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Possible mitochondrial disorder, nuclear genes v1.60 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 3, 615330 to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330; ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Undiagnosed metabolic disorders v1.499 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Multiple mitochondrial dysfunctions syndrome 3, 615330; ?Spastic paraplegia 74, autosomal recessive to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330; ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Hereditary spastic paraplegia, childhood onset v2.113 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Neurodegenerative disorders, adult onset v2.255 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Hereditary spastic paraplegia, adult onset v1.87 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Hereditary spastic paraplegia v1.274 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Hereditary spastic paraplegia, childhood onset v2.112 IBA57 Arina Puzriakova changed review comment from: Comment on list classification: No further evidence was emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.; to: Comment on list classification: No further evidence has emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.
Hereditary spastic paraplegia, childhood onset v2.112 IBA57 Arina Puzriakova Classified gene: IBA57 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.112 IBA57 Arina Puzriakova Added comment: Comment on list classification: No further evidence was emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.
Hereditary spastic paraplegia, childhood onset v2.112 IBA57 Arina Puzriakova Gene: iba57 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v1.59 PHKB Sarah Leigh edited their review of gene: PHKB: Added comment: Although pathogenic variants in PHKB result in reduced levels of phosphorylase kinase in the liver and muscle, it would appear that this results in hepatomegaly and minimal effect on the muscles (PMID 9215682 & 30397902).; Changed rating: RED
Rhabdomyolysis and metabolic muscle disorders v1.59 PHKB Sarah Leigh Publications for gene: PHKB were set to 27604308; 9215682; 30397902
Rhabdomyolysis and metabolic muscle disorders v1.58 PHKB Sarah Leigh Tag Q4_21_rating tag was added to gene: PHKB.
Tag Q4_21_phenotype tag was added to gene: PHKB.
Rhabdomyolysis and metabolic muscle disorders v1.58 PHKB Sarah Leigh Publications for gene: PHKB were set to 27604308
Mosaic skin disorders - Deep sequencing v1.12 BRAF Eleanor Williams Classified gene: BRAF as Amber List (moderate evidence)
Mosaic skin disorders - Deep sequencing v1.12 BRAF Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation for GREEN rating following GMS review. More than 3 cases with tissue specific mosaic missense variants reported and a relevant skin phenotype.
Mosaic skin disorders - Deep sequencing v1.12 BRAF Eleanor Williams Gene: braf has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - Deep sequencing v1.11 BRAF Eleanor Williams Phenotypes for gene: BRAF were changed from Melanocytic naevus syndrome (MIM 137550); Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 (MIM 613707); Cardio-facio-cutaneous syndrome 1 (MIM 115150) to Melanocytic naevus syndrome, OMIM:137550; Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 , OMIM:613707; Cardio-facio-cutaneous syndrome 1, OMIM:115150
Mosaic skin disorders - Deep sequencing v1.10 BRAF Eleanor Williams Publications for gene: BRAF were set to PMID: 31111470; 31891627; 29461977
Mosaic skin disorders - Deep sequencing v1.9 BRAF Eleanor Williams Tag Q4_21_rating tag was added to gene: BRAF.
Mosaic skin disorders - Deep sequencing v1.9 BRAF Eleanor Williams commented on gene: BRAF
Severe microcephaly v2.274 GPT2 Arina Puzriakova Classified gene: GPT2 as Amber List (moderate evidence)
Severe microcephaly v2.274 GPT2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at then next GMS panel update.
Severe microcephaly v2.274 GPT2 Arina Puzriakova Gene: gpt2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.273 GPT2 Arina Puzriakova gene: GPT2 was added
gene: GPT2 was added to Severe microcephaly. Sources: Literature
Q4_21_rating tags were added to gene: GPT2.
Mode of inheritance for gene: GPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPT2 were set to 25758935; 27601654; 29226631; 29882329; 31471722
Phenotypes for gene: GPT2 were set to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Review for gene: GPT2 was set to GREEN
Added comment: Microcephaly is a prominent features of the neurodevelopmental disorder associated with biallelic variants in the GPT2 gene. Mostly all patients are to some degree microcephalic but at least 6 unrelated families (out of 11 total) have been reported with microcephaly of relevant severity to this panel (≥ -3SD). This gene is associated with a relevant phenotype in OMIM (OMIM:616281) but is not yet listed in G2P.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.111 GPT2 Arina Puzriakova Publications for gene: GPT2 were set to 29882329; 31471722; 27601654
Hereditary spastic paraplegia, childhood onset v2.110 GPT2 Arina Puzriakova Tag Q4_21_rating tag was added to gene: GPT2.
Hereditary spastic paraplegia, childhood onset v2.110 GPT2 Arina Puzriakova Classified gene: GPT2 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.110 GPT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update. Spastic paraplegia is a frequently reported sign which develops later in the course of disease but is often severe. As this is a prominent feature of the condition there is value in including GPT2 on this panel. This gene is associated with a relevant phenotype in OMIM (OMIM:616281) but is not yet listed in G2P.
Hereditary spastic paraplegia, childhood onset v2.110 GPT2 Arina Puzriakova Gene: gpt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1468 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Microcephaly; Mental retardation, autosomal recessive 49, 138210; Intellectual disability; Progressive spasticity to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Hereditary spastic paraplegia, childhood onset v2.109 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Mental retardation, autosomal recessive 49 MIM#616281 to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Skeletal dysplasia v2.156 PRKG2 Eleanor Williams Phenotypes for gene: PRKG2 were changed from Acromesomelic dysplasia to acromesomelic dysplasia, MONDO:0019696; spondylometaphyseal dysplasia, MONDO:0016763
Skeletal dysplasia v2.155 PRKG2 Eleanor Williams Publications for gene: PRKG2 were set to 33106379
Hereditary spastic paraplegia, childhood onset v2.108 EXOSC3 Arina Puzriakova Classified gene: EXOSC3 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.108 EXOSC3 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only two families have been reported to date with early-onset spastic paraplegia associated with biallelic variants in this gene. Other features included variable cognitive impairment and cerebellar atrophy but normal pons.
Hereditary spastic paraplegia, childhood onset v2.108 EXOSC3 Arina Puzriakova Gene: exosc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1467 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057; 34764295
Severe microcephaly v2.272 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057; 34764295
Severe microcephaly v2.271 ATP9A Sarah Leigh reviewed gene: ATP9A: Rating: AMBER; Mode of pathogenicity: None; Publications: 27626380; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1466 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 1 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Dystonia, chorea or related movement disorder, childhood onset v1.202 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Hereditary ataxia, adult onset v2.127 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia type 1B, 614678; Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Early onset or syndromic epilepsy v2.473 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Fetal anomalies v1.815 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 1 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Neurodegenerative disorders, adult onset v2.254 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Cerebellar hypoplasia v1.61 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar Hypoplasia type 1B; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Arthrogryposis v3.144 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Hereditary ataxia v1.280 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Ataxia and cerebellar anomalies - childhood onset v2.276 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia, type 1B, 614678; Pontocerebellar Hypoplasia type 1B to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Intellectual disability v3.1465 ATP9A Sarah Leigh edited their review of gene: ATP9A: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants reported in four unrelated families with a neurodevelopmental disorder (PMIDs: 34379057, 34764295). Model Atp9a−/− mice had neurobehavioural disabilities reminiscent to the behavioral patterns in the publications quoted here (PMID: 27626380).; Changed rating: GREEN; Changed publications to: 27626380
Intellectual disability v3.1465 ATP9A Sarah Leigh Classified gene: ATP9A as Amber List (moderate evidence)
Intellectual disability v3.1465 ATP9A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1465 ATP9A Sarah Leigh Gene: atp9a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1464 ATP9A Sarah Leigh Tag Q4_21_rating tag was added to gene: ATP9A.
Primary ovarian insufficiency v1.55 C14orf39 Andrey Gagunashvili reviewed gene: C14orf39: Rating: ; Mode of pathogenicity: None; Publications: 34718620; Phenotypes: Premature ovarian failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.55 SYCE1 Andrey Gagunashvili reviewed gene: SYCE1: Rating: ; Mode of pathogenicity: None; Publications: 34718620; Phenotypes: Premature ovarian failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1464 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057
Severe microcephaly v2.271 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057
Cholestasis v1.98 MPI Ivone Leong Added comment: Comment on publications: Comment on publications: New publications added.
Cholestasis v1.98 MPI Ivone Leong Publications for gene: MPI were set to 12414827; 9585601; 10980531; 33098580; 33204592; 32905087; 32266963; 30242110
Cholestasis v1.97 MPI Ivone Leong Tag Q4_21_NHS_review tag was added to gene: MPI.
Cholestasis v1.97 LIPA Ivone Leong Added comment: Comment on publications: Comment on publications: New publications added.
Cholestasis v1.97 LIPA Ivone Leong Publications for gene: LIPA were set to 8254026; 29702543; 8617513; 7759067; 8598644; 26137452; 29731497; 23485521
Cholestasis v1.96 LIPA Ivone Leong Tag Q4_21_NHS_review tag was added to gene: LIPA.
Cholestasis v1.96 CFTR Ivone Leong changed review comment from: Comment on publications: New publicatins added.; to: Comment on publications: New publications added.
Cholestasis v1.96 CFTR Ivone Leong Added comment: Comment on publications: New publicatins added.
Cholestasis v1.96 CFTR Ivone Leong Publications for gene: CFTR were set to 21194565; 27806795; 22798282; 9934970; 26436368; 31041076
Cholestasis v1.95 CFTR Ivone Leong Publications for gene: CFTR were set to 21194565; 27806795; 22798282; 9934970
Cholestasis v1.94 CFTR Ivone Leong Tag Q4_21_NHS_review tag was added to gene: CFTR.
Cholestasis v1.94 ADK Ivone Leong Tag Q4_21_NHS_review tag was added to gene: ADK.
Cholestasis v1.94 ADK Ivone Leong Publications for gene: ADK were set to 21963049; 27500280; 26642971
White matter disorders and cerebral calcification - childhood onset v1.217 ELOVL1 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - childhood onset v2.107
White matter disorders and cerebral calcification - childhood onset v1.217 ELOVL1 Arina Puzriakova gene: ELOVL1 was added
gene: ELOVL1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list,Expert Review Amber
missense, Q4_21_rating tags were added to gene: ELOVL1.
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 23689133; 29496980; 30487246; 32123819
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Ichthyosis and erythrokeratoderma v1.69 ELOVL1 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - childhood onset v2.107
Ichthyosis and erythrokeratoderma v1.69 ELOVL1 Arina Puzriakova gene: ELOVL1 was added
gene: ELOVL1 was added to Ichthyosis and erythrokeratoderma. Sources: Expert list,Expert Review Amber
missense, Q4_21_rating tags were added to gene: ELOVL1.
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 23689133; 29496980; 30487246; 32123819
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Hereditary spastic paraplegia, childhood onset v2.107 ELOVL1 Arina Puzriakova Publications for gene: ELOVL1 were updated from 29496980; 32123819; 30487246 to 23689133; 29496980; 30487246; 32123819
Hereditary spastic paraplegia, childhood onset v2.106 ELOVL1 Arina Puzriakova Classified gene: ELOVL1 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.106 ELOVL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Although only a single variant has been reported to date this was shown to arise de novo in unrelated individuals and the possibility of a founder effect was ruled out. Pathogenicity is supported by functional data including in vitro studies of the variant and complimentary animal models. Overall this is sufficient evidence to rate this gene as Green at the next GMS panel update.
Hereditary spastic paraplegia, childhood onset v2.106 ELOVL1 Arina Puzriakova Gene: elovl1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.105 ELOVL1 Arina Puzriakova Tag missense tag was added to gene: ELOVL1.
Tag Q4_21_rating tag was added to gene: ELOVL1.
Hereditary spastic paraplegia, childhood onset v2.105 ELOVL1 Arina Puzriakova reviewed gene: ELOVL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23689133, 29496980, 30487246, 32123819; Phenotypes: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.236 ELOVL1 Arina Puzriakova Mode of inheritance for gene: ELOVL1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.235 ELOVL1 Arina Puzriakova Phenotypes for gene: ELOVL1 were changed from to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Hereditary spastic paraplegia, childhood onset v2.105 ELOVL1 Arina Puzriakova Phenotypes for gene: ELOVL1 were changed from Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, MIM# 618527 to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Hereditary spastic paraplegia, adult onset v1.86 CPT1C Arina Puzriakova Classified gene: CPT1C as Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.86 CPT1C Arina Puzriakova Added comment: Comment on list classification: Overall one family with confirmed adult-onset and one with childhood-onset have been reported, as well as two further unrelated cases but unfortunately without indication of age of onset. Although onset is variable, the gene-disease relationship is supported by a strong animal model, and therefore it is worth including CPT1C on both HSP panels as Green.
Hereditary spastic paraplegia, adult onset v1.86 CPT1C Arina Puzriakova Gene: cpt1c has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, adult onset v1.85 CPT1C Arina Puzriakova Tag Q4_21_rating tag was added to gene: CPT1C.
Hereditary spastic paraplegia, childhood onset v2.104 CPT1C Arina Puzriakova Classified gene: CPT1C as Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.104 CPT1C Arina Puzriakova Added comment: Comment on list classification: Overall one family with confirmed adult-onset and one with childhood-onset have been reported, as well as two further unrelated cases but unfortunately without indication of age of onset. Although onset is variable, the gene-disease relationship is supported by a strong animal model, and therefore it is worth including CPT1C on both HSP panels as Green.
Hereditary spastic paraplegia, childhood onset v2.104 CPT1C Arina Puzriakova Gene: cpt1c has been classified as Green List (High Evidence).
Hereditary spastic paraplegia, childhood onset v2.103 CPT1C Arina Puzriakova Publications for gene: CPT1C were set to 25751282; 30564185
Hereditary spastic paraplegia, childhood onset v2.102 CPT1C Arina Puzriakova reviewed gene: CPT1C: Rating: ; Mode of pathogenicity: None; Publications: 30911584; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pigmentary skin disorders v1.23 HCCS Ivone Leong Tag Q4_21_rating was removed from gene: HCCS.
Pigmentary skin disorders v1.23 HCCS Ivone Leong Tag Q4_21_rating tag was added to gene: HCCS.
Tag Q4_21_NHS_review tag was added to gene: HCCS.
Pigmentary skin disorders v1.23 HCCS Ivone Leong Phenotypes for gene: HCCS were changed from Linear Skin Defects with Multiple Congenital Anomalies to Linear skin defects with multiple congenital anomalies 1, OMIM:309801
Intellectual disability v3.1463 HCCS Ivone Leong Tag Q4_21_MOI tag was added to gene: HCCS.
Intellectual disability v3.1463 HCCS Ivone Leong reviewed gene: HCCS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Hereditary spastic paraplegia, adult onset v1.85 CPT1C Arina Puzriakova Phenotypes for gene: CPT1C were changed from ?Spastic paraplegia 73, autosomal dominant, 616282 to Spastic paraplegia 73, autosomal dominant, OMIM:616282
Hereditary spastic paraplegia, childhood onset v2.102 CPT1C Arina Puzriakova Phenotypes for gene: CPT1C were changed from ?Spastic paraplegia 73, autosomal dominant, 616282, AD to Spastic paraplegia 73, autosomal dominant, OMIM:616282
Hereditary spastic paraplegia, childhood onset v2.101 AP5Z1 Arina Puzriakova Publications for gene: AP5Z1 were set to Slabicki et al. (2010); 20613862; 24833714; 27606357
Hereditary spastic paraplegia, childhood onset v2.100 AP5Z1 Arina Puzriakova reviewed gene: AP5Z1: Rating: ; Mode of pathogenicity: None; Publications: 24833714, 27606357, 33543803; Phenotypes: Spastic paraplegia 48, autosomal recessive, OMIM:613647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Tag Q4_21_rating tag was added to gene: DDX3X.
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Tag Q4_21_NHS_review tag was added to gene: DDX3X.
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Classified gene: DDX3X as Amber List (moderate evidence)
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. It should be noted that not all patient develops skin pigmentation anomalies; however, there are >3 unrelated cases. This gene should be rated Green at the next review.
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Gene: ddx3x has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1463 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic paraplegia 48, autosomal recessive 613647 to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Hereditary spastic paraplegia, childhood onset v2.100 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic paraplegia 48, autosomal recessive, OMIM:613647 to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Pigmentary skin disorders v1.21 DDX3X Ivone Leong Phenotypes for gene: DDX3X were changed from INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNIJDERS BLOK TYPE to Intellectual developmental disorder, X-linked, syndrome, Snijders Blok type, OMIM:300958
Hereditary spastic paraplegia, childhood onset v2.99 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic Paraplegia, Recessive; Spastic paraplegia 48, autosomal recessive to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Hereditary spastic paraplegia v1.273 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic Paraplegia, Recessive ; Spastic paraplegia 48, autosomal recessive to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Dystonia, chorea or related movement disorder, childhood onset v1.201 HPRT1 Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: HPRT1.
Tag Q4_21_rating tag was added to gene: HPRT1.
Dystonia, chorea or related movement disorder, childhood onset v1.201 HPRT1 Arina Puzriakova commented on gene: HPRT1
Dystonia, chorea or related movement disorder, childhood onset v1.201 HPRT1 Arina Puzriakova Publications for gene: HPRT1 were set to
Early onset dystonia v1.98 HPRT1 Arina Puzriakova Mode of inheritance for gene: HPRT1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Neurodegenerative disorders, adult onset v2.253 HPRT1 Arina Puzriakova Mode of inheritance for gene: HPRT1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Neurodegenerative disorders, adult onset v2.252 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Dystonia to Lesch-Nyhan syndrome, OMIM:300322
Early onset dystonia v1.97 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Dystonia to Lesch-Nyhan syndrome, OMIM:300322; Dystonia
Dystonia, chorea or related movement disorder, childhood onset v1.200 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322 to Lesch-Nyhan syndrome, OMIM:300322; Dystonia
Dystonia, chorea or related movement disorder, adult onset v1.158 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322; Dystonia to Lesch-Nyhan syndrome, OMIM:300322; Dystonia
Intellectual disability v3.1462 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322HPRT-related gout, 300323; GOUT HPRT-RELATED (GOUT-HPRT) to Lesch-Nyhan syndrome, OMIM:300322
Early onset or syndromic epilepsy v2.472 HPRT1 Arina Puzriakova Mode of inheritance for gene: HPRT1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v2.471 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from to Lesch-Nyhan syndrome, OMIM:300322
Fetal anomalies v1.814 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from LESCH-NYHAN SYNDROME; GOUT HPRT-RELATED to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Likely inborn error of metabolism v2.200 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from HPRT-related gout to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Nephrocalcinosis or nephrolithiasis v2.25 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322 to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Undiagnosed metabolic disorders v1.498 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from HPRT-related gout 300323; Lesch-Nyhan syndrome 300322 to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Pigmentary skin disorders v1.20 COX7B Ivone Leong Classified gene: COX7B as Amber List (moderate evidence)
Pigmentary skin disorders v1.20 COX7B Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Pigmentary skin disorders v1.20 COX7B Ivone Leong Gene: cox7b has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.19 COX7B Ivone Leong Tag Q4_21_rating tag was added to gene: COX7B.
Tag Q4_21_NHS_review tag was added to gene: COX7B.
Structural eye disease v1.92 COX7B Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "X-LINKED: hemizygous mutation in males, biallelic mutations in females" to "X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)" as the latter is the correct MOI.
Structural eye disease v1.92 COX7B Ivone Leong Mode of inheritance for gene: COX7B was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Severe early-onset obesity v2.45 KIDINS220 Arina Puzriakova Classified gene: KIDINS220 as Amber List (moderate evidence)
Severe early-onset obesity v2.45 KIDINS220 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Severe early-onset obesity v2.45 KIDINS220 Arina Puzriakova Gene: kidins220 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v2.44 KIDINS220 Arina Puzriakova gene: KIDINS220 was added
gene: KIDINS220 was added to Severe early-onset obesity. Sources: Literature
Q4_21_rating tags were added to gene: KIDINS220.
Mode of inheritance for gene: KIDINS220 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIDINS220 were set to 27005418; 29667355; 33763417
Phenotypes for gene: KIDINS220 were set to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Review for gene: KIDINS220 was set to GREEN
Added comment: Seven individuals from five unrelated families have been reported with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome (OMIM:617296) associated with monoallelic variants in the KIDINS220 gene. Phenotypes include early-onset obesity and, where indicated, this translates to a weight above the 99th percentile in infancy.
Sources: Literature
Intellectual disability v3.1461 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296
Intellectual disability v3.1460 KIDINS220 Arina Puzriakova Publications for gene: KIDINS220 were set to 27005418; 29667355
Hereditary spastic paraplegia, adult onset v1.84 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, autosomal dominant, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Hereditary spastic paraplegia, childhood onset v2.98 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Neurodegenerative disorders, adult onset v2.251 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Fetal anomalies v1.813 KIDINS220 Arina Puzriakova Added comment: Comment on phenotypes: Added relevant phenotype now listed in OMIM (MIM# 619501)
Fetal anomalies v1.813 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296; spastic paraplegia, intellectual disability, nystagmus, and obesity MONDO:0015007; cerebral ventriculomegaly; limb contractures to Ventriculomegaly and arthrogryposis, OMIM:619501
Hydrocephalus v2.125 KIDINS220 Arina Puzriakova Added comment: Comment on phenotypes: Added relevant phenotype now listed in OMIM (MIM# 619501)
Hydrocephalus v2.125 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from brain ventriculomegaly and limb contractures to Ventriculomegaly and arthrogryposis, OMIM:619501
Arthrogryposis v3.143 KIDINS220 Arina Puzriakova Added comment: Comment on phenotypes: Added relevant phenotype now listed in OMIM (MIM# 619501)
Arthrogryposis v3.143 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from brain ventriculomegaly and limb contractures to Ventriculomegaly and arthrogryposis, OMIM:619501
Hereditary spastic paraplegia v1.272 KIDINS220 Sarah Leigh Added comment: Comment on mode of pathogenicity: Personal communication from Dmitrijs Rots (RadboudUMC). Prompted by the occurrence of a KIDINS220 nonsense variant in the middle of the gene, in a family without spastic paraplegia (HSP) or other features; an in-depth analysis of KIDINS220 variants was performed. It would appear that KIDINS220 gene is tolerant of LOF variants (nonsense, frameshift) in gnomAD population (hence pLI~ 0, in the PanelApp review by Dmitrijs Rots (RadboudUMC), 4 Nov 2021). This was unexpected, as KIDINS220-associated-HSP presents in childhood, so it would appear that haploinsufficiency is unlikely as the mechanism. In addition, there were nonsense/frameshift HSP-associated variants in KIDINS220, but they were located in the last two exons of the gene and so likely to escape nonsense mediated decay. Therefore, it is proposed that rather a LOF mechanism a dominant negative effect may be responsible, however, further cases need to be identified to confirm this.
Hereditary spastic paraplegia v1.272 KIDINS220 Sarah Leigh Mode of pathogenicity for gene: KIDINS220 was changed from None to None
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 MARS Arina Puzriakova commented on gene: MARS
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 MARS Arina Puzriakova Tag watchlist tag was added to gene: MARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 AARS Arina Puzriakova changed review comment from: Gene was reassessed in view of the recent Green review by Alan Lehmann. An additional case is necessary to allow corroboration of this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel.; to: Gene was reassessed in view of the recent Green review by Alan Lehmann (5 Nov 2021). An additional case is necessary to allow corroboration of this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 AARS Arina Puzriakova commented on gene: AARS
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 AARS Arina Puzriakova Tag watchlist tag was added to gene: AARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Tag watchlist tag was added to gene: TARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Classified gene: TARS as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Added comment: Comment on list classification: Adding this gene as Amber as currently only two unrelated individuals have been reported with variants and trichothiodystrophy (PMID: 31374204). Familial segregation was not reported in either case. Functional studies demonstrate the variants exert a loss-of-function effect but an additional case would help corroborate this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Gene: tars has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.24 TARS Arina Puzriakova Mode of pathogenicity for gene: TARS was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.23 TARS Arina Puzriakova Publications for gene: TARS were set to PMID 31374204
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.22 TARS Arina Puzriakova Phenotypes for gene: TARS were changed from Trichothiodystrophy 7, nonphotosensitive to Trichothiodystrophy 7, nonphotosensitive, OMIM:618546
DDG2P v2.53 TARS Arina Puzriakova Tag new-gene-name tag was added to gene: TARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.21 TARS Arina Puzriakova Tag new-gene-name tag was added to gene: TARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.21 CARS Arina Puzriakova Publications for gene: CARS were set to PMID 30824121
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.20 CARS Arina Puzriakova Classified gene: CARS as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.20 CARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least four individuals from three unrelated families harbouring different biallelic variants in the CARS gene. Clinical presentation includes ID and brittle hair and nails, features which overlap with the trichothiodystrophy component of this panel. Some supportive functional studies included.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.20 CARS Arina Puzriakova Gene: cars has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.19 CARS Arina Puzriakova Tag Q4_21_rating tag was added to gene: CARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.19 CARS Arina Puzriakova Tag new-gene-name tag was added to gene: CARS.
Pigmentary skin disorders v1.19 COX7B Ivone Leong Phenotypes for gene: COX7B were changed from Linear Skin Defects with Multiple Congenital Anomalies to Linear skin defects with multiple congenital anomalies 2, OMIM:300887
Intellectual disability v3.1459 CARS Arina Puzriakova Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891 to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.19 CARS Arina Puzriakova Phenotypes for gene: CARS were changed from Microcephaly; Developmental Delay; Brittle Hair to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
Rare multisystem ciliopathy disorders v1.153 TMEM218 Ivone Leong Classified gene: TMEM218 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.153 TMEM218 Ivone Leong Gene: tmem218 has been classified as Green List (High Evidence).
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is sufficient evidence to support a gene-disease association. This gene has been rated Green.
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong Tag Q4_21_rating was removed from gene: TMEM218.
Tag Q4_21_NHS_review was removed from gene: TMEM218.
Ophthalmological ciliopathies v1.26 TMEM218 Ivone Leong Entity copied from Neurological ciliopathies v1.24
Ophthalmological ciliopathies v1.26 TMEM218 Ivone Leong gene: TMEM218 was added
gene: TMEM218 was added to Ophthalmological ciliopathies. Sources: Literature,Expert Review Amber
Q4_21_rating, Q4_21_NHS_review tags were added to gene: TMEM218.
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; 33791682
Phenotypes for gene: TMEM218 were set to Joubert syndrome 39, OMIM:619562
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong Entity copied from Neurological ciliopathies v1.24
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong gene: TMEM218 was added
gene: TMEM218 was added to Rare multisystem ciliopathy disorders. Sources: Literature,Expert Review Amber
Q4_21_rating, Q4_21_NHS_review tags were added to gene: TMEM218.
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; 33791682
Phenotypes for gene: TMEM218 were set to Joubert syndrome 39, OMIM:619562
Retinal disorders v2.234 TMEM218 Ivone Leong Entity copied from Neurological ciliopathies v1.24
Retinal disorders v2.234 TMEM218 Ivone Leong gene: TMEM218 was added
gene: TMEM218 was added to Retinal disorders. Sources: Literature,Expert Review Amber
Q4_21_rating, Q4_21_NHS_review tags were added to gene: TMEM218.
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; 33791682
Phenotypes for gene: TMEM218 were set to Joubert syndrome 39, OMIM:619562
Neurological ciliopathies v1.24 TMEM218 Ivone Leong Classified gene: TMEM218 as Amber List (moderate evidence)
Neurological ciliopathies v1.24 TMEM218 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.
Neurological ciliopathies v1.24 TMEM218 Ivone Leong Gene: tmem218 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v1.23 TMEM218 Ivone Leong Tag Q4_21_NHS_review tag was added to gene: TMEM218.
Neurological ciliopathies v1.23 TMEM218 Ivone Leong Tag Q4_21_rating tag was added to gene: TMEM218.
Intellectual disability v3.1458 GABRD Arina Puzriakova Classified gene: GABRD as Amber List (moderate evidence)
Intellectual disability v3.1458 GABRD Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases to rate this gene as Green at the next GMS panel update. Although all patients presented epilepsy, it is not clear from the case reports whether cognitive impairment was secondary or independent of seizures. For this reason I think its worth including GABRD on this panel as it is plausible that DD may be evident prior to seizure onset (ranging from 4 months to 4 years in report)
Intellectual disability v3.1458 GABRD Arina Puzriakova Gene: gabrd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1457 GABRD Arina Puzriakova gene: GABRD was added
gene: GABRD was added to Intellectual disability. Sources: Literature
Q4_21_rating tags were added to gene: GABRD.
Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRD were set to 34633442
Phenotypes for gene: GABRD were set to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060
Mode of pathogenicity for gene: GABRD 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: GABRD was set to GREEN
Added comment: Ahring et al., 2021 (PMID: 34633442) reports on at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene. All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID (learning difficulties in 1, mild ID in 2, mild to moderate ID in 1, and severe to profound ID in 2).

