypes: Ritscher-Schinzel syndrome 4, MIM# 619435, Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Callosome v0.307 DPYSL5 Zornitza Stark Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, MIM# 619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Callosome v0.306 DPYSL5 Zornitza Stark edited their review of gene: DPYSL5: Changed phenotypes: Ritscher-Schinzel syndrome 4, MIM# 619435, Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Mendeliome v0.8497 DPYSL5 Zornitza Stark Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, MIM# 619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Mendeliome v0.8496 DPYSL5 Zornitza Stark reviewed gene: DPYSL5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ritscher-Schinzel syndrome 4, MIM# 619435; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Microcephaly v1.35 RRP7A Zornitza Stark Phenotypes for gene: RRP7A were changed from Microcephaly to Microcephaly 28, primary, autosomal recessive MIM#619453
Microcephaly v1.34 RRP7A Zornitza Stark edited their review of gene: RRP7A: Changed phenotypes: Microcephaly 28, primary, autosomal recessive MIM#619453
Mendeliome v0.8496 RRP7A Zornitza Stark Phenotypes for gene: RRP7A were changed from Microcephaly to Microcephaly 28, primary, autosomal recessive MIM#619453
Mendeliome v0.8495 RRP7A Zornitza Stark edited their review of gene: RRP7A: Changed phenotypes: Microcephaly 28, primary, autosomal recessive MIM#619453
Phagocyte Defects v0.75 CYBA Zornitza Stark Marked gene: CYBA as ready
Phagocyte Defects v0.75 CYBA Zornitza Stark Gene: cyba has been classified as Green List (High Evidence).
Phagocyte Defects v0.75 CYBA Zornitza Stark Phenotypes for gene: CYBA were changed from to Chronic granulomatous disease 4, autosomal recessive, MIM# 233690; MONDO:0009308
Phagocyte Defects v0.74 CYBA Zornitza Stark Publications for gene: CYBA were set to
Phagocyte Defects v0.73 CYBA Zornitza Stark Mode of inheritance for gene: CYBA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8495 CEBPE Zornitza Stark Marked gene: CEBPE as ready
Mendeliome v0.8495 CEBPE Zornitza Stark Gene: cebpe has been classified as Green List (High Evidence).
Phagocyte Defects v0.72 CEBPE Zornitza Stark Marked gene: CEBPE as ready
Phagocyte Defects v0.72 CEBPE Zornitza Stark Gene: cebpe has been classified as Green List (High Evidence).
Phagocyte Defects v0.72 CEBPE Zornitza Stark Phenotypes for gene: CEBPE were changed from Specific granule deficiency, MIM# 245480 to Specific granule deficiency, MIM# 245480
Phagocyte Defects v0.71 CEBPE Zornitza Stark Phenotypes for gene: CEBPE were changed from Specific granule deficiency, MIM# 245480 to Specific granule deficiency, MIM# 245480
Mendeliome v0.8495 CEBPE Zornitza Stark Phenotypes for gene: CEBPE were changed from to Specific granule deficiency, MIM# 245480
Phagocyte Defects v0.71 CEBPE Zornitza Stark Phenotypes for gene: CEBPE were changed from to Specific granule deficiency, MIM# 245480
Mendeliome v0.8494 CEBPE Zornitza Stark Publications for gene: CEBPE were set to
Mendeliome v0.8493 CEBPE Zornitza Stark Mode of inheritance for gene: CEBPE was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.70 CEBPE Zornitza Stark Publications for gene: CEBPE were set to
Mendeliome v0.8492 CEBPE Zornitza Stark reviewed gene: CEBPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 10359588, 11313242, 31256937, 29651288; Phenotypes: Specific granule deficiency, MIM# 245480; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.69 CEBPE Zornitza Stark Mode of inheritance for gene: CEBPE was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Phagocyte Defects v0.68 CEBPE Zornitza Stark reviewed gene: CEBPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 10359588, 11313242, 31256937, 29651288; Phenotypes: Specific granule deficiency, MIM# 245480; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Chronic granulomatous disease v1.0 Zornitza Stark promoted panel to version 1.0
Chronic granulomatous disease v0.18 G6PD Zornitza Stark Marked gene: G6PD as ready
Chronic granulomatous disease v0.18 G6PD Zornitza Stark Gene: g6pd has been classified as Green List (High Evidence).
Chronic granulomatous disease v0.18 G6PD Zornitza Stark Publications for gene: G6PD were set to
Chronic granulomatous disease v0.17 G6PD Zornitza Stark reviewed gene: G6PD: Rating: GREEN; Mode of pathogenicity: None; Publications: 34175765, 27458052; Phenotypes: Haemolytic anemia, G6PD deficient (favism), MIM# 300908; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Chronic granulomatous disease v0.17 C17orf62 Zornitza Stark Marked gene: C17orf62 as ready
Chronic granulomatous disease v0.17 C17orf62 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name: CYBC1
Chronic granulomatous disease v0.17 C17orf62 Zornitza Stark Gene: c17orf62 has been classified as Green List (High Evidence).
Chronic granulomatous disease v0.17 C17orf62 Zornitza Stark Tag new gene name tag was added to gene: C17orf62.
Chronic granulomatous disease v0.17 NCF2 Zornitza Stark Marked gene: NCF2 as ready
Chronic granulomatous disease v0.17 NCF2 Zornitza Stark Gene: ncf2 has been classified as Green List (High Evidence).