NB. A further three individuals were excluded from phenotypic analysis as their variants (p.M87L and p.V442I) did not show any detectable functional changes. There was also another patient with a loss-of-function variant but they displayed ASD, normal intelligence and no seizure history.
Sources: Literature
Neurological ciliopathies v1.23 TMEM218 Ivone Leong Phenotypes for gene: TMEM218 were changed from Joubert syndrome; retinal dystrophy; polycystic kidneys; occipital encephalocele to Joubert syndrome 39, OMIM:619562
Neurological ciliopathies v1.22 TMEM218 Ivone Leong Publications for gene: TMEM218 were set to 25161209; https://doi.org/10.1016/j.xhgg.2020.100016
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Tag Q4_21_rating tag was added to gene: GABRD.
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Classified gene: GABRD as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but this gene should now be promoted to Green at the next GMS panel update.

New evidence identified by Helen Lord (OUH NHS) highlights at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene (PMID: 34633442). All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID.
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Gene: gabrd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.469 GABRD Arina Puzriakova Mode of pathogenicity for gene: GABRD 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
Early onset or syndromic epilepsy v2.468 GABRD Arina Puzriakova Publications for gene: GABRD were set to 29785705
Early onset or syndromic epilepsy v2.467 GABRD Arina Puzriakova Phenotypes for gene: GABRD were changed from {Epilepsy, idiopathic generalized, 10} 613060; {Epilepsy, juvenile myoclonic, susceptibility to} 613060; {Epilepsy, generalized, with febrile seizures plus, type 5, susceptibility to} 613060 to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060; {Generalized epilepsy with febrile seizures plus, type 5, susceptibility to}, OMIM:613060
Early onset or syndromic epilepsy v2.466 GABRD Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: GABRD.
Ichthyosis and erythrokeratoderma v1.68 ASPRV1 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: ASPRV1.
Skeletal dysplasia v2.154 PRKG2 Alistair Pagnamenta reviewed gene: PRKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34782440, 33106379, 34680883; Phenotypes: spondylometaphyseal, acromesomelic dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited polyposis and early onset colorectal cancer - germline testing v1.26 AXIN2 Arina Puzriakova Classified gene: AXIN2 as Amber List (moderate evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v1.26 AXIN2 Arina Puzriakova Gene: axin2 has been classified as Amber List (Moderate Evidence).
Inherited polyposis and early onset colorectal cancer - germline testing v1.25 AXIN2 Arina Puzriakova gene: AXIN2 was added
gene: AXIN2 was added to Inherited polyposis. Sources: Literature
Q4_21_rating tags were added to gene: AXIN2.
Mode of inheritance for gene: AXIN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXIN2 were set to 15042511; 21416598; 30671715; 32807118; 34637023
Phenotypes for gene: AXIN2 were set to Oligodontia-colorectal cancer syndrome, OMIM:608615
Review for gene: AXIN2 was set to GREEN
Added comment: AXIN2 is associated with a relevant phenotype in OMIM (MIM# 608615) but is not yet listed in Gen2Phen. At least 6 unrelated families reported with colorectal cancer and/or colon polyps due to monoallelic variants in the AXIN2. This is often concurrent with oligodontia. Sufficient cases to rate as Green on this panel.
Sources: Literature
Ectodermal dysplasia v1.30 AXIN2 Arina Puzriakova Publications for gene: AXIN2 were set to 15042511
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: AXIN2.
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Classified gene: AXIN2 as Amber List (moderate evidence)
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Variants are associated with tooth agenesis (PMID: 15042511; 21626677; 30671715; 32807118), often additionally with colon polyps and colorectal cancer. Two families have been identified with concurrent ectodermal dysplasia including sparse or brittle hair and/or eyebrows and dry skin (PMID: 21416598; 34637023).

Given that in most families ectodermal features are isolated to oligodontia only, this gene will be flagged for GMS review to determine whether there is enough evidence to rate AXIN2 as Green on this panel.
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Gene: axin2 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.28 AXIN2 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: AXIN2.
Cutaneous photosensitivity with a likely genetic cause v1.8 ANAPC1 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: ANAPC1.
Ectodermal dysplasia v1.28 ANAPC1 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: ANAPC1.
Ectodermal dysplasia v1.28 AXIN2 Arina Puzriakova Phenotypes for gene: AXIN2 were changed from OLIGODONTIA-COLORECTAL CANCER SYNDROME to Oligodontia-colorectal cancer syndrome, OMIM:608615
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 AXIN2 Arina Puzriakova Mode of inheritance for gene: AXIN2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.59 AXIN2 Arina Puzriakova Phenotypes for gene: AXIN2 were changed from Oligodontia-colorectal cancer syndrome 604025 to Oligodontia-colorectal cancer syndrome, OMIM:608615
Cholestasis v1.93 MPI Miranda Durkie reviewed gene: MPI: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33413482, PMID: 28108845; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.93 LIPA Miranda Durkie reviewed gene: LIPA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26137452, PMID: 33964214; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.93 CFTR Miranda Durkie reviewed gene: CFTR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22798282, PMID: 27806795, PMID: 26436368, PMID: 31041076; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.93 ADK Miranda Durkie reviewed gene: ADK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33309011, PMID: 27500280, PMID: 21963049; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.466 CLPB Arina Puzriakova Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: CLPB.
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova reviewed gene: CLPB: Rating: ; Mode of pathogenicity: None; Publications: 25597510, 25597511, 26916670, 28687938, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.199 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Dystonia, chorea or related movement disorder, childhood onset v1.199 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Dystonia, chorea or related movement disorder, childhood onset v1.198 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with at least 7 affected individuals reported with a movement disorder. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease. Three individuals were nonambulatory and one was ambulatory but with a wide based gait and not able to run or jump. Some functional studies of heterozygous variants were performed.
Dystonia, chorea or related movement disorder, childhood onset v1.198 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.812 CLPB Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: CLPB.
Tag Q4_21_MOI tag was added to gene: CLPB.
Fetal anomalies v1.812 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Fetal anomalies v1.811 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease. No prenatal findings were specifically mentioned but given the otherwise comparable clinical presentations, monoallelic inheritance may also be of relevance to this panel. Therefore, will flag this for further GMS review.
Fetal anomalies v1.811 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.62 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Possible mitochondrial disorder, nuclear genes v1.59 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Mitochondrial disorders v2.62 CLPB Arina Puzriakova Publications for gene: CLPB were set to PMID: 25595726; PMID: 25597510; PMID: 25597511; PMID: 25650066
Possible mitochondrial disorder, nuclear genes v1.59 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Mitochondrial disorders v2.61 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease including 3-MGA-uria in all cases. Some functional studies were performed which demonstrated changes in the mitochondrial proteome in patient fibroblasts.
Mitochondrial disorders v2.61 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.58 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease including 3-MGA-uria in all cases. Some functional studies were performed which demonstrated changes in the mitochondrial proteome in patient fibroblasts.
Possible mitochondrial disorder, nuclear genes v1.58 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.496 CLPB Arina Puzriakova changed review comment from: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than >10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.; to: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.496 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.496 CLPB Arina Puzriakova Publications for gene: CLPB were set to 27891836; 25597510; 28687938; 25597511; 25650066; 26916670
Primary immunodeficiency or monogenic inflammatory bowel disease v2.495 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than >10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.495 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1456 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510
Intellectual disability v3.1455 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including mild to severe DD/ID in all cases. Some functional studies of heterozygous variants were performed.
Intellectual disability v3.1455 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1454 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Tag Q4_21_rating tag was added to gene: CLPB.
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Classified gene: CLPB as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but should be made Green at the next GMS panel update.

Neutropenia is often reported and can be a severe and early feature, sometimes present from birth. Neutropenia was observed in at least 11 biallelic cases and 5 monoallelic cases which is sufficient for a Green rating under the MOI 'Both mono- and biallelic'
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Gene: clpb has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.46 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Cytopenia - NOT Fanconi anaemia v1.45 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.497 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'Biallelic' to 'Both mono- and biallelic'.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, six unrelated individuals with de novo monoallelic missense variants in CLPB were identified (PMID: 34140661). The phenotype strongly overlapped with that observed in the recessive disease, including 3-MGA-uria in all cases.
Undiagnosed metabolic disorders v1.497 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.496 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25595726; 25597510; 25597511; 25650066
Likely inborn error of metabolism v2.199 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510; 25597511; 25650066; 25595726
Likely inborn error of metabolism v2.198 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Likely inborn error of metabolism v2.198 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype overlapped with that observed in the recessive disease including neurodevelopmental delay, seizures, 3-MGA-uria, and neutropenia. Some functional studies of heterozygous variants were performed.
Likely inborn error of metabolism v2.198 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.60 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Dystonia, chorea or related movement disorder, childhood onset v1.197 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Fetal anomalies v1.810 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-METHYLGLUTACONIC ACIDURIA, TYPE VII, WITH CATARACTS, NEUROLOGIC INVOLVEMENT AND NEUTROPENIA to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Possible mitochondrial disorder, nuclear genes v1.57 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Primary immunodeficiency or monogenic inflammatory bowel disease v2.494 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271; 3-methylglutaconic aciduria, type 7; Recurrent or severe infection; Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR; Congenital defects of phagocyte number or function to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Undiagnosed metabolic disorders v1.495 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Likely inborn error of metabolism v2.197 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Cytopenia - NOT Fanconi anaemia v1.44 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Primary immunodeficiency or monogenic inflammatory bowel disease v2.493 IKZF3 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.; to: Comment on list classification: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.493 IKZF3 Arina Puzriakova Classified gene: IKZF3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.493 IKZF3 Arina Puzriakova Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.492 IKZF3 Arina Puzriakova edited their review of gene: IKZF3: Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v2.492 IKZF3 Arina Puzriakova Added comment: Comment on mode of inheritance: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.492 IKZF3 Arina Puzriakova Mode of inheritance for gene: IKZF3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.491 IKZF3 Arina Puzriakova Added comment: Comment on mode of pathogenicity: Variants discovered to date located in DNA binding domain of IKZF3/AIOLOS, with dominant-negative effect on WT.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.491 IKZF3 Arina Puzriakova Mode of pathogenicity for gene: IKZF3 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
Primary immunodeficiency or monogenic inflammatory bowel disease v2.490 IKZF3 Arina Puzriakova Publications for gene: IKZF3 were set to 34155405
Primary immunodeficiency or monogenic inflammatory bowel disease v2.489 IKZF3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: IKZF3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.489 IKZF3 Arina Puzriakova Phenotypes for gene: IKZF3 were changed from B cell deficiency; EBV inefctions suspectibility; hypogammaglobulinemia to Immunodeficiency 84, OMIM:619437
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Tag Q4_21_rating tag was added to gene: DEF6.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Classified gene: DEF6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Added comment: Comment on list classification: There are now at least 3 unrelated cases of immunodeficiency associated with different biallelic variants in this gene (PMID:31308374; 32562707). DEF6 is also associated with a relevant phenotype in OMIM (MIM# 619573) and should be promoted to Green at the next GMS panel update (tagged).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Gene: def6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.487 DEF6 Arina Puzriakova Publications for gene: DEF6 were set to 32086639; 31308374; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.486 DEF6 Arina Puzriakova Phenotypes for gene: DEF6 were changed from DEF6 deficiency; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections; Diseases of Immune Dysregulation to Immunodeficiency 87 and autoimmunity, OMIM:619573; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections
Cytopenia - NOT Fanconi anaemia v1.43 RPA1 Dmitrijs Rots gene: RPA1 was added
gene: RPA1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
Mode of inheritance for gene: RPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RPA1 were set to bone marrow failure; T- and B-cell lymphopenia; pulmonary fibrosis; skin manifestations.
Penetrance for gene: RPA1 were set to unknown
Mode of pathogenicity for gene: RPA1 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: RPA1 was set to GREEN
Added comment: 4 cases with gain of function mutations with "including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations." described in
https://doi.org/10.1182/blood.2021011980
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.485 UBA1 Dmitrijs Rots reviewed gene: UBA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34048852; Phenotypes: VEXAS autoinflammatory condition; Mode of inheritance: Other
Fetal anomalies v1.809 AR Arina Puzriakova Phenotypes for gene: AR were changed from ANDROGEN INSENSITIVITY SYNDROME; SPINAL AND BULBAR MUSCULAR ATROPHY to ANDROGEN INSENSITIVITY SYNDROME
Differences in sex development v2.52 AR Arina Puzriakova Phenotypes for gene: AR were changed from Gender Assignment Gene Panel UKGTN; Androgen insensitivity, OMIM:300068; Androgen insensitivity,partial,with/without breast cancer, OMIM:312300; Hypospadias 1,X-linked, OMIM:300633 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633
Ectodermal dysplasia v1.27 AR Arina Puzriakova Phenotypes for gene: AR were changed from Androgen insensitivity, 300068; Androgen insensitivity, partial, with or without breast cancer, 312300; Hypospadias 1, X-linked, 300633; Spinal and bulbar muscular atrophy of Kennedy, 313200 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633; Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Hereditary ataxia, adult onset v2.126 RFC1 Michael Bonello reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32582864, 31824583, 33969391; Phenotypes: CANVAS Syndrome, Cerebellar ataxia, Idiopathic Sensory Neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Inherited ovarian cancer (without breast cancer) v2.22 AR Arina Puzriakova Phenotypes for gene: AR were changed from Androgen insensitivity, 300068; Spinal and bulbar muscular atrophy of Kennedy, 313200; Androgen insensitivity, partial, with or without breast cancer, 312300; {Prostate cancer, susceptibility to}, 176807; Hypospadias 1, X-linked, 300633 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300
Neurodegenerative disorders, adult onset v2.250 AR Arina Puzriakova Phenotypes for gene: AR were changed from Spinal and bulbar muscular atrophy of Kennedy, 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Familial breast cancer v1.15 AR Arina Puzriakova Phenotypes for gene: AR were changed from Androgen insensitivity, 300068; Spinal and bulbar muscular atrophy of Kennedy, 313200; Androgen insensitivity, partial, with or without breast cancer, 312300; {Prostate cancer, susceptibility to}, 176807; Hypospadias 1, X-linked, 300633 to Androgen insensitivity, partial, with or without breast cancer, OMIM:312300
Intellectual disability v3.1454 AR Arina Puzriakova Phenotypes for gene: AR were changed from Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633; Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Paediatric motor neuronopathies v1.72 AR Arina Puzriakova Tag Q2_21_MOI tag was added to gene: AR.
Paediatric motor neuronopathies v1.72 AR Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed to 'Other' to maintain consistency with other panels for this phenotype due to lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paediatric motor neuronopathies v1.72 AR Arina Puzriakova Mode of inheritance for gene: AR was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Neurodegenerative disorders, adult onset v2.249 AR Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.249 AR Arina Puzriakova Mode of inheritance for gene: AR was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to Other
Amyotrophic lateral sclerosis/motor neuron disease v1.49 AR Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Amyotrophic lateral sclerosis/motor neuron disease v1.49 AR Arina Puzriakova Mode of inheritance for gene: AR was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to Other
Hereditary neuropathy or pain disorder v1.67 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Hereditary neuropathy v1.430 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Amyotrophic lateral sclerosis/motor neuron disease v1.48 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases, OMIM:313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Neurodegenerative disorders, adult onset v2.248 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Congenital myopathy v2.68 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Distal myopathies v1.38 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Paediatric motor neuronopathies v1.71 AR_CAG Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this STR to Green at the next GMS panel update.

The AR gene was already Green on this panel for Kennedy disease, MIM# 313200 (https://panelapp.genomicsengland.co.uk/panels/79/gene/AR/); however, this was downgraded as the disease mechanism is an expansion of 36 or more CAG trinucleotide repeats in the AR gene and there is a lack of phenotypic relevance for SNVs. STR testing is appropriate route for detecting cases.; to: Comment on list classification: There is sufficient evidence to promote this STR to Green at the next GMS panel update.

The AR gene was Green on this panel for Kennedy disease, MIM# 313200 (https://panelapp.genomicsengland.co.uk/panels/79/gene/AR/); however, this has been flagged to be downgraded as the disease mechanism is an expansion of 36 or more CAG trinucleotide repeats in the AR gene and there is a lack of phenotypic relevance for SNVs. STR testing is appropriate route for detecting cases.
Neurodegenerative disorders, adult onset v2.247 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Neurodegenerative disorders, adult onset v2.246 FXN_GAA Arina Puzriakova Tag watchlist tag was added to STR: FXN_GAA.
Hereditary neuropathy v1.429 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Mitochondrial disorders v2.59 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary ataxia, adult onset v2.126 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary spastic paraplegia, adult onset v1.83 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary spastic paraplegia, childhood onset v2.97 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary spastic paraplegia v1.271 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Dystonia, chorea or related movement disorder, childhood onset v1.196 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Mitochondrial disorders v2.58 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Mitochondrial disorders v2.57 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Intellectual disability v3.1453 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia 229300; Friedreich ataxia with retained reflexes 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Possible mitochondrial disorder, nuclear genes v1.56 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Possible mitochondrial disorder, nuclear genes v1.55 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Likely inborn error of metabolism v2.196 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Undiagnosed metabolic disorders v1.494 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Undiagnosed metabolic disorders v1.493 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Neurodegenerative disorders, adult onset v2.246 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreichataxia,229300Friedreichataxiawithretainedreflexes,229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary spastic paraplegia, adult onset v1.82 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Hereditary spastic paraplegia, childhood onset v2.96 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Optic neuropathy v2.51 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia (FRDA), 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Optic neuropathy v2.50 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Hypertrophic cardiomyopathy v2.32 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from syndromic HCM to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Ataxia and cerebellar anomalies - childhood onset v2.275 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Hereditary neuropathy or pain disorder v1.66 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Hereditary Neuropathies; Friedreich ataxia, 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary neuropathy or pain disorder v1.65 FXN Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI to 'Biallelic' as monoallelic variants have not been associated with disease. Patients either harbour a homozygous expansion or are compound heterozygous for an expansion and a point mutation.
Hereditary neuropathy or pain disorder v1.65 FXN Arina Puzriakova Mode of inheritance for gene: FXN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.64 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Hereditary neuropathy v1.428 FXN Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI to 'Biallelic' as monoallelic variants have not been associated with disease. Patients either harbour a homozygous expansion or are compound heterozygous for an expansion and a point mutation.
Hereditary neuropathy v1.428 FXN Arina Puzriakova Mode of inheritance for gene: FXN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy v1.427 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Intellectual disability v3.1452 GLS_GCA Arina Puzriakova Phenotypes for STR: GLS_GCA were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Likely inborn error of metabolism v2.196 GLS_GCA Arina Puzriakova Phenotypes for STR: GLS_GCA were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Ataxia and cerebellar anomalies - childhood onset v2.275 GLS_GCA Arina Puzriakova Phenotypes for STR: GLS_GCA were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Intellectual disability v3.1451 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Intellectual disability v3.1451 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Intellectual disability v3.1450 GLS Arina Puzriakova Tag watchlist_moi tag was added to gene: GLS.
Ataxia and cerebellar anomalies - childhood onset v2.274 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Likely inborn error of metabolism v2.195 GLS Arina Puzriakova edited their review of gene: GLS: Changed rating: GREEN
Early onset or syndromic epilepsy v2.464 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678 to Developmental and epileptic encephalopathy 71, OMIM:618328
Likely inborn error of metabolism v2.195 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Undiagnosed metabolic disorders v1.493 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Likely inborn error of metabolism v2.195 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Likely inborn error of metabolism v2.194 GLS Arina Puzriakova Tag watchlist_moi tag was added to gene: GLS.
Undiagnosed metabolic disorders v1.493 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Undiagnosed metabolic disorders v1.492 GLS Arina Puzriakova Tag watchlist_moi tag was added to gene: GLS.
Bilateral congenital or childhood onset cataracts v2.89 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Hereditary ataxia, adult onset v2.125 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Hereditary neuropathy v1.427 NOP56_GGCCTGTT Arina Puzriakova Phenotypes for STR: NOP56_GGCCTGTT were changed from to Spinocerebellar ataxia 36, OMIM:614153
Hereditary neuropathy v1.426 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36, 614153Late adult onset gait ataxia, tongue atrophy and fasciculation, distal motor neuropathy to Spinocerebellar ataxia 36, OMIM:614153
Amyotrophic lateral sclerosis/motor neuron disease v1.47 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Neurodegenerative disorders, adult onset v2.245 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Neurodegenerative disorders, adult onset v2.244 NOP56_GGCCTG Arina Puzriakova Tag watchlist tag was added to STR: NOP56_GGCCTG.
Hereditary ataxia v1.279 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - childhood onset v2.273 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - childhood onset v2.272 NOP56_GGCCTG Arina Puzriakova Tag watchlist tag was added to STR: NOP56_GGCCTG.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.64 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Dystonia, chorea or related movement disorder, childhood onset v1.196 NOP56 Arina Puzriakova Classified gene: NOP56 as Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.196 NOP56 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red, this review is for the STR entity and not the gene entity
Dystonia, chorea or related movement disorder, childhood onset v1.196 NOP56 Arina Puzriakova Gene: nop56 has been classified as Red List (Low Evidence).
Intellectual disability v3.1450 NOP56 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1450 NOP56 Arina Puzriakova Mode of inheritance for gene: NOP56 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, childhood onset v1.195 NOP56 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, childhood onset v1.195 NOP56 Arina Puzriakova Mode of inheritance for gene: NOP56 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, childhood onset v1.194 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellar ataxia 36, 614153 to Spinocerebellar ataxia 36, OMIM:614153
Intellectual disability v3.1449 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellar ataxia 36, 614153 to Spinocerebellar ataxia 36, OMIM:614153
Dystonia, chorea or related movement disorder, childhood onset v1.193 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Hereditary ataxia, adult onset v2.124 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Intellectual disability v3.1448 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Neurodegenerative disorders, adult onset v2.244 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - childhood onset v2.272 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Hereditary ataxia v1.278 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - childhood onset v2.272 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Dystonia, chorea or related movement disorder, childhood onset v1.193 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, 604326 to Spinocerebellar ataxia 12, OMIM:604326
Dystonia, chorea or related movement disorder, childhood onset v1.192 PPP2R2B Arina Puzriakova Classified gene: PPP2R2B as Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.192 PPP2R2B Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red, this review is for the STR entity and not the gene entity
Dystonia, chorea or related movement disorder, childhood onset v1.192 PPP2R2B Arina Puzriakova Gene: ppp2r2b has been classified as Red List (Low Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.191 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, childhood onset v1.191 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, childhood onset v1.190 PPP2R2B Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: PPP2R2B.
Tag currently-ngs-unreportable tag was added to gene: PPP2R2B.
Intellectual disability v3.1448 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B 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
Dystonia, chorea or related movement disorder, adult onset v1.157 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B 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
Dystonia, chorea or related movement disorder, adult onset v1.156 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.156 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from to Other
Hereditary ataxia, adult onset v2.123 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.123 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Unknown to Other
Hereditary ataxia v1.277 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.277 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from to Other
Intellectual disability v3.1447 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1447 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Other - please specify in evaluation comments to Other
Ataxia and cerebellar anomalies - childhood onset v2.271 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.271 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Unknown to Other
Neurodegenerative disorders, adult onset v2.243 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B 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
Neurodegenerative disorders, adult onset v2.242 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.242 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Unknown to Other
Dystonia, chorea or related movement disorder, adult onset v1.155 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from to Spinocerebellar ataxia 12, OMIM:604326
Dystonia, chorea or related movement disorder, adult onset v1.154 PPP2R2B Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: PPP2R2B.
Tag currently-ngs-unreportable tag was added to gene: PPP2R2B.
Hereditary ataxia, adult onset v2.122 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia, adult onset v2.121 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Hereditary ataxia v1.276 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1446 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia v1.275 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Ataxia and cerebellar anomalies - childhood onset v2.270 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Ataxia and cerebellar anomalies - childhood onset v2.269 PPP2R2B Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: PPP2R2B.
Tag currently-ngs-unreportable tag was added to gene: PPP2R2B.
Neurodegenerative disorders, adult onset v2.241 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1445 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Neurodegenerative disorders, adult onset v2.240 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Structural eye disease v1.91 FOXE3 Eleanor Williams Tag watchlist_moi tag was added to gene: FOXE3.
Structural eye disease v1.91 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving mode of inheritance as biallelic for now. 2 monoallelic cases with coloboma, or both coloboma and microphthalmia so flagged with MOI_watchlist tag.
Structural eye disease v1.91 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.90 FOXE3 Eleanor Williams Phenotypes for gene: FOXE3 were changed from Anterior segment mesenchymal dysgenesis 107250; Anterior segment dysgenesis 2, multiple subtypes 610256 to Anterior segment mesenchymal dysgenesis, OMIM:107250; Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256
Structural eye disease v1.89 FOXE3 Eleanor Williams Publications for gene: FOXE3 were set to 16826526; 24859618, 19708017; 20361012; 11159941; 27218149; 21150893
Structural eye disease v1.88 FOXE3 Eleanor Williams changed review comment from: Review of mode of inheritance:

There are many reported cases of biallelic variants in FOXE3 associated with an eye phenotype, particularly cataracts, aphakia, microphthalmia and sclerocornea (PMID: 27218149 Khan et al 2016, PMID: 16826526 Valleix et al 2006, PMID: 19708017 Iseri et al 2009, PMID: 20140963 Reis et al 2010, PMID: 20664696 Ali et al 2010, PMID: 20361012 Anjum et al 2010, PMID: 24019743 Pantoja-Melendez et al 2013, PMID: 27669367 Saboo et al 2017, PMID: 29878917 Quiroz-Casian et al 2018, PMID: 32436650 Taha Najim et al 2020, PMID: 34046667 Reis et al 2021). Glaucoma is also noted in some individuals. Heterozygous carriers are largely unaffected in these cases.

Patients with monoallelic variants in FOXE3 and an eye phenotype are also reported:

PMID: 11159941 - Semina et al 2001 - screened FOXE3 in a cohort of 161 unrelated individuals affected with anterior segment ocular disorders and identified a 1 bp insertion in FOXE3 in a proband and affected mother that was not found in controls. Both affected individuals had prominent anterior Schwalbe’s line (posterior embryotoxon) and cataracts.

PMID: 19708017 - Iseri et al 2009 - identified 2 pedigrees with dominant mutations in the FOXE3 gene by screening a large cohort of 236 anophthalmia-microphthalmia subjects; one with anterior segment anomalies, including Peters’ anomaly, early onset cataract, and coloboma, and another with microphthalmia,coloboma, and cerulean type (blue dot) cataracts.

PMID: 20806047 - Bremond-Ginac et al 2010 - a dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract.

PMID: 21150893 - Doucette et al 2011 - sequenced 9 candidate genes in a large Newfoundland family with 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly and found a c.959G>T) substitution that replaces the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Analysis of lympohocytes suggests the c.959T allele is absent rather than an extended protein being expressed.