Chronic granulomatous disease v0.17 NCF2 Zornitza Stark Publications for gene: NCF2 were set to
Chronic granulomatous disease v0.16 NCF2 Zornitza Stark reviewed gene: NCF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7795241, 10498624; Phenotypes: Chronic granulomatous disease 2, autosomal recessive, MIM# 233710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Chronic granulomatous disease v0.16 CYBB Zornitza Stark Marked gene: CYBB as ready
Chronic granulomatous disease v0.16 CYBB Zornitza Stark Gene: cybb has been classified as Green List (High Evidence).
Chronic granulomatous disease v0.16 CYBB Zornitza Stark Publications for gene: CYBB were set to
Chronic granulomatous disease v0.15 CYBB Zornitza Stark reviewed gene: CYBB: Rating: GREEN; Mode of pathogenicity: None; Publications: 2556453, 1710153, 9585602; Phenotypes: Chronic granulomatous disease, X-linked, MIM# 306400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mackenzie's Mission_Reproductive Carrier Screening v0.102 GK Sarah Righetti reviewed gene: GK: Rating: RED; Mode of pathogenicity: None; Publications: 8651297, 9719371; Phenotypes: Glycerol kinase deficiency, MIM# 307030; Mode of inheritance: None
Mackenzie's Mission_Reproductive Carrier Screening v0.102 SAMD9 Sarah Righetti reviewed gene: SAMD9: Rating: AMBER; Mode of pathogenicity: None; Publications: 16960814, 18094730; Phenotypes: Tumoral calcinosis, familial, normophosphatemic, MIM# 610455; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mackenzie's Mission_Reproductive Carrier Screening v0.102 FTCD Sarah Righetti reviewed gene: FTCD: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 5956503, 5897668, 4413489, 29178637; Phenotypes: Glutamate formiminotransferase deficiency MIM#229100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8492 NCF1 Zornitza Stark Marked gene: NCF1 as ready
Mendeliome v0.8492 NCF1 Zornitza Stark Gene: ncf1 has been classified as Green List (High Evidence).
Mendeliome v0.8492 NCF1 Zornitza Stark Phenotypes for gene: NCF1 were changed from to Chronic granulomatous disease 1, autosomal recessive, MIM# 233700
Mendeliome v0.8491 NCF1 Zornitza Stark Publications for gene: NCF1 were set to
Mendeliome v0.8490 NCF1 Zornitza Stark Mode of inheritance for gene: NCF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8489 NCF1 Zornitza Stark reviewed gene: NCF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2011585, 11133775, 10706888, 16972229, 16972229; Phenotypes: Chronic granulomatous disease 1, autosomal recessive, MIM# 233700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Chronic granulomatous disease v0.15 NCF1 Zornitza Stark Marked gene: NCF1 as ready
Chronic granulomatous disease v0.15 NCF1 Zornitza Stark Gene: ncf1 has been classified as Green List (High Evidence).
Chronic granulomatous disease v0.15 NCF1 Zornitza Stark Phenotypes for gene: NCF1 were changed from Chronic granulomatous disease due to deficiency of NCF-1 MIM#233700 to Chronic granulomatous disease 1, autosomal recessive, MIM# 233700
Chronic granulomatous disease v0.14 NCF1 Zornitza Stark Publications for gene: NCF1 were set to
Chronic granulomatous disease v0.13 NCF1 Zornitza Stark reviewed gene: NCF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2011585, 11133775, 10706888, 16972229, 16972229; Phenotypes: Chronic granulomatous disease 1, autosomal recessive, MIM# 233700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.8489 COL25A1 Zornitza Stark Publications for gene: COL25A1 were set to 25500261; 26486031
Mendeliome v0.8488 COL25A1 Zornitza Stark Classified gene: COL25A1 as Green List (high evidence)
Mendeliome v0.8488 COL25A1 Zornitza Stark Gene: col25a1 has been classified as Green List (High Evidence).
Mendeliome v0.8487 COL25A1 Zornitza Stark edited their review of gene: COL25A1: Added comment: PMID: 2643702 - Patient: 273182 reported in DECIPHER, chet COL25A1 missense variants (listed as Likely Pathogenic). Phenotype includes Duane anomaly of the eye.

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

PMID: 31875546 - Functional studies in human cell lines showed that the reported COL25A1 variants (G382R and G497X) impaired the interaction of COL25A1 with receptor protein tyrosine phosphatases, thereby reducing the ability to attract motor axons.; Changed rating: GREEN; Changed publications: 25500261, 26486031, 31875546, 26437029
Congenital ophthalmoplegia v1.4 COL25A1 Zornitza Stark Publications for gene: COL25A1 were set to 25500261; 26486031
Congenital ophthalmoplegia v1.3 COL25A1 Zornitza Stark Classified gene: COL25A1 as Green List (high evidence)
Congenital ophthalmoplegia v1.3 COL25A1 Zornitza Stark Gene: col25a1 has been classified as Green List (High Evidence).
Congenital ophthalmoplegia v1.2 COL25A1 Melanie Marty reviewed gene: COL25A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25500261, 26486031, 31875546, 26437029; Phenotypes: Fibrosis of extraocular muscles, congenital, 5, 610004; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4000 LTBP1 Zornitza Stark Marked gene: LTBP1 as ready