PMID: 11980846 - Ormestad et al 2002 - one individual with Peters anomaly (with eccentric corneal opacities and glaucoma but not cataract) was found to be heterozygous for a nonconservative missense mutation in FOXE3. 40% of mice heterozygous for Foxe3(dyl) have corneal and lenticular defects.

PMID: 34046667 - Reis et al 2021 - 2 families reported with dominant pathogenic extension alleles which modify the stop codon but keep the amino acids in frame, adding a 72–amino acid nonsense peptide. Cataracts were found in all cases where the lens could be evaluated. Eye size was normal in all individuals, but mild anterior segment anomalies affecting the cornea and/or iris were noted in some individuals. Sclerocornea was observed in two family members (15C and 16B).; to: Review of mode of inheritance:

There are many reported cases of biallelic variants in FOXE3 associated with an eye phenotype, particularly cataracts, aphakia, microphthalmia and sclerocornea (PMID: 27218149 Khan et al 2016, PMID: 16826526 Valleix et al 2006, PMID: 19708017 Iseri et al 2009, PMID: 20140963 Reis et al 2010, PMID: 20664696 Ali et al 2010, PMID: 20361012 Anjum et al 2010, PMID: 24019743 Pantoja-Melendez et al 2013, PMID: 27669367 Saboo et al 2017, PMID: 29878917 Quiroz-Casian et al 2018, PMID: 32436650 Taha Najim et al 2020, PMID: 34046667 Reis et al 2021). Glaucoma is also noted in some individuals. Heterozygous carriers are largely unaffected in these cases.

Patients with monoallelic variants in FOXE3 and an eye phenotype are also reported, but only 2 patients show coloboma, or both coloboma and microphthalmia (both reported in Iseri et al 2009).

PMID: 11159941 - Semina et al 2001 - screened FOXE3 in a cohort of 161 unrelated individuals affected with anterior segment ocular disorders and identified a 1 bp insertion in FOXE3 in a proband and affected mother that was not found in controls. Both affected individuals had prominent anterior Schwalbe’s line (posterior embryotoxon) and cataracts.

PMID: 19708017 - Iseri et al 2009 - identified 2 pedigrees with dominant mutations in the FOXE3 gene by screening a large cohort of 236 anophthalmia-microphthalmia subjects; one with anterior segment anomalies, including Peters’ anomaly, early onset cataract, and coloboma, and another with microphthalmia, coloboma, and cerulean type (blue dot) cataracts.

PMID: 20806047 - Bremond-Ginac et al 2010 - a dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract.

PMID: 21150893 - Doucette et al 2011 - sequenced 9 candidate genes in a large Newfoundland family with 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly and found a c.959G>T) substitution that replaces the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Analysis of lympohocytes suggests the c.959T allele is absent rather than an extended protein being expressed.

PMID: 11980846 - Ormestad et al 2002 - one individual with Peters anomaly (with eccentric corneal opacities and glaucoma but not cataract) was found to be heterozygous for a nonconservative missense mutation in FOXE3. 40% of mice heterozygous for Foxe3(dyl) have corneal and lenticular defects.

PMID: 34046667 - Reis et al 2021 - 2 families reported with dominant pathogenic extension alleles which modify the stop codon but keep the amino acids in frame, adding a 72–amino acid nonsense peptide. Cataracts were found in all cases where the lens could be evaluated. Eye size was normal in all individuals, but mild anterior segment anomalies affecting the cornea and/or iris were noted in some individuals. Sclerocornea was observed in two family members (15C and 16B).
Dystonia, chorea or related movement disorder, adult onset v1.154 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Dystonia, chorea or related movement disorder, adult onset v1.153 PPP2R2B_CAG Arina Puzriakova Tag watchlist tag was added to STR: PPP2R2B_CAG.
Intellectual disability v3.1445 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia, adult onset v2.121 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary neuropathy v1.425 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326; Adult onset cerebellar ataxia, tremor of head and arms, subclinical sensory-motor axonal neuropathy; neuropathy minor feature to Spinocerebellar ataxia 12, OMIM:604326
Neurodegenerative disorders, adult onset v2.240 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Neurodegenerative disorders, adult onset v2.239 PPP2R2B_CAG Arina Puzriakova Tag watchlist tag was added to STR: PPP2R2B_CAG.
Hereditary spastic paraplegia, adult onset v1.82 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary spastic paraplegia, childhood onset v2.96 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary spastic paraplegia v1.270 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia v1.275 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Ataxia and cerebellar anomalies - childhood onset v2.269 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Ataxia and cerebellar anomalies - childhood onset v2.268 PPP2R2B_CAG Arina Puzriakova Tag watchlist tag was added to STR: PPP2R2B_CAG.
Parkinson Disease and Complex Parkinsonism v1.92 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Dystonia, chorea or related movement disorder, childhood onset v1.190 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17, 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary ataxia, adult onset v2.120 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary spastic paraplegia, adult onset v1.81 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary spastic paraplegia, childhood onset v2.95 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary spastic paraplegia v1.269 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary ataxia v1.274 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - childhood onset v2.268 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - childhood onset v2.267 TBP_CAG Arina Puzriakova Tag watchlist tag was added to STR: TBP_CAG.
Brain channelopathy v1.70 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Dystonia, chorea or related movement disorder, adult onset v1.153 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Neurodegenerative disorders, adult onset v2.239 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Neurodegenerative disorders, adult onset v2.238 TBP_CAG Arina Puzriakova Tag watchlist tag was added to STR: TBP_CAG.
Paroxysmal central nervous system disorders v1.34 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.63 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.91 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Intellectual disability v3.1444 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1444 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from Other - please specify in evaluation comments to Other
Intellectual disability v3.1443 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP 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
Neurodegenerative disorders, adult onset v2.238 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP 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
Paroxysmal central nervous system disorders v1.33 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP 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
Dystonia, chorea or related movement disorder, adult onset v1.152 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.152 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia, adult onset v2.119 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.119 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from Unknown to Other
Neurodegenerative disorders, adult onset v2.237 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.237 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.32 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.32 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from to Other
Hereditary ataxia v1.273 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.273 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from to Other
Ataxia and cerebellar anomalies - childhood onset v2.267 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.267 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from Unknown to Other
Parkinson Disease and Complex Parkinsonism v1.90 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.90 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, adult onset v1.151 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from {Parkinson disease, susceptibility to}, 168600; Mohr-Tranebjaerg syndrome, 304700; Spinocerebellar ataxia 17, 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Dystonia, chorea or related movement disorder, adult onset v1.150 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Intellectual disability v3.1442 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary ataxia, adult onset v2.118 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600 to Spinocerebellar ataxia 17, OMIM:607136
Intellectual disability v3.1441 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Neurodegenerative disorders, adult onset v2.236 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Paroxysmal central nervous system disorders v1.31 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Paroxysmal central nervous system disorders v1.31 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Hereditary ataxia v1.272 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - childhood onset v2.266 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - childhood onset v2.265 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Parkinson Disease and Complex Parkinsonism v1.89 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.88 TBP Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: TBP.
Leukodystrophy, adult onset v1.35 RNASET2 Ivone Leong Tag Q4_21_expert_review tag was added to gene: RNASET2.
Leukodystrophy, adult onset v1.35 POLR1C Ivone Leong Tag Q4_21_expert_review tag was added to gene: POLR1C.
Leukodystrophy, adult onset v1.35 MARS Ivone Leong Tag Q4_21_expert_review tag was added to gene: MARS.
Tag Q4_21_phenotype tag was added to gene: MARS.
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Tag Q4_21_phenotype tag was added to gene: RNU12.
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Classified gene: RNU12 as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Added comment: Comment on list classification: Promoted from red to amber. It could be promoted to green after GMS review if the working group decide that the phenotype is appropriate for this panel. However, variants in this gene would not currently be reported as it is not a protein coding gene. An Ensembl ID also needs to be added before it is promoted to green.
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Gene: rnu12 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v1.41 RNU12 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: RNU12.
Tag Q4_21_expert_review tag was added to gene: RNU12.
Tag Q4_21_rating tag was added to gene: RNU12.
Rare genetic inflammatory skin disorders v1.41 RNU12 Eleanor Williams changed review comment from: Note RNU12 has Ensembl gene ID ENSG00000276027 in GRCh38. It is not listed in OMIM. I

PMID: 34085356 (Xing et al 2021) report the analysis of 5 patients from 4 unrelated families with clinical features of CDAGS (Craniosynostosis and clavicular hypoplasia; Delayed closure of the fontanelles and cranial defects (and deafness in some patients); Anal anomalies; Genitourinary malformations; and Skin eruption, including porokeratosis). WES and Sanger sequencing was used to identify rare biallelic variants in RNU12. All affected individuals were compound heterozygous, with all 5 patients sharing NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide. Each individual also carried another variant (4 different variants) in RNU12 thought to disrupt the secondary structure or the Sm binding site of the RNU12 snRNA. All 5 individuals were reported to have skin anomalies; erythematous cutaneous eruption consistent with porokeratosis (1), erythematous skin eruption involving the cheeks, arms, and legs (1), porokeratosis (2 siblings), disseminated dermatosis (1 individual)
Sources: Literature; to: Note RNU12 has Ensembl gene ID ENSG00000276027 in GRCh38. It is not listed in OMIM. It encodes a small nuclear RNA.

PMID: 34085356 (Xing et al 2021) report the analysis of 5 patients from 4 unrelated families with clinical features of CDAGS (Craniosynostosis and clavicular hypoplasia; Delayed closure of the fontanelles and cranial defects (and deafness in some patients); Anal anomalies; Genitourinary malformations; and Skin eruption, including porokeratosis). WES and Sanger sequencing was used to identify rare biallelic variants in RNU12. All affected individuals were compound heterozygous, with all 5 patients sharing NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide. Each individual also carried another variant (4 different variants) in RNU12 thought to disrupt the secondary structure or the Sm binding site of the RNU12 snRNA. All 5 individuals were reported to have skin anomalies; erythematous cutaneous eruption consistent with porokeratosis (1), erythematous skin eruption involving the cheeks, arms, and legs (1), porokeratosis (2 siblings), disseminated dermatosis (1 individual)
Sources: Literature
Rare genetic inflammatory skin disorders v1.41 RNU12 Eleanor Williams gene: RNU12 was added
gene: RNU12 was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 34085356
Phenotypes for gene: RNU12 were set to porokeratosis; erythematous cutaneous eruption
Review for gene: RNU12 was set to GREEN
Added comment: Note RNU12 has Ensembl gene ID ENSG00000276027 in GRCh38. It is not listed in OMIM. I

PMID: 34085356 (Xing et al 2021) report the analysis of 5 patients from 4 unrelated families with clinical features of CDAGS (Craniosynostosis and clavicular hypoplasia; Delayed closure of the fontanelles and cranial defects (and deafness in some patients); Anal anomalies; Genitourinary malformations; and Skin eruption, including porokeratosis). WES and Sanger sequencing was used to identify rare biallelic variants in RNU12. All affected individuals were compound heterozygous, with all 5 patients sharing NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide. Each individual also carried another variant (4 different variants) in RNU12 thought to disrupt the secondary structure or the Sm binding site of the RNU12 snRNA. All 5 individuals were reported to have skin anomalies; erythematous cutaneous eruption consistent with porokeratosis (1), erythematous skin eruption involving the cheeks, arms, and legs (1), porokeratosis (2 siblings), disseminated dermatosis (1 individual)
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.189 HTT Arina Puzriakova Publications for gene: HTT were set to
Intellectual disability v3.1441 HTT Arina Puzriakova Publications for gene: HTT were set to 26740508; 27329733
Dystonia, chorea or related movement disorder, childhood onset v1.188 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Biallelic SNVs have been reported for Lopes-Maciel-Rodan syndrome
Dystonia, chorea or related movement disorder, childhood onset v1.188 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.187 HTT Arina Puzriakova Classified gene: HTT as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.187 HTT Arina Puzriakova Gene: htt has been classified as Amber List (Moderate Evidence).
Leukodystrophy, adult onset v1.35 EARS2 Ivone Leong Tag Q4_21_expert_review tag was added to gene: EARS2.
Dystonia, chorea or related movement disorder, childhood onset v1.186 HTT Arina Puzriakova reviewed gene: HTT: Rating: ; Mode of pathogenicity: None; Publications: 26740508, 27329733, 33432339; Phenotypes: Lopes-Maciel-Rodan syndrome, OMIM:617435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.186 HTT Arina Puzriakova Tag watchlist tag was added to gene: HTT.
Leukodystrophy, adult onset v1.35 CTC1 Ivone Leong Phenotypes for gene: CTC1 were changed from Cerebroretinal microangiopathy with calcifications and cysts, 612199 to Cerebroretinal microangiopathy with calcifications and cysts, OMIM:612199
Leukodystrophy, adult onset v1.34 CTC1 Ivone Leong Publications for gene: CTC1 were set to 27159321; 25527826; 28334938; 20301621; 24357685
Dystonia, chorea or related movement disorder, adult onset v1.150 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.150 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia, adult onset v2.117 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. Biallelic variants not relevant to this panel.
Hereditary ataxia, adult onset v2.117 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to Other
Mitochondrial disorders v2.57 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Mitochondrial disorders v2.57 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Possible mitochondrial disorder, nuclear genes v1.55 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Possible mitochondrial disorder, nuclear genes v1.55 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Neurodegenerative disorders, adult onset v2.235 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.235 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.30 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.30 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Structural basal ganglia disorders v1.25 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Structural basal ganglia disorders v1.25 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Brain channelopathy v1.69 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Brain channelopathy v1.69 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Parkinson Disease and Complex Parkinsonism v1.88 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.88 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Leukodystrophy, adult onset v1.33 COL4A2 Ivone Leong Tag Q4_21_expert_review tag was added to gene: COL4A2.
Tag Q4_21_phenotype tag was added to gene: COL4A2.
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is not enough evidence to support a gene-disease association as only 2 of 3 cases had seizures.
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong Tag Q4_21_rating was removed from gene: COLGALT1.
Tag watchlist tag was added to gene: COLGALT1.
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Tag Q4_21_rating was removed from gene: COLGALT1.
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Classified gene: COLGALT1 as Green List (high evidence)
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my review.
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Gene: colgalt1 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.146 COLGALT1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association.
Familial cerebral small vessel disease v1.13 COLGALT1 Ivone Leong Classified gene: COLGALT1 as Green List (high evidence)
Familial cerebral small vessel disease v1.13 COLGALT1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my review.
Familial cerebral small vessel disease v1.13 COLGALT1 Ivone Leong Gene: colgalt1 has been classified as Green List (High Evidence).
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong Tag Q4_21_rating was removed from gene: COLGALT1.
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association.
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.216
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong gene: COLGALT1 was added
gene: COLGALT1 was added to Familial cerebral small vessel disease. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: COLGALT1.
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, OMIM:618360
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.216
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong gene: COLGALT1 was added
gene: COLGALT1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: COLGALT1.
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, OMIM:618360
Inherited white matter disorders v1.146 COLGALT1 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.216
Inherited white matter disorders v1.146 COLGALT1 Ivone Leong gene: COLGALT1 was added
gene: COLGALT1 was added to Inherited white matter disorders. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: COLGALT1.
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, OMIM:618360
White matter disorders and cerebral calcification - childhood onset v1.216 COLGALT1 Ivone Leong Phenotypes for gene: COLGALT1 were changed from Brain small vessel disease 3 MIM#618360 to Brain small vessel disease 3, OMIM:618360
White matter disorders and cerebral calcification - childhood onset v1.215 COLGALT1 Ivone Leong Classified gene: COLGALT1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.215 COLGALT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.215 COLGALT1 Ivone Leong Gene: colgalt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1440 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Lopes-Maciel-Rodan syndrome, 617435; LOMARS; Intellectual disability to Lopes-Maciel-Rodan syndrome, OMIM:617435; LOMARS
Dystonia, chorea or related movement disorder, childhood onset v1.186 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Lopes-Maciel-Rodan syndrome, OMIM:617435; LOMARS
Dystonia, chorea or related movement disorder, adult onset v1.149 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease to Huntington disease, OMIM:143100
Dystonia, chorea or related movement disorder, adult onset v1.148 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Hereditary ataxia, adult onset v2.116 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100; Lopes-Maciel-Rodan syndrome, 617432 to Huntington disease, OMIM:143100
Mitochondrial disorders v2.56 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Huntington disease, OMIM:143100
Mitochondrial disorders v2.55 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Possible mitochondrial disorder, nuclear genes v1.54 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Huntington disease, OMIM:143100
Possible mitochondrial disorder, nuclear genes v1.53 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Neurodegenerative disorders, adult onset v2.234 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100; Huntingtons disease (HD) to Huntington disease, OMIM:143100
Paroxysmal central nervous system disorders v1.29 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Huntington disease, OMIM:143100
Paroxysmal central nervous system disorders v1.28 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Structural basal ganglia disorders v1.24 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Brain channelopathy v1.68 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Parkinson Disease and Complex Parkinsonism v1.87 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntingtons disease (HD) to Huntington disease, OMIM:143100
Dystonia, chorea or related movement disorder, adult onset v1.148 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary ataxia, adult onset v2.115 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Neurodegenerative disorders, adult onset v2.233 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary spastic paraplegia, adult onset v1.80 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary spastic paraplegia, childhood onset v2.94 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary spastic paraplegia v1.268 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Structural basal ganglia disorders v1.23 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary ataxia v1.271 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Ataxia and cerebellar anomalies - childhood onset v2.265 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Brain channelopathy v1.67 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
White matter disorders and cerebral calcification - childhood onset v1.214 COLGALT1 Ivone Leong Tag Q4_21_rating tag was added to gene: COLGALT1.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.62 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Parkinson Disease and Complex Parkinsonism v1.86 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary neuropathy v1.424 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624; Late onset tremor, ataxia, parkinsonism, sensory axonal neuropathy, middle cerebellar peduncle changes on MRI to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Hereditary neuropathy v1.423 FMR1_CGG Arina Puzriakova Tag currently-ngs-unreportable was removed from STR: FMR1_CGG.
Intellectual disability v3.1439 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624 to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Intellectual disability v3.1438 FMR1_CGG Arina Puzriakova Tag currently-ngs-unreportable was removed from STR: FMR1_CGG.
Hereditary ataxia, adult onset v2.114 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome, 300624 to Fragile X tremor/ataxia syndrome, OMIM:300623
Hereditary ataxia v1.270 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624 to Fragile X tremor/ataxia syndrome, OMIM:300623
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Classified gene: SMAD3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Added comment: Comment on list classification: On advice from Genomics England clinical team, promoting this gene from grey to amber. The number of cases with a craniosynostosis phenotype is borderline so rating as amber for now. Only 1 biallelic case reported so far so keeping the mode of inheritance as monoallelic.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Gene: smad3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.57 SMAD3 Eleanor Williams Phenotypes for gene: SMAD3 were changed from Loeys-Dietz syndrome 3, MIM# 613795 to Loeys-Dietz syndrome 3, OMIM:613795
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.56 SMAD3 Eleanor Williams Publications for gene: SMAD3 were set to 20301312; 29392890
Primary ovarian insufficiency v1.55 FMR1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Primary ovarian insufficiency v1.55 FMR1 Arina Puzriakova Mode of inheritance for gene: FMR1 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 Other
Ataxia and cerebellar anomalies - childhood onset v2.264 FMR1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FMR1.
Intellectual disability v3.1438 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome, 300624Fragile X tremor/ataxia syndrome, 300623Premature ovarian failure 1, 311360; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1 (POF1) to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Intellectual disability v3.1437 FMR1 Arina Puzriakova Tag currently-ngs-unreportable was removed from gene: FMR1.
Hereditary ataxia v1.269 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); FragileXtremor/ataxiasyndrome,300623; males with a tremor phenotype to Fragile X tremor/ataxia syndrome, OMIM:300623
Ataxia and cerebellar anomalies - childhood onset v2.264 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); males with a tremor phenotype; FragileXtremor/ataxiasyndrome,300623 to Fragile X tremor/ataxia syndrome, OMIM:300623
Hereditary ataxia, adult onset v2.113 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FragileXtremor/ataxiasyndrome,300623; Fragile X tremor/ataxia syndrome; FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); males with a tremor phenotype to Fragile X tremor/ataxia syndrome, OMIM:300623
Fetal anomalies v1.808 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FRAGILE X SYNDROME; FRAGILE X TREMOR/ATAXIA SYNDROME; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1 to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Neurodegenerative disorders, adult onset v2.232 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); males with a tremor phenotype; FragileXtremor/ataxiasyndrome,300623 to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Hydrocephalus v2.124 FMR1 Arina Puzriakova Tag currently-ngs-unreportable was removed from gene: FMR1.
Hydrocephalus v2.124 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome 300624 to Fragile X syndrome, OMIM:300624
Hydrocephalus v2.123 FMR1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FMR1.
Tag currently-ngs-unreportable tag was added to gene: FMR1.
Primary ovarian insufficiency v1.54 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624 to Premature ovarian failure 1, OMIM:311360
Primary ovarian insufficiency v1.53 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome, 300624; Fragile X tremor ataxia syndrome, 300623; Premature ovarian failure 1, 311360; Premature Ovarian Insufficiency to Premature ovarian failure 1, OMIM:311360
Non-syndromic familial congenital anorectal malformations v1.8 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the mode of inheritance to X-linked: hemizygous mutation in males, monallelic mutations in females after advice from the Genomics England clinical team. There are 5 reported relevant cases in females.
Non-syndromic familial congenital anorectal malformations v1.8 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Skeletal dysplasia v2.154 ZNF687 Eleanor Williams Phenotypes for gene: ZNF687 were changed from Paget Disease of Bone with associated Giant Cell Tumour. to Paget disease of bone 6, OMIM:616833
Skeletal dysplasia v2.153 ZNF687 Eleanor Williams Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110
Skeletal dysplasia v2.152 ZNF687 Eleanor Williams Classified gene: ZNF687 as Amber List (moderate evidence)
Skeletal dysplasia v2.152 ZNF687 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for a green rating following GMS review.
Skeletal dysplasia v2.152 ZNF687 Eleanor Williams Gene: znf687 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.151 ZNF687 Eleanor Williams Tag Q4_21_rating tag was added to gene: ZNF687.
Skeletal dysplasia v2.151 ZNF687 Eleanor Williams reviewed gene: ZNF687: Rating: GREEN; Mode of pathogenicity: None; Publications: 29493781, 26849110; Phenotypes: Paget disease of bone 6, OMIM:616833; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary spastic paraplegia v1.267 KIDINS220 Sarah Leigh Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296
Hereditary spastic paraplegia v1.266 KIDINS220 Sarah Leigh Publications for gene: KIDINS220 were set to 27005418; 29667355; 31630374
COVID-19 research v1.85 LZTFL1 Sarah Leigh Classified gene: LZTFL1 as Red List (low evidence)
COVID-19 research v1.85 LZTFL1 Sarah Leigh Gene: lztfl1 has been classified as Red List (Low Evidence).
COVID-19 research v1.84 LZTFL1 Sarah Leigh reviewed gene: LZTFL1: Rating: RED; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v1.84 LZTFL1 Sarah Leigh Phenotypes for gene: LZTFL1 were changed from Visceral Heterotaxy; Bardet-Biedl Syndrome 17 to Bardet-Biedl syndrome 17 OMIM:615994
COVID-19 research v1.83 LZTFL1 Sarah Leigh Publications for gene: LZTFL1 were set to 22510444; 23692385
COVID-19 research v1.82 LZTFL1 Sarah Leigh Entity copied from Primary ciliary disorders v1.36
COVID-19 research v1.82 LZTFL1 Sarah Leigh gene: LZTFL1 was added
gene: LZTFL1 was added to COVID-19 research. Sources: UKGTN,Expert Review Amber
watchlist tags were added to gene: LZTFL1.
Mode of inheritance for gene: LZTFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LZTFL1 were set to 22510444; 23692385
Phenotypes for gene: LZTFL1 were set to Visceral Heterotaxy; Bardet-Biedl Syndrome 17
Penetrance for gene: LZTFL1 were set to Complete
Primary ciliary disorders v1.36 LZTFL1 Sarah Leigh Phenotypes for gene: LZTFL1 were changed from Visceral Heterotaxy; Bardet-Biedl Syndrome 17 to Visceral Heterotaxy; Bardet-Biedl Syndrome 17
Publications for gene: LZTFL1 were updated from 22510444; 23692385 to 22510444; 23692385
Intellectual disability v3.1437 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1436 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1436 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to Other
Neurodegenerative disorders, adult onset v2.231 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.231 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from Unknown to Other
Hereditary ataxia v1.268 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.268 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from to Other
Ataxia and cerebellar anomalies - childhood onset v2.263 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.263 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from Unknown to Other
Hereditary ataxia, adult onset v2.112 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.112 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from Unknown to Other
Dystonia, chorea or related movement disorder, adult onset v1.147 ATXN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN1.
Tag currently-ngs-unreportable tag was added to gene: ATXN1.
Dystonia, chorea or related movement disorder, adult onset v1.147 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.147 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from to Other
Dystonia, chorea or related movement disorder, childhood onset v1.185 ATXN1 Arina Puzriakova Mode of pathogenicity for gene: ATXN1 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
Dystonia, chorea or related movement disorder, childhood onset v1.184 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1, 164400 to Spinocerebellar ataxia 1, OMIM:164400
Dystonia, chorea or related movement disorder, adult onset v1.146 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia, adult onset v2.111 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1, 164400; Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Neurodegenerative disorders, adult onset v2.230 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia v1.267 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - childhood onset v2.262 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - childhood onset v2.261 ATXN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN1.
Tag currently-ngs-unreportable tag was added to gene: ATXN1.
Dystonia, chorea or related movement disorder, adult onset v1.145 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Dystonia, chorea or related movement disorder, adult onset v1.144 ATXN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN1_CAG.
Intellectual disability v3.1435 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia, adult onset v2.110 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary neuropathy v1.423 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Neurodegenerative disorders, adult onset v2.229 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Neurodegenerative disorders, adult onset v2.228 ATXN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN1_CAG.
Hereditary spastic paraplegia, adult onset v1.79 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary spastic paraplegia, childhood onset v2.93 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary spastic paraplegia v1.265 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia v1.266 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - childhood onset v2.261 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - childhood onset v2.260 ATXN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN1_CAG.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.61 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Parkinson Disease and Complex Parkinsonism v1.85 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1434 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092; Paroxysmal dystonia, MONDO:0016058
Dystonia, chorea or related movement disorder, adult onset v1.144 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.144 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Neurodegenerative disorders, adult onset v2.228 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.228 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.60 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.60 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Parkinson Disease and Complex Parkinsonism v1.84 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.84 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.59 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Neurodegenerative disorders, adult onset v2.227 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Dystonia, chorea or related movement disorder, adult onset v1.143 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 to Huntington disease-like 2, OMIM:606438
Parkinson Disease and Complex Parkinsonism v1.83 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Dystonia, chorea or related movement disorder, adult onset v1.142 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Neurodegenerative disorders, adult onset v2.226 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Neurodegenerative disorders, adult onset v2.225 JPH3_CTG Arina Puzriakova Tag watchlist tag was added to STR: JPH3_CTG.
Early onset dystonia v1.96 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.58 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Parkinson Disease and Complex Parkinsonism v1.82 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Skeletal muscle channelopathy v1.36 DMPK_CTG Arina Puzriakova Tag STR tag was added to STR: DMPK_CTG.
Intellectual disability v3.1433 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Mitochondrial disorders v2.55 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Paediatric motor neuronopathies v1.71 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Likely inborn error of metabolism v2.194 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Congenital myopathy v2.67 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Congenital muscular dystrophy v2.21 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Paroxysmal central nervous system disorders v1.28 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Gastrointestinal neuromuscular disorders v1.18 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Fetal hydrops v1.42 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Skeletal Muscle Channelopathies v1.41 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Fetal anomalies v1.807 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from DYSTROPHIA MYOTONICA TYPE 1 to Myotonic dystrophy 1, OMIM:160900
Fetal anomalies v1.806 DMPK Arina Puzriakova Mode of pathogenicity for gene: DMPK 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
Arthrogryposis v3.142 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Dilated Cardiomyopathy and conduction defects v1.74 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from syndromic DCM to Myotonic dystrophy 1, OMIM:160900
Gastrointestinal neuromuscular disorders v1.17 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Fetal hydrops v1.41 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 160900; DM1; Myotonic dystrophy, congenital onset associated with a high triplet repeat number to Myotonic dystrophy 1, OMIM:160900
Congenital myopathy v2.66 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Skeletal muscle channelopathy v1.36 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 160900 to Myotonic dystrophy 1, OMIM:160900
Intellectual disability v3.1432 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 160900; DYSTROPHIA MYOTONICA TYPE 1 (DM1) to Myotonic dystrophy 1, OMIM:160900
Dystonia, chorea or related movement disorder, childhood onset v1.183 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, childhood onset v1.183 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1431 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1431 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
DDG2P v2.53 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. MOI should be changed to 'Other' to maintain consistency with other panels
DDG2P v2.53 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v2.52 DMPK Arina Puzriakova Tag Q3_21_MOI tag was added to gene: DMPK.
Paediatric motor neuronopathies v1.70 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paediatric motor neuronopathies v1.70 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Fetal anomalies v1.805 DMPK Arina Puzriakova Tag Q3_21_MOI tag was added to gene: DMPK.
Fetal anomalies v1.805 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. MOI should be changed to 'Other' to maintain consistency with other panels
Fetal anomalies v1.805 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v1.35 DMPK Arina Puzriakova Mode of pathogenicity for gene: DMPK 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
Skeletal muscle channelopathy v1.34 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal muscle channelopathy v1.34 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Skeletal muscle channelopathy v1.33 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Congenital myopathy v2.65 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Congenital myopathy v2.65 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Arthrogryposis v3.141 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Arthrogryposis v3.141 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Arthrogryposis v3.140 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Paroxysmal central nervous system disorders v1.27 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.27 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.26 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Dilated Cardiomyopathy and conduction defects v1.73 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dilated Cardiomyopathy and conduction defects v1.73 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Dilated Cardiomyopathy and conduction defects v1.72 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Gastrointestinal neuromuscular disorders v1.16 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Gastrointestinal neuromuscular disorders v1.16 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Gastrointestinal neuromuscular disorders v1.15 DMPK Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: DMPK.
Distal myopathies v1.37 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Distal myopathies v1.37 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Distal myopathies v1.36 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Fetal hydrops v1.40 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Fetal hydrops v1.40 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Skeletal Muscle Channelopathies v1.40 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal Muscle Channelopathies v1.40 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, adult onset v1.141 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Hereditary ataxia, adult onset v2.109 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
DDG2P v2.52 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Fetal anomalies v1.804 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Likely inborn error of metabolism v2.193 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Undiagnosed metabolic disorders v1.492 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Neurodegenerative disorders, adult onset v2.225 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Paroxysmal central nervous system disorders v1.26 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Hereditary ataxia v1.265 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Fetal anomalies v1.804 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from UNVERRICHT-LUNDBORG DISEASE to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset or syndromic epilepsy v2.462 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Intellectual disability v3.1430 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from UNVERRICHT-LUNDBORG DISEASE to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Dystonia, chorea or related movement disorder, childhood onset v1.182 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Early onset dystonia v1.95 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A, 254800; microcephaly and severe dyskinesia (26843564) to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset dystonia v1.94 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Dystonia, chorea or related movement disorder, childhood onset v1.182 CSTB Arina Puzriakova reviewed gene: CSTB: Rating: ; Mode of pathogenicity: None; Publications: 26843564; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) OMIM:254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.193 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Undiagnosed metabolic disorders v1.492 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Myoclonic epilepsy of Unverricht and Lundborg (Other metabolic disorders); Intellectual disability to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Neurodegenerative disorders, adult onset v2.225 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A, 254800; Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800; microcephaly and severe dyskinesia (26843564) to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Paroxysmal central nervous system disorders v1.26 CSTB Arina Puzriakova Mode of inheritance for gene: CSTB was changed from to BIALLELIC, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.25 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Hereditary ataxia v1.265 CSTB Arina Puzriakova Classified gene: CSTB as Green List (high evidence)
Hereditary ataxia v1.265 CSTB Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green as ataxia is a common part of the phenotype. This also reflects the current rating on GMS ataxia panels.
Hereditary ataxia v1.265 CSTB Arina Puzriakova Gene: cstb has been classified as Green List (High Evidence).
Hereditary ataxia v1.264 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Ataxia and cerebellar anomalies - childhood onset v2.260 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Hereditary ataxia, adult onset v2.109 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Progressive myoclonic epilepsy 1A, 254800; Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Dystonia, chorea or related movement disorder, adult onset v1.141 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from microcephaly and severe dyskinesia (26843564); Epilepsy, progressive myoclonic 1A, 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Dystonia, chorea or related movement disorder, childhood onset v1.182 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Dystonia, chorea or related movement disorder, adult onset v1.140 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Intellectual disability v3.1429 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Dystonia, chorea or related movement disorder, adult onset v1.139 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag watchlist tag was added to STR: CSTB_CCCCGCCCCGCG.
Hereditary ataxia, adult onset v2.108 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset or syndromic epilepsy v2.461 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Neurodegenerative disorders, adult onset v2.224 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Neurodegenerative disorders, adult onset v2.223 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag watchlist tag was added to STR: CSTB_CCCCGCCCCGCG.
Paroxysmal central nervous system disorders v1.24 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Hereditary ataxia v1.263 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Brain channelopathy v1.66 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Skeletal muscle channelopathy v1.33 CNBP_CCTG Arina Puzriakova commented on STR: CNBP_CCTG
Skeletal muscle channelopathy v1.33 CNBP_CCTG Arina Puzriakova Tag Q4_21_expert_review tag was added to STR: CNBP_CCTG.
Fetal anomalies v1.803 CNBP_CCTG Arina Puzriakova Classified STR: CNBP_CCTG as Red List (low evidence)
Fetal anomalies v1.803 CNBP_CCTG Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support the gene-disease association but setting rating to Red as currently the performance of the pipeline for this STR is very poor as it is located in a complex locus.
Fetal anomalies v1.803 CNBP_CCTG Arina Puzriakova Str: cnbp_cctg has been classified as Red List (Low Evidence).
Fetal anomalies v1.802 CNBP_CCTG Arina Puzriakova STR: CNBP_CCTG was added
STR: CNBP_CCTG was added to Fetal anomalies. Sources: Expert Review
STR, NGS Not Validated tags were added to STR: CNBP_CCTG.
Mode of inheritance for STR: CNBP_CCTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: CNBP_CCTG were set to Myotonic dystrophy 2, OMIM:602668
Added comment: The mutation is a CCTG repeat expansion in intron 1 of the CNBP (ZNF9) gene. The range of expanded allele sizes is 75 to 11,000 CCTG repeats, whereas normal is up to 30.

The CCTG repeat tract in normal alleles typically contains one or more tetranucleotide interruptions. The sequence interruptions that are routinely found within the CCTG tracts of normal alleles are not found in sequenced pathogenic CCTG expansions of CNBP alleles. On transmission to the next generation, CNBP repeat length sometimes diminishes dramatically, without significant differences determined by the gender of the transmitting parent.
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Copied from Rhiannon Mellis (GOSH) review of gene CNBP on Fetal anomalies panel:

This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Expert Review
Fetal anomalies v1.801 CNBP Arina Puzriakova changed review comment from: Comment on list classification: Demoted to Red, this review is for the STR entity and not the gene entity.; to: Comment on list classification: Demoted to Red, this review is for the STR entity and not the gene entity. STR added separately.
Distal myopathies v1.36 CNBP Arina Puzriakova changed review comment from: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism; to: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. MOI should be changed to 'Other' to maintain consistency with other panels
Distal myopathies v1.36 CNBP Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CNBP.
Tag Q4_21_rating tag was added to gene: CNBP.
Distal myopathies v1.36 CNBP Arina Puzriakova Classified gene: CNBP as Green List (high evidence)
Distal myopathies v1.36 CNBP Arina Puzriakova Added comment: Comment on list classification: Should be demoted to Red at the next GMS update, this review is for the STR entity and not the gene entity.
Distal myopathies v1.36 CNBP Arina Puzriakova Gene: cnbp has been classified as Green List (High Evidence).
Distal myopathies v1.35 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.801 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Fetal anomalies v1.801 CNBP Arina Puzriakova Tag for-review was removed from gene: CNBP.
Fetal anomalies v1.801 CNBP Arina Puzriakova Classified gene: CNBP as Red List (low evidence)
Fetal anomalies v1.801 CNBP Arina Puzriakova Added comment: Comment on list classification: Demoted to Red, this review is for the STR entity and not the gene entity.
Fetal anomalies v1.801 CNBP Arina Puzriakova Gene: cnbp has been classified as Red List (Low Evidence).
Fetal anomalies v1.800 CNBP Arina Puzriakova Mode of pathogenicity for gene: CNBP 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
Fetal anomalies v1.799 CNBP Arina Puzriakova Classified gene: CNBP as Red List (low evidence)
Fetal anomalies v1.799 CNBP Arina Puzriakova Gene: cnbp has been classified as Red List (Low Evidence).
Fetal anomalies v1.798 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668
COVID-19 research v1.81 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Mosaic skin disorders - Deep sequencing v1.9 PORCN Tom Cullup gene: PORCN was added
gene: PORCN was added to Mosaic skin disorders - deep sequencing. Sources: Other
Mode of inheritance for gene: PORCN was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: PORCN were set to 17546030
Phenotypes for gene: PORCN were set to Focal dermal hypoplasia (https://omim.org/entry/305600)
Penetrance for gene: PORCN were set to unknown
Review for gene: PORCN was set to GREEN
Added comment: Sources: Other
Skeletal muscle channelopathy v1.33 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal muscle channelopathy v1.33 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.23 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.23 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Primary immunodeficiency or monogenic inflammatory bowel disease v2.485 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Primary immunodeficiency or monogenic inflammatory bowel disease v2.485 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
COVID-19 research v1.81 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
COVID-19 research v1.81 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Unknown to Other
Fetal anomalies v1.797 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Fetal anomalies v1.797 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Distal myopathies v1.34 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Distal myopathies v1.34 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Skeletal Muscle Channelopathies v1.39 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal Muscle Channelopathies v1.39 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Cholestasis v1.93 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
Cholestasis v1.93 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber as there is now an additional case (see comment for publication).
Cholestasis v1.93 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
Cholestasis v1.92 FARSA Ivone Leong Added comment: Comment on publications: PMID:33598926 describes one other case with cholestasis
Cholestasis v1.92 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Cholestasis v1.91 FARSA Ivone Leong Tag watchlist tag was added to gene: FARSA.
Familial pulmonary fibrosis v1.18 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Familial pulmonary fibrosis v1.17 FARSA Ivone Leong Classified gene: FARSA as Green List (high evidence)
Familial pulmonary fibrosis v1.17 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. There is now enough evidence to support a gene-disease association (>3 cases).
Familial pulmonary fibrosis v1.17 FARSA Ivone Leong Gene: farsa has been classified as Green List (High Evidence).
Intellectual disability v3.1428 FARSA Ivone Leong Tag Q4_21_rating tag was added to gene: FARSA.
Intellectual disability v3.1428 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
Intellectual disability v3.1428 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There is now enough evidence to support a gene-disease association (>3 cases). This gene should be rated Green at the next review.
Intellectual disability v3.1428 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
Intracerebral calcification disorders v1.32 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Intracerebral calcification disorders v1.31 FARSA Ivone Leong Classified gene: FARSA as Green List (high evidence)
Intracerebral calcification disorders v1.31 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. There is now enough evidence to support a gene-disease association (>3 cases).
Intracerebral calcification disorders v1.31 FARSA Ivone Leong Gene: farsa has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - childhood onset v1.214 FARSA Ivone Leong Tag Q4_21_rating tag was added to gene: FARSA.
White matter disorders and cerebral calcification - childhood onset v1.214 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.214 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There is now enough evidence to support a gene-disease association (>3 cases). This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.214 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.213 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Familial cerebral small vessel disease v1.11 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2 108500; Migraine, familial hemiplegic, 1 141500 AD; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia 6 183086 to Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Intellectual disability v3.1427 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42 617106; Episodic ataxia, type 2 108500; Migraine, familial hemiplegic, 1 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia 6 183086 to Developemental and epileptic encephalopathy 42, OMIM:617106
Early onset or syndromic epilepsy v2.460 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42, 617106; Epilepsy and migraine; Absence epilepsy; Migraine, familial hemiplegic, 1, 141500; Familial hemiplegic migraine 1 (FHM) to Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Neurodegenerative disorders, adult onset v2.223 CACNA1A Arina Puzriakova Added comment: Comment on mode of inheritance: CACNA1A is associated with several phenotypes including SCA6 (OMIM:183086), episodic ataxia (OMIM:108500), familial hemiplegic migraine with or without ataxia (OMIM:141500), or developmental and epileptic encephalopathy (OMIM:617106). SCA6 is the only condition that may align with this panel; however, it is caused by nucleotide repeat expansions and there is a lack of relevance for SNVs.
Neurodegenerative disorders, adult onset v2.223 CACNA1A Arina Puzriakova Mode of inheritance for gene: CACNA1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Congenital myaesthenic syndrome v2.39 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from episodic ataxia plus myasthenic syndrome; hemiplegic migraine plus disturbed NMJ function to Lambert-Eaton myasthenic syndrome, MONDO:0018556
Neurodegenerative disorders, adult onset v2.222 CACNA1A Arina Puzriakova Tag treatable was removed from gene: CACNA1A.
Tag currently-ngs-unreportable tag was added to gene: CACNA1A.
Neurodegenerative disorders, adult onset v2.222 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from episodic ataxia type 2 (EA2),108500; familial hemiplegic migraine type 1, 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia; Dystonia; Spinocerebellar ataxia 6; Episodic ataxia, type 2 to Spinocerebellar ataxia 6, OMIM:183086
Paroxysmal central nervous system disorders v1.22 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, 141500; EA2; Migraine, familial hemiplegic, 1, 141500; Episodic Ataxia, Type 2; familial hemiplegic migraine type 1, 141500; episodic ataxia type 2 (EA2),108500; Spinocerebellar ataxia 6, 183086; Episodic ataxia, type 2, 108500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Albinism or congenital nystagmus v1.20 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from CACNA1A-Related Episodic Ataxia Type 2; Acetazolamide-Responsive Hereditary Paroxysmal Cerebellar Ataxia; Episodic Ataxia Type 2 (EA2) Episodic Ataxia, Nystagmus-Associated to Episodic ataxia, type 2, OMIM:108500
Hereditary ataxia v1.262 CACNA1A Arina Puzriakova Tag nucleotide-repeat-expansion was removed from gene: CACNA1A.
Dystonia, chorea or related movement disorder, adult onset v1.139 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2, OMIM:108500; Spinocerebellar ataxia 6, OMIM:183086; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Hereditary ataxia, adult onset v2.107 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from SCA6, 183086; familial hemiplegic migraine type 1, 141500; Episodic ataxia, type 2; Spinocerebellar ataxia 6; Familial hemiplegic migraine 1, 141500; Episodic ataxia type 2, 108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia; episodic ataxia type 2 (EA2),108500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Hereditary ataxia v1.262 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2; Spinocerebellar ataxia 6; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Ataxia and cerebellar anomalies - childhood onset v2.260 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia; Spinocerebellar ataxia 6; Episodic ataxia, type 2 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Skeletal muscle channelopathy v1.32 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia 2 with periodic paralysis; Epileptic encephalopathy, early infantile, 42 OMIM:617106; Migraine, familial hemiplegic, 1 OMIM:141500; Episodic ataxia, type 2 OMIM:108500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Dystonia, chorea or related movement disorder, childhood onset v1.181 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from familial hemiplegic migraine type 1, 141500; Dystonia; episodic ataxia type 2 (EA2), 108500 to Episodic ataxia, type 2, OMIM:108500
Early onset dystonia v1.94 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Dystonia to Episodic ataxia, type 2, OMIM:108500
Early onset dystonia v1.93 CACNA1A Arina Puzriakova Mode of inheritance for gene: CACNA1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain channelopathy v1.65 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from episodic ataxia type 2 (EA2),108500; familial hemiplegic migraine type 1, 141500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Skeletal Muscle Channelopathies v1.38 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Migraine, familial hemiplegic, 1, 141500; Episodic ataxia, type 2, 108500; Spinocerebellar ataxia 6, 183086; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, 141500; Episodic Ataxia, Type 2; EA2 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Familial Meniere Disease v1.2 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia type 2; migraine familial hemiplegic type 1 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Infantile nystagmus v1.4 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from CACNA1A-Related Episodic Ataxia Type 2; Episodic Ataxia Type 2 (EA2) Episodic Ataxia, Nystagmus-Associated; Acetazolamide-Responsive Hereditary Paroxysmal Cerebellar Ataxia to Episodic ataxia, type 2, OMIM:108500
Dystonia, chorea or related movement disorder, adult onset v1.138 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Dystonia, chorea or related movement disorder, adult onset v1.137 CACNA1A_CAG Arina Puzriakova Tag watchlist tag was added to STR: CACNA1A_CAG.
Hereditary ataxia, adult onset v2.106 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Neurodegenerative disorders, adult onset v2.221 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Neurodegenerative disorders, adult onset v2.220 CACNA1A_CAG Arina Puzriakova Tag watchlist tag was added to STR: CACNA1A_CAG.
Hereditary spastic paraplegia, adult onset v1.78 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Hereditary spastic paraplegia, childhood onset v2.92 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Hereditary spastic paraplegia v1.264 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Paroxysmal central nervous system disorders v1.21 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Hereditary ataxia v1.261 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Ataxia and cerebellar anomalies - childhood onset v2.259 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Ataxia and cerebellar anomalies - childhood onset v2.258 CACNA1A_CAG Arina Puzriakova Tag watchlist tag was added to STR: CACNA1A_CAG.
Brain channelopathy v1.64 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Dystonia, chorea or related movement disorder, adult onset v1.137 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Intellectual disability v3.1426 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Amyotrophic lateral sclerosis/motor neuron disease v1.46 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Neurodegenerative disorders, adult onset v2.220 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.57 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Parkinson Disease and Complex Parkinsonism v1.81 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Dystonia, chorea or related movement disorder, childhood onset v1.180 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Parkinson Disease and Complex Parkinsonism v1.80 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from (Hexanucleotideexpansion); clinical presentation suggestive of cortico-basal/PSP syndrome; complex parkinsonism to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Parkinson Disease and Complex Parkinsonism v1.79 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.79 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Parkinson Disease and Complex Parkinsonism v1.78 C9orf72 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: C9orf72.
Intellectual disability v3.1425 C9orf72 Arina Puzriakova Mode of pathogenicity for gene: C9orf72 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
Dystonia, chorea or related movement disorder, adult onset v1.136 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.136 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1424 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1424 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Amyotrophic lateral sclerosis/motor neuron disease v1.45 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Amyotrophic lateral sclerosis/motor neuron disease v1.45 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Neurodegenerative disorders, adult onset v2.219 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.219 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.56 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.56 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, childhood onset v1.179 C9orf72 Arina Puzriakova commented on gene: C9orf72
Dystonia, chorea or related movement disorder, childhood onset v1.179 C9orf72 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: C9orf72.
Dystonia, chorea or related movement disorder, childhood onset v1.179 C9orf72 Arina Puzriakova Tag Q2_21_phenotype was removed from gene: C9orf72.
Tag Q2_21_expert_review was removed from gene: C9orf72.
Tag Q4_21_rating tag was added to gene: C9orf72.
Dystonia, chorea or related movement disorder, childhood onset v1.179 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Dystonia, chorea or related movement disorder, adult onset v1.135 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from complex parkinsonism; (Hexanucleotideexpansion); clinical presentation suggestive of cortico-basal/PSP syndrome to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Intellectual disability v3.1423 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Dystonia, chorea or related movement disorder, adult onset v1.134 C9orf72 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: C9orf72.
Tag currently-ngs-unreportable tag was added to gene: C9orf72.
Amyotrophic lateral sclerosis/motor neuron disease v1.44 C9orf72 Arina Puzriakova Publications for gene: C9orf72 were set to PMID: 21944778; 21944779; 25638642; 27059391; 23597494
Amyotrophic lateral sclerosis/motor neuron disease v1.43 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; Hexanucleotide repeat expansion; Frontotemporal Dementia, Amyotrophic Lateral Sclerosis; amyotrophic lateral sclerosis; frontotemporal dementia; Frontotemporal Dementia, Amyotrophic Lateral Sclerosis to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Amyotrophic lateral sclerosis/motor neuron disease v1.42 C9orf72 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: C9orf72.
Neurodegenerative disorders, adult onset v2.218 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from complex parkinsonism; Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; clinical presentation suggestive of cortico-basal/PSP syndrome; (Hexanucleotideexpansion); Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis; Clinical syndrome FTLD (Frontotemporal lobar degeneration); Frontotemporal Dementia, Amyotrophic Lateral Sclerosis; Hexanucleotide repeat expansion; amyotrophic lateral sclerosis; frontotemporal dementia to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.55 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis; Clinical syndrome FTLD (Frontotemporal lobar degeneration) to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Fetal anomalies v1.796 MMP15 Ivone Leong Tag watchlist tag was added to gene: MMP15.
Fetal anomalies v1.796 MMP15 Ivone Leong Classified gene: MMP15 as Amber List (moderate evidence)
Fetal anomalies v1.796 MMP15 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 describes 3 patients from 2 families with biallelic variants in MMP15 (one is Pro353fs and other is Gly231Arg). One family with 2 affected siblings presented with cholestasis, hepatomegaly, high hepatic transaminases, and congenital heart disease. The other unrelated case showed similar symptoms.

As there are only 2 cases and currently there are no animal models that replicate the human phenotype this gene has been given an Amber rating until more evidence is available.
Fetal anomalies v1.796 MMP15 Ivone Leong Gene: mmp15 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.795 MMP15 Ivone Leong Phenotypes for gene: MMP15 were changed from Cholestasis; congenital heart disease to Cholestasis, MONDO:0001751; congenital heart disease, MONDO:0005453
Fetal anomalies v1.794 MMP15 Ivone Leong Publications for gene: MMP15 were set to PMID: 33875846
Cholestasis v1.91 MMP15 Ivone Leong Tag watchlist tag was added to gene: MMP15.
Cholestasis v1.91 MMP15 Ivone Leong Classified gene: MMP15 as Amber List (moderate evidence)
Cholestasis v1.91 MMP15 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 describes 3 patients from 2 families with biallelic variants in MMP15 (one is Pro353fs and other is Gly231Arg). One family with 2 affected siblings presented with cholestasis, hepatomegaly, high hepatic transaminases, and congenital heart disease. The other unrelated case showed similar symptoms.

As there are only 2 cases and currently there are no animal models that replicate the human phenotype this gene has been given an Amber rating until more evidence is available.
Cholestasis v1.91 MMP15 Ivone Leong Gene: mmp15 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.90 MMP15 Ivone Leong Phenotypes for gene: MMP15 were changed from Cholestasis; congenital heart disease to Cholestasis, MONDO:0001751; congenital heart disease, MONDO:0005453
Cholestasis v1.89 MMP15 Ivone Leong Publications for gene: MMP15 were set to PMID: 33875846
Retinal disorders v2.233 ATXN7 Arina Puzriakova Mode of pathogenicity for gene: ATXN7 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
Retinal disorders v2.232 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Intellectual disability v3.1422 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia, adult onset v2.105 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary neuropathy v1.422 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500; Adult onset, cerebellar ataxia, pigmentary macular degeneration, sensory-motor axonal neuropathy to Spinocerebellar ataxia 7, OMIM:164500
Undiagnosed metabolic disorders v1.491 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Neurodegenerative disorders, adult onset v2.217 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Neurodegenerative disorders, adult onset v2.216 ATXN7_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN7_CAG.
Hereditary spastic paraplegia, adult onset v1.77 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary spastic paraplegia, childhood onset v2.91 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary spastic paraplegia v1.263 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia v1.260 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Ataxia and cerebellar anomalies - childhood onset v2.258 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Retinal disorders v2.232 ATXN7 Arina Puzriakova Classified gene: ATXN7 as Red List (low evidence)
Retinal disorders v2.232 ATXN7 Arina Puzriakova Gene: atxn7 has been classified as Red List (Low Evidence).
Retinal disorders v2.231 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Retinal disorders v2.231 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from to Other
Retinal disorders v2.230 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from to Spinocerebellar ataxia 7, OMIM:164500
Intellectual disability v3.1421 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Likely inborn error of metabolism v2.192 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7 164500; Spinocerebellar ataxia-7 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Spinocerebellar ataxia 7, OMIM:164500; Mitochondrial respiratory chain disorders (caused by nuclear variants only)
Dystonia, chorea or related movement disorder, childhood onset v1.178 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7, 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia, adult onset v2.104 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia 7,164500; Spinocerebellar ataxia 7, 164500 to Spinocerebellar ataxia 7, OMIM:164500
Undiagnosed metabolic disorders v1.490 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia-7 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Neurodegenerative disorders, adult onset v2.216 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia7,164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia v1.259 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia7,164500 to Spinocerebellar ataxia 7, OMIM:164500
Ataxia and cerebellar anomalies - childhood onset v2.257 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia7,164500 to Spinocerebellar ataxia 7, OMIM:164500
Dystonia, chorea or related movement disorder, childhood onset v1.177 ATXN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN1.
Tag currently-ngs-unreportable tag was added to gene: ATXN1.
Dystonia, chorea or related movement disorder, childhood onset v1.177 ATXN1 Arina Puzriakova Classified gene: ATXN1 as Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.177 ATXN1 Arina Puzriakova Gene: atxn1 has been classified as Red List (Low Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.176 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, childhood onset v1.176 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, childhood onset v1.175 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, childhood onset v1.175 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Dystonia, chorea or related movement disorder, childhood onset v1.174 ATXN7 Arina Puzriakova Classified gene: ATXN7 as Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.174 ATXN7 Arina Puzriakova Gene: atxn7 has been classified as Red List (Low Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.173 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Intellectual disability v3.1420 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1420 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Likely inborn error of metabolism v2.191 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Likely inborn error of metabolism v2.191 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Hereditary ataxia, adult onset v2.103 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.103 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from Unknown to Other
Likely inborn error of metabolism v2.190 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Undiagnosed metabolic disorders v1.489 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Undiagnosed metabolic disorders v1.489 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Neurodegenerative disorders, adult onset v2.215 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.215 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from Unknown to Other
Hereditary ataxia v1.258 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.258 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from to Other
Ataxia and cerebellar anomalies - childhood onset v2.256 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.256 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from Unknown to Other
Ataxia and cerebellar anomalies - childhood onset v2.255 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Dystonia, chorea or related movement disorder, adult onset v1.134 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Dystonia, chorea or related movement disorder, adult onset v1.133 ATXN3_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN3_CAG.
Hereditary ataxia, adult onset v2.102 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Hereditary neuropathy v1.421 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1419 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Neurodegenerative disorders, adult onset v2.214 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Neurodegenerative disorders, adult onset v2.213 ATXN3_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN3_CAG.
Hereditary spastic paraplegia, adult onset v1.76 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Hereditary spastic paraplegia, childhood onset v2.90 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Hereditary spastic paraplegia v1.262 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Hereditary ataxia v1.257 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - childhood onset v2.255 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - childhood onset v2.254 ATXN3_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN3_CAG.
Early onset dystonia v1.92 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Parkinson Disease and Complex Parkinsonism v1.78 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1418 ATXN3 Arina Puzriakova Mode of pathogenicity for gene: ATXN3 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
Dystonia, chorea or related movement disorder, adult onset v1.133 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.133 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia, adult onset v2.101 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.101 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from Unknown to Other
Neurodegenerative disorders, adult onset v2.213 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.213 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia v1.256 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.256 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from to Other
Intellectual disability v3.1417 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1417 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Ataxia and cerebellar anomalies - childhood onset v2.254 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.254 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from Unknown to Other
Parkinson Disease and Complex Parkinsonism v1.77 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.77 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1416 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Dystonia, chorea or related movement disorder, adult onset v1.132 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from (CAGexpansion); familial parkinsonism to Machado-Joseph disease, OMIM:109150
Dystonia, chorea or related movement disorder, adult onset v1.131 ATXN3 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN3.
Tag currently-ngs-unreportable tag was added to gene: ATXN3.
Hereditary ataxia, adult onset v2.100 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from Machado-Joseph disease, 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1415 ATXN3 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN3.
Neurodegenerative disorders, adult onset v2.212 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from familial parkinsonism; (CAGexpansion) to Machado-Joseph disease, OMIM:109150; Susceptibility to Late-Onset Parkinson Disease
Hereditary ataxia v1.255 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - childhood onset v2.253 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - childhood onset v2.252 ATXN3 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN3.
Tag currently-ngs-unreportable tag was added to gene: ATXN3.
Parkinson Disease and Complex Parkinsonism v1.76 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from (CAGexpansion); familial parkinsonism to Machado-Joseph disease, OMIM:109150; Susceptibility to Late-Onset Parkinson Disease
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 TARS Alan Lehmann reviewed gene: TARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 CARS Alan Lehmann reviewed gene: CARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1415 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 MARS Alan Lehmann reviewed gene: MARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.261 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 AARS Alan Lehmann reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy v1.420 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Hereditary spastic paraplegia, adult onset v1.75 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Hereditary spastic paraplegia, childhood onset v2.89 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Ataxia and cerebellar anomalies - childhood onset v2.252 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090
Amyotrophic lateral sclerosis/motor neuron disease v1.42 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Neurodegenerative disorders, adult onset v2.211 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Neurodegenerative disorders, adult onset v2.210 ATXN2_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN2_CAG.
Hereditary ataxia v1.254 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090
Hereditary ataxia, adult onset v2.99 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090
Dystonia, chorea or related movement disorder, adult onset v1.131 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Dystonia, chorea or related movement disorder, adult onset v1.130 ATXN2_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN2_CAG.
Dystonia, chorea or related movement disorder, childhood onset v1.173 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2, 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Early onset dystonia v1.91 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.54 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.75 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1414 ATXN2 Arina Puzriakova Mode of pathogenicity for gene: ATXN2 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
Neurodegenerative disorders, adult onset v2.210 ATXN2 Arina Puzriakova Mode of pathogenicity for gene: ATXN2 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
Dystonia, chorea or related movement disorder, adult onset v1.130 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.130 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia, adult onset v2.98 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.98 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from Unknown to Other
Intellectual disability v3.1413 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1413 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Amyotrophic lateral sclerosis/motor neuron disease v1.41 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Amyotrophic lateral sclerosis/motor neuron disease v1.41 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from to Other
Hereditary ataxia v1.253 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.253 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from to Other
Ataxia and cerebellar anomalies - childhood onset v2.251 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.251 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from Unknown to Other
Neurodegenerative disorders, adult onset v2.209 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.209 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Ataxia and cerebellar anomalies - childhood onset v2.250 ATXN2 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN2.
Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Hereditary ataxia, adult onset v2.97 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellarataxia2, 183090; Spinocerebellar ataxia 2, 183090; {Amyotrophiclateralsclerosis,susceptibilityto,13},183090 to Spinocerebellar ataxia 2, OMIM:183090
Dystonia, chorea or related movement disorder, adult onset v1.129 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from {Parkinson disease, late-onset, susceptibility to}, 168600; (CAGexpansion); familial parkinsonism; Spinocerebellar ataxia 2, 183190; {Amyotrophic lateral sclerosis, susceptibility to, 13}, 183190 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Dystonia, chorea or related movement disorder, adult onset v1.128 ATXN2 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN2.
Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Intellectual disability v3.1412 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2 183090; {Amyotrophic lateral sclerosis, susceptibility to, 13} 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1411 ATXN2 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Amyotrophic lateral sclerosis/motor neuron disease v1.40 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2, 183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, 183090 to {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Amyotrophic lateral sclerosis/motor neuron disease v1.39 ATXN2 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Hereditary ataxia v1.252 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellarataxia2,183090{Amyotrophiclateralsclerosis,susceptibilityto,13},183090 to Spinocerebellar ataxia 2, OMIM:183090
Ataxia and cerebellar anomalies - childhood onset v2.250 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellarataxia2,183090{Amyotrophiclateralsclerosis,susceptibilityto,13},183090 to Spinocerebellar ataxia 2, OMIM:183090
Neurodegenerative disorders, adult onset v2.208 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2, 183090; familial parkinsonism; {Amyotrophic lateral sclerosis, susceptibility to, 13}, 183090; Spinocerebellarataxia2,183090{Amyotrophiclateralsclerosis,susceptibilityto,13},183090; (CAGexpansion) to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.74 ATXN2 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Parkinson Disease and Complex Parkinsonism v1.74 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.74 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Parkinson Disease and Complex Parkinsonism v1.73 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from (CAGexpansion); familial parkinsonism to {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1411 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary ataxia, adult onset v2.96 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary neuropathy v1.419 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Neurodegenerative disorders, adult onset v2.207 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Neurodegenerative disorders, adult onset v2.206 ATXN10_ATTCT Arina Puzriakova Tag watchlist tag was added to STR: ATXN10_ATTCT.
Hereditary spastic paraplegia, adult onset v1.74 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary spastic paraplegia, adult onset v1.73 ATXN10_ATTCT Arina Puzriakova Tag watchlist tag was added to STR: ATXN10_ATTCT.
Skeletal dysplasia v2.151 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary spastic paraplegia, childhood onset v2.88 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary spastic paraplegia v1.260 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary ataxia v1.251 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Thoracic dystrophies v1.15 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - childhood onset v2.249 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - childhood onset v2.248 ATXN10_ATTCT Arina Puzriakova Tag watchlist tag was added to STR: ATXN10_ATTCT.
Early onset dystonia v1.90 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.53 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Dystonia, chorea or related movement disorder, childhood onset v1.172 ATXN10 Arina Puzriakova Mode of pathogenicity for gene: ATXN10 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
Dystonia, chorea or related movement disorder, childhood onset v1.171 ATXN10 Arina Puzriakova Classified gene: ATXN10 as Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.171 ATXN10 Arina Puzriakova Gene: atxn10 has been classified as Red List (Low Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.170 ATXN10 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN10.
Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Rare multisystem ciliopathy disorders v1.151 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Neurodegenerative disorders, adult onset v2.206 ATXN10 Arina Puzriakova Tag watchlist was removed from gene: ATXN10.
Skeletal dysplasia v2.150 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Primary ciliary disorders v1.35 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Hereditary ataxia v1.250 ATXN10 Arina Puzriakova Tag watchlist was removed from gene: ATXN10.
Thoracic dystrophies v1.14 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Ataxia and cerebellar anomalies - childhood onset v2.248 ATXN10 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN10.
Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Dystonia, chorea or related movement disorder, childhood onset v1.170 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, childhood onset v1.170 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1410 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1410 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Rare multisystem ciliopathy disorders v1.151 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Rare multisystem ciliopathy disorders v1.151 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Hereditary ataxia, adult onset v2.95 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.95 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from Unknown to Other
Skeletal dysplasia v2.150 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal dysplasia v2.150 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Neurodegenerative disorders, adult onset v2.206 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.206 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from Unknown to Other
Primary ciliary disorders v1.35 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Primary ciliary disorders v1.35 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Hereditary ataxia v1.250 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.250 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Thoracic dystrophies v1.14 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Thoracic dystrophies v1.14 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Ataxia and cerebellar anomalies - childhood onset v2.248 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.248 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from Unknown to Other
Dystonia, chorea or related movement disorder, childhood onset v1.169 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10, 603516 to Spinocerebellar ataxia 10, OMIM:603516
Rare multisystem ciliopathy disorders v1.150 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10, 603516; Ciliopathies to Spinocerebellar ataxia 10, OMIM:603516; Ciliopathies
Hereditary ataxia, adult onset v2.94 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10, 603516; Spinocerebellarataxia10, 603516 to Spinocerebellar ataxia 10, OMIM:603516
Intellectual disability v3.1409 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Neurodegenerative disorders, adult onset v2.205 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellarataxia10,603516 to Spinocerebellar ataxia 10, OMIM:603516
Skeletal dysplasia v2.149 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from to Spinocerebellar ataxia 10, OMIM:603516
Primary ciliary disorders v1.34 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from ciliopathies to Spinocerebellar ataxia 10, OMIM:603516; Ciliopathies
Hereditary ataxia v1.249 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellarataxia10,603516 to Spinocerebellar ataxia 10, OMIM:603516
Thoracic dystrophies v1.13 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - childhood onset v2.247 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellarataxia10,603516 to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - childhood onset v2.246 ATN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.128 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia, adult onset v2.93 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset or syndromic epilepsy v2.459 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Neurodegenerative disorders, adult onset v2.204 ATN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATN1_CAG.
Neurodegenerative disorders, adult onset v2.204 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Paroxysmal central nervous system disorders v1.20 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia v1.248 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Ataxia and cerebellar anomalies - childhood onset v2.246 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Brain channelopathy v1.63 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.52 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Parkinson Disease and Complex Parkinsonism v1.72 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Neurodegenerative disorders, adult onset v2.203 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Paroxysmal central nervous system disorders v1.19 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy, 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Brain channelopathy v1.62 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.51 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia v1.247 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Ataxia and cerebellar anomalies - childhood onset v2.245 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Dystonia, chorea or related movement disorder, childhood onset v1.168 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, childhood onset v1.168 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Dystonia, chorea or related movement disorder, childhood onset v1.167 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy, 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Dystonia, chorea or related movement disorder, childhood onset v1.166 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Dystonia, chorea or related movement disorder, adult onset v1.127 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia, adult onset v2.92 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentato-pallidoluysian atrophy; Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Dystonia, chorea or related movement disorder, adult onset v1.126 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Dystonia, chorea or related movement disorder, adult onset v1.126 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dystonia, chorea or related movement disorder, adult onset v1.126 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Hereditary ataxia, adult onset v2.91 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia, adult onset v2.91 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Hereditary ataxia v1.246 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.246 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from Other - please specifiy in evaluation comments to Other
Ataxia and cerebellar anomalies - childhood onset v2.244 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - childhood onset v2.244 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from Other - please specifiy in evaluation comments to Other
DDG2P v2.52 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from congenital hypotonia, epilepsy, developmental delay, digit abnormalities to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Paroxysmal central nervous system disorders v1.18 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Ataxia and cerebellar anomalies - childhood onset v2.243 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.50 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.50 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Brain channelopathy v1.61 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Brain channelopathy v1.61 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Paroxysmal central nervous system disorders v1.18 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.18 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Neurodegenerative disorders, adult onset v2.202 ATN1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Nucleotide repeat expansion; to: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Neurodegenerative disorders, adult onset v2.202 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Nucleotide repeat expansion
Neurodegenerative disorders, adult onset v2.202 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Intellectual disability v3.1408 ATN1 Arina Puzriakova Publications for gene: ATN1 were set to 24972706; 30827498
Intellectual disability v3.1407 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Early onset or syndromic epilepsy v2.458 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures; Generalized hypotonia to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 ZNFX1 Sophie Hambleton reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Haematological malignancies cancer susceptibility v2.21 RPS27A Arina Puzriakova Tag pharmacogenetic was removed from gene: RPS27A.
Tag pharmacogenetics tag was added to gene: RPS27A.
Sarcoma cancer susceptibility v1.20 T Arina Puzriakova Tag cnvs was removed from gene: T.
Tag cnv tag was added to gene: T.
Intellectual disability v3.1406 KIDINS220 Dmitrijs Rots reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33763417; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia v1.259 KIDINS220 Dmitrijs Rots reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33763417; Phenotypes: Spastic paraplegia, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1406 VAMP7 Ivone Leong Tag Pseudoautosomal region 2 tag was added to gene: VAMP7.
Intellectual disability v3.1406 SPRY3 Ivone Leong Tag Pseudoautosomal region 2 tag was added to gene: SPRY3.
Intellectual disability v3.1406 SLC25A6 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SLC25A6.
Skeletal dysplasia v2.148 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Limb disorders v2.65 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
IUGR and IGF abnormalities v1.41 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Radial dysplasia v1.15 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Fetal anomalies v1.793 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Osteogenesis imperfecta v2.37 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
DDG2P v2.51 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Intellectual disability v3.1406 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Intellectual disability v3.1406 PLCXD1 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: PLCXD1.
Intellectual disability v3.1406 P2RY8 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: P2RY8.
Intellectual disability v3.1406 IL3RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: IL3RA.
Intellectual disability v3.1406 DHRSX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: DHRSX.
Intellectual disability v3.1406 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Familial pulmonary fibrosis v1.16 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
COVID-19 research v1.80 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Intellectual disability v3.1406 CRLF2 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CRLF2.
Intellectual disability v3.1406 CD99 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CD99.
Intellectual disability v3.1406 ASMTL Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: ASMTL.
Intellectual disability v3.1406 ASMT Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: ASMT.
Intellectual disability v3.1406 AKAP17A Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: AKAP17A.
Fetal anomalies v1.793 RFT1 Ivone Leong Tag for-reivew was removed from gene: RFT1.
Fetal anomalies v1.793 RFT1 Ivone Leong Tag for-review tag was added to gene: RFT1.
Intellectual disability v3.1406 NUP85 Eleanor Williams Classified gene: NUP85 as Amber List (moderate evidence)
Intellectual disability v3.1406 NUP85 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 2 cases reported but degree of ID not confirmed in the second family.
Intellectual disability v3.1406 NUP85 Eleanor Williams Gene: nup85 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1405 NUP85 Eleanor Williams changed review comment from: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature; to: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction.

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro) in NUP85.
Sources: Literature
Intellectual disability v3.1405 NUP85 Eleanor Williams gene: NUP85 was added
gene: NUP85 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NUP85 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP85 were set to 34170319
Phenotypes for gene: NUP85 were set to Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS)
Review for gene: NUP85 was set to AMBER
Added comment: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature
DDG2P v2.51 EDNRB Ivone Leong Tag Q4_21_MOI tag was added to gene: EDNRB.
DDG2P v2.51 EDNRB Ivone Leong Publications for gene: EDNRB were set to 7778600
DDG2P v2.50 EDNRB Ivone Leong reviewed gene: EDNRB: Rating: ; Mode of pathogenicity: None; Publications: 7778600, 11891690; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.18 EDNRB Ivone Leong Added comment: Comment on mode of inheritance: MOI 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" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Pigmentary skin disorders v1.18 EDNRB Ivone Leong Mode of inheritance for gene: EDNRB 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
Monogenic hearing loss v2.209 EDNRB Ivone Leong Added comment: Comment on mode of inheritance: MOI 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" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Monogenic hearing loss v2.209 EDNRB Ivone Leong Mode of inheritance for gene: EDNRB 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
Fetal anomalies v1.793 EDNRB Ivone Leong Publications for gene: EDNRB were set to
Fetal anomalies v1.792 EDNRB Ivone Leong reviewed gene: EDNRB: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.792 EDNRB Ivone Leong Tag Q4_21_MOI tag was added to gene: EDNRB.
Fetal anomalies v1.792 SMARCE1 Arina Puzriakova Classified gene: SMARCE1 as Amber List (moderate evidence)
Fetal anomalies v1.792 SMARCE1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.792 SMARCE1 Arina Puzriakova Gene: smarce1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.791 SMARCE1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SMARCE1.
Skeletal dysplasia v2.148 SMARCE1 Arina Puzriakova Mode of inheritance for gene: SMARCE1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.147 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from Coffin-Siris syndrome to Coffin-Siris syndrome 5, OMIM:616938
Familial Tumours Syndromes of the central & peripheral Nervous system v1.11 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from familial spinal and cranial meningiomas to {Meningioma, familial, susceptibility to}, OMIM:607174
Fetal anomalies v1.791 SMARCE1 Arina Puzriakova Publications for gene: SMARCE1 were set to
Fetal anomalies v1.790 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from COFFIN SIRIS to Coffin-Siris syndrome 5, OMIM:616938
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 CXCR2 Sophie Hambleton reviewed gene: CXCR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.208 EDN3 Ivone Leong Added comment: Comment on mode of inheritance: MOI 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" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Monogenic hearing loss v2.208 EDN3 Ivone Leong Mode of inheritance for gene: EDN3 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
Pigmentary skin disorders v1.17 EDN3 Ivone Leong Added comment: Comment on mode of inheritance: MOI 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" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Pigmentary skin disorders v1.17 EDN3 Ivone Leong Mode of inheritance for gene: EDN3 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
Arthrogryposis v3.140 SLC6A9 Arina Puzriakova Classified gene: SLC6A9 as Amber List (moderate evidence)
Arthrogryposis v3.140 SLC6A9 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Arthrogryposis v3.140 SLC6A9 Arina Puzriakova Gene: slc6a9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.789 SLC6A9 Arina Puzriakova Classified gene: SLC6A9 as Amber List (moderate evidence)
Fetal anomalies v1.789 SLC6A9 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.789 SLC6A9 Arina Puzriakova Gene: slc6a9 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.139 SLC6A9 Arina Puzriakova Publications for gene: SLC6A9 were set to 27773429; 27481395
Fetal anomalies v1.788 SLC6A9 Arina Puzriakova Publications for gene: SLC6A9 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 CTNNBL1 Sophie Hambleton reviewed gene: CTNNBL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.138 SLC6A9 Arina Puzriakova Phenotypes for gene: SLC6A9 were changed from Glycine encephalopathy with normal serum glycine, 617301; Glycine Encephalopathy with Arthrogryposis to Glycine encephalopathy with normal serum glycine, OMIM:617301
Fetal anomalies v1.787 SLC6A9 Arina Puzriakova Phenotypes for gene: SLC6A9 were changed from Glycine Encephalopathy with Arthrogryposis to Glycine encephalopathy with normal serum glycine, OMIM:617301; Arthrogryposis, MONDO:0008779
Fetal anomalies v1.786 SLC6A9 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SLC6A9.
Arthrogryposis v3.137 SLC6A9 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SLC6A9.
Intellectual disability v3.1404 SLC6A9 Arina Puzriakova Phenotypes for gene: SLC6A9 were changed from Glycine encephalopathy with normal serum glycine, 617301; Glycine encephalopathy and global developmental delay to Glycine encephalopathy with normal serum glycine, OMIM:617301
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: PRRX1.
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Classified gene: PRRX1 as Amber List (moderate evidence)
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Gene: prrx1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.785 PRRX1 Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' for now as 3 unrelated cases of otocephaly with private heterozygous LoF variants have been reported in literature to date, but only one patient with a homozygous alteration. May be reviewed if evidence of further cases emerges.
Fetal anomalies v1.785 PRRX1 Arina Puzriakova Mode of inheritance for gene: PRRX1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.207 PRRX1 Arina Puzriakova Phenotypes for gene: PRRX1 were changed from to Agnathia-otocephaly complex, OMIM:202650
Fetal anomalies v1.784 PRRX1 Arina Puzriakova Phenotypes for gene: PRRX1 were changed from Agnathia-otocephaly complex to Agnathia-otocephaly complex, OMIM:202650
Fetal anomalies v1.783 PRIM1 Arina Puzriakova Classified gene: PRIM1 as Amber List (moderate evidence)
Fetal anomalies v1.783 PRIM1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.783 PRIM1 Arina Puzriakova Gene: prim1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.782 PRIM1 Arina Puzriakova Publications for gene: PRIM1 were set to PMID: 33060134
Fetal anomalies v1.781 PRIM1 Arina Puzriakova Phenotypes for gene: PRIM1 were changed from Primordial dwarfism to Microcephalic primordial dwarfism, MONDO:0017950
Fetal anomalies v1.780 PRIM1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: PRIM1.
Fetal anomalies v1.780 POLR1B Arina Puzriakova Publications for gene: POLR1B were set to PMID: 31649276
Fetal anomalies v1.779 POLR1B Arina Puzriakova Phenotypes for gene: POLR1B were changed from Treacher-Collins syndrome 4 to Treacher-Collins syndrome 4 OMIM:618939
Fetal anomalies v1.778 POLR1B Arina Puzriakova Classified gene: POLR1B as Amber List (moderate evidence)
Fetal anomalies v1.778 POLR1B Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.778 POLR1B Arina Puzriakova Gene: polr1b has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.777 POLR1B Arina Puzriakova Tag Q4_21_rating tag was added to gene: POLR1B.
Fetal anomalies v1.777 MN1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: MN1.
Intellectual disability v3.1403 CLPB Ivone Leong Phenotypes for gene: CLPB were changed from 3-METHYLGLUTACONIC ACIDURIA, TYPE VII, WITH CATARACTS, NEUROLOGIC INVOLVEMENT AND NEUTROPENIA to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Early onset or syndromic epilepsy v2.457 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from {Lipodystrophy, partial, acquired, susceptibility to}, 608709; ?Epilepsy, progressive myoclonic, 9, 616540 to ?Epilepsy, progressive myoclonic, 9, OMIM:616540
Intellectual disability v3.1402 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Severe microcephaly v2.270 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Early onset or syndromic epilepsy v2.456 GNB2 Eleanor Williams Entity copied from Mosaic skin disorders - deep sequencing v1.9
Early onset or syndromic epilepsy v2.456 GNB2 Eleanor Williams gene: GNB2 was added
gene: GNB2 was added to Genetic epilepsy syndromes. Sources: Literature
somatic tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 34124757
Phenotypes for gene: GNB2 were set to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Early onset or syndromic epilepsy v2.455 GNAQ Eleanor Williams Tag mosaicism tag was added to gene: GNAQ.
Tag somatic tag was added to gene: GNAQ.
Early onset or syndromic epilepsy v2.455 GNAQ Eleanor Williams Phenotypes for gene: GNAQ were changed from Sturge-Weber syndrome, somatic, mosaic, 185300 to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Early onset or syndromic epilepsy v2.454 GNAQ Eleanor Williams Publications for gene: GNAQ were set to 25374402; 23656586; 28126187
Early onset or syndromic epilepsy v2.453 GNAQ Eleanor Williams reviewed gene: GNAQ: Rating: ; Mode of pathogenicity: None; Publications: 34124757; Phenotypes: Sturge-Weber syndrome, somatic, mosaic, OMIM:185300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mosaic skin disorders - Deep sequencing v1.9 GNB2 Eleanor Williams gene: GNB2 was added
gene: GNB2 was added to Mosaic skin disorders - deep sequencing. Sources: Literature
somatic tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 34124757
Phenotypes for gene: GNB2 were set to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Review for gene: GNB2 was set to RED
Added comment: PMID: 34124757 Fjaer et al 2021 report 1 case of a patient with phenotypic features of Sturge–Weber syndrome (skin legion on left eyelid, nose and brow, mild intellectual disability, refractory eplipsy, left-sided leptomeningeal vascular malformation and atrophy, no eye abnormality) and a variant in GNB2 (NM_005273.3):c.232A>G:p.Lys78Glu, which was present in 6% of the reads from the lesional dermis and 21% of the reads in an endothelial culture from the biopsy, but only present at 0.15% of the reads in non-lesional dermis. The patient was negative for the GNAQ R183Q variant more frequently associated with Sturge–Weber syndrome.
Sources: Literature
Fetal anomalies v1.777 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Microcephaly 27, primary, autosomal dominant to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Fetal anomalies v1.776 LMNB2 Arina Puzriakova Publications for gene: LMNB2 were set to PMID: 33033404
Fetal anomalies v1.775 LMNB2 Arina Puzriakova Classified gene: LMNB2 as Amber List (moderate evidence)
Fetal anomalies v1.775 LMNB2 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.775 LMNB2 Arina Puzriakova Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.774 LMNB2 Arina Puzriakova Tag Q4_21_rating tag was added to gene: LMNB2.
Fetal anomalies v1.774 LMNB1 Arina Puzriakova Publications for gene: LMNB1 were set to PMID: 33033404
Fetal anomalies v1.773 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Microcephaly 26, primary, autosomal dominant to Microcephaly 26, primary, autosomal dominant, OMIM:619179
White matter disorders and cerebral calcification - childhood onset v1.212 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Leukodystrophy,adult-onset, autosomal dominant,169500; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Adult onset autosomal dominant leukodystrophy (ADLD) to Leukodystrophy, adult-onset, autosomal dominant, OMIM:169500
Leukodystrophy, adult onset v1.33 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Leukodystrophy, adult-onset, autosomal dominant, 169500 to Leukodystrophy, adult-onset, autosomal dominant, OMIM:169500
Inherited white matter disorders v1.145 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Leukodystrophy,adult-onset, autosomal dominant,169500; Adult onset autosomal dominant leukodystrophy (ADLD); General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukodystrophy, adult-onset, autosomal dominant, OMIM:169500
Early onset or syndromic epilepsy v2.453 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Intellectual disability v3.1401 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Severe microcephaly v2.269 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Fetal anomalies v1.772 LMNB1 Arina Puzriakova Classified gene: LMNB1 as Amber List (moderate evidence)
Fetal anomalies v1.772 LMNB1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.772 LMNB1 Arina Puzriakova Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.771 LMNB1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: LMNB1.
Fetal anomalies v1.771 GREB1L Arina Puzriakova Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, 617805; renal agenesis to Renal hypodysplasia/aplasia 3, OMIM:617805; Renal agenesis, MONDO:0018470
Fetal anomalies v1.770 FLNC Arina Puzriakova Tag Q4_21_rating tag was added to gene: FLNC.
Fetal anomalies v1.770 FLNC Arina Puzriakova Classified gene: FLNC as Amber List (moderate evidence)
Fetal anomalies v1.770 FLNC Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.770 FLNC Arina Puzriakova Gene: flnc has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.769 FLNC Arina Puzriakova Publications for gene: FLNC were set to PMID: 33060286; 29858533
Fetal anomalies v1.768 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Arthrogryposis to Arthrogryposis, MONDO:0008779
Mosaic skin disorders - Deep sequencing v1.8 GNAQ Eleanor Williams Phenotypes for gene: GNAQ were changed from Phakomatosis pigmentovascularis; Extensive dermal melanocytosis; Sturge Weber syndrome to Phakomatosis pigmentovascularis; Extensive dermal melanocytosis; Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Mosaic skin disorders - Deep sequencing v1.7 GNAQ Eleanor Williams Publications for gene: GNAQ were set to 26778290
Mosaic skin disorders - Deep sequencing v1.6 GNAQ Eleanor Williams Mode of pathogenicity for gene: GNAQ 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
Mosaic skin disorders - Deep sequencing v1.5 GNAQ Eleanor Williams reviewed gene: GNAQ: Rating: ; Mode of pathogenicity: None; Publications: 34124757; Phenotypes: Sturge-Weber syndrome, somatic, mosaic, OMIM:185300; Mode of inheritance: None
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: EXTL3.
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Classified gene: EXTL3 as Amber List (moderate evidence)
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Gene: extl3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.766 EXTL3 Arina Puzriakova Publications for gene: EXTL3 were set to
Intellectual disability v3.1400 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425 to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Skeletal dysplasia v2.146 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425; Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425 to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities, 617425; EXTL3 deficiency; Platyspondyly, kyphosis, variable skeletal dysplasias, developmental delay; Combined immunodeficiencies with associated or syndromic features to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Fetal anomalies v1.765 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Fetal anomalies v1.764 ENPP1 Arina Puzriakova Classified gene: ENPP1 as Amber List (moderate evidence)
Fetal anomalies v1.764 ENPP1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.764 ENPP1 Arina Puzriakova Gene: enpp1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.763 ENPP1 Arina Puzriakova Phenotypes for gene: ENPP1 were changed from HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2; ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1 to Arterial calcification, generalized, of infancy, 1, OMIM:208000
Fetal anomalies v1.762 ENPP1 Arina Puzriakova Publications for gene: ENPP1 were set to
Fetal anomalies v1.761 ENPP1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: ENPP1.
Fetal anomalies v1.761 EIF5A Arina Puzriakova Classified gene: EIF5A as Amber List (moderate evidence)
Fetal anomalies v1.761 EIF5A Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.761 EIF5A Arina Puzriakova Gene: eif5a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1399 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Intellectual disability; microcephaly; dysmorphism to Faundes-Banka syndrome, OMIM:619376
Fetal anomalies v1.760 EIF5A Arina Puzriakova Publications for gene: EIF5A were set to PMID: 33547280
Severe microcephaly v2.268 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Intellectual disability; microcephaly; dysmorphism to Faundes-Banka syndrome, OMIM:619376
Fetal anomalies v1.759 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Faundes-Banka syndrome to Faundes-Banka syndrome, OMIM:619376
Fetal anomalies v1.758 EIF5A Arina Puzriakova Tag Q4_21_rating tag was added to gene: EIF5A.
White matter disorders and cerebral calcification - childhood onset v1.211 CSF1R Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CSF1R.
White matter disorders and cerebral calcification - childhood onset v1.211 CSF1R Arina Puzriakova Publications for gene: CSF1R were set to Parikh et al. Molecular Genetics and Metabolism 114 (2015) 501_605
White matter disorders and cerebral calcification - childhood onset v1.210 CSF1R Arina Puzriakova Added comment: Comment on mode of inheritance: CSF1R is associated with two relevant disorders both including white matter abnormalities and calcifications. One is an adult-onset rapidly progressive neurodegenerative disorder, associated with monoallelic inheritance (Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820). Conversely, biallelic variants cause a condition with a variable onset but mostly childhood (Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476).

Both phenotypes are relevant to this panel and therefore the MOI may be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS review.
White matter disorders and cerebral calcification - childhood onset v1.210 CSF1R Arina Puzriakova Mode of inheritance for gene: CSF1R was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited white matter disorders v1.144 CSF1R Arina Puzriakova Publications for gene: CSF1R were set to Parikh et al. Molecular Genetics and Metabolism 114 (2015) 501_605
Inherited white matter disorders v1.143 CSF1R Arina Puzriakova Added comment: Comment on mode of inheritance: MOI was updated from 'Monoallelic' to 'Both mono- and biallelic'. CSF1R is associated with two relevant disorders both including white matter abnormalities - one of which shows biallelic inheritance (Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476) while the other is associated with monoallelic inheritance (Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820)
Inherited white matter disorders v1.143 CSF1R Arina Puzriakova Mode of inheritance for gene: CSF1R was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Leukodystrophy, adult onset v1.32 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from Leukoencephalopathy, diffuse hereditary, with spheroids, 221820 to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820
White matter disorders and cerebral calcification - childhood onset v1.209 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820; Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476
Inherited white matter disorders v1.142 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820; Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.49 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from Dementia to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820; Dementia
Parkinson Disease and Complex Parkinsonism v1.71 CSF1R Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: 'diffuse leukoencephalopathy with spheroids, dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy'
Parkinson Disease and Complex Parkinsonism v1.71 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from diffuse leukoencephalopathy with spheroids; dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820
Fetal anomalies v1.758 CSF1R Arina Puzriakova Classified gene: CSF1R as Amber List (moderate evidence)
Fetal anomalies v1.758 CSF1R Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.758 CSF1R Arina Puzriakova Gene: csf1r has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.757 CSF1R Arina Puzriakova Publications for gene: CSF1R were set to PMID: 30982608
Fetal anomalies v1.756 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) to Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476; BANDDOS
Fetal anomalies v1.755 CSF1R Arina Puzriakova Tag Q4_21_rating tag was added to gene: CSF1R.
Fetal anomalies v1.755 CRADD Arina Puzriakova Tag Q4_21_rating tag was added to gene: CRADD.
Fetal anomalies v1.755 CRADD Arina Puzriakova Classified gene: CRADD as Amber List (moderate evidence)
Fetal anomalies v1.755 CRADD Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.755 CRADD Arina Puzriakova Gene: cradd has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.754 CRADD Arina Puzriakova Phenotypes for gene: CRADD were changed from Megalencephaly with Variant Lissencephaly to Mental retardation, autosomal recessive 34, with variant lissencephaly, OMIM:614499
Fetal anomalies v1.753 CRADD Arina Puzriakova Publications for gene: CRADD were set to
Fetal anomalies v1.752 CDK8 Arina Puzriakova Publications for gene: CDK8 were set to PMID: 31742715; 30905399
Fetal anomalies v1.751 CDK8 Arina Puzriakova Phenotypes for gene: CDK8 were changed from Syndromic developmental disorder with hypotonia and behavioural abnormalities to Intellectual developmental disorder with hypotonia and behavioral abnormalities, OMIM:618748
Intellectual disability v3.1398 CDK8 Arina Puzriakova Phenotypes for gene: CDK8 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748 to Intellectual developmental disorder with hypotonia and behavioral abnormalities, OMIM:618748
Fetal anomalies v1.750 CDK8 Arina Puzriakova Classified gene: CDK8 as Amber List (moderate evidence)
Fetal anomalies v1.750 CDK8 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.750 CDK8 Arina Puzriakova Gene: cdk8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.749 CDK8 Arina Puzriakova Tag Q4_21_rating tag was added to gene: CDK8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.483 RNU7-1 Arina Puzriakova Publications for gene: RNU7-1 were set to 33230297
Gastrointestinal epithelial barrier disorders v1.62 COL7A1 Arina Puzriakova Publications for gene: COL7A1 were set to
Infantile enterocolitis & monogenic inflammatory bowel disease v1.31 COL7A1 Arina Puzriakova Publications for gene: COL7A1 were set to 27537055; 11781296
Primary immunodeficiency or monogenic inflammatory bowel disease v2.482 COL7A1 Arina Puzriakova Publications for gene: COL7A1 were set to 18363753; 23517353; 33346580
Infantile enterocolitis & monogenic inflammatory bowel disease v1.30 RIPK1 Ivone Leong Phenotypes for gene: RIPK1 were changed from Immunodeficiency 57, MIM#618108 to Immunodeficiency 57, OMIM:618108
Infantile enterocolitis & monogenic inflammatory bowel disease v1.29 BACH2 Ivone Leong Classified gene: BACH2 as Green List (high evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.29 BACH2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. This gene is Green on "Primary immunodeficiency" (ID: 298, version 2.481). There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.29 BACH2 Ivone Leong Gene: bach2 has been classified as Green List (High Evidence).
Infantile enterocolitis & monogenic inflammatory bowel disease v1.28 BACH2 Ivone Leong Phenotypes for gene: BACH2 were changed from Immunodeficiency 60, MIM# 618394; inflammatory bowel disease; recurrent sinopulmonary infections to Immunodeficiency 60, OMIM:618394; inflammatory bowel disease; recurrent sinopulmonary infections
Palmoplantar keratodermas v1.9 DSC2 Ivone Leong Tag Q4_21_MOI tag was added to gene: DSC2.
Palmoplantar keratodermas v1.9 DSC2 Ivone Leong reviewed gene: DSC2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratoderma and erythrokeratodermas v1.22 DSC2 Ivone Leong Mode of inheritance for gene: DSC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratoderma and erythrokeratodermas v1.21 DSC2 Ivone Leong Deleted their review
Ichthyosis and erythrokeratoderma v1.68 DSC2 Ivone Leong Deleted their review
Ichthyosis and erythrokeratoderma v1.68 DSC2 Ivone Leong Deleted their comment
Palmoplantar keratoderma and erythrokeratodermas v1.21 DSC2 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as Monoallelic variants in this gene also cause disease.
Palmoplantar keratoderma and erythrokeratodermas v1.21 DSC2 Ivone Leong Mode of inheritance for gene: DSC2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1397 ERCC6 Ivone Leong Added comment: Comment on phenotypes: Previous phenotype entry:
Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980;DE SANCTIS-CACCHIONE SYNDROME (DSC)
Intellectual disability v3.1397 ERCC6 Ivone Leong Phenotypes for gene: ERCC6 were changed from Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980; DE SANCTIS-CACCHIONE SYNDROME (DSC) to De Sanctis-Cacchione syndrome, OMIM:278800
Retinal disorders v2.229 ERCC6 Ivone Leong Phenotypes for gene: ERCC6 were changed from Cockayne syndrome, type B 133540 to Cockayne syndrome, type B, OMIM:133540
Early onset or syndromic epilepsy v2.452 GABRD Helen Lord changed review comment from: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onse epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4.
From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher.
The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic.
The T291I variant was detected in an aff mother and her aff twin boys.
The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients.
All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD.
The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits.
Functional analysis suggests:
P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaeed propensity to desensitise - LOF trait.
The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait.
No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis.

The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~).
The patient with the LOF variant has ASD, normal intelligence and no seizure history.

In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder.
One GOF variant was identifed (de novo) in a patient with ASD but no seizures.
Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.; to: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onset epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4.
From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher.
The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic.
The T291I variant was detected in an aff mother and her aff twin boys.
The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients.
All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD.
The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits.
Functional analysis suggests:
P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaesed propensity to desensitise - LOF trait.
The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait.
No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis.

The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~).
The patient with the LOF variant has ASD, normal intelligence and no seizure history.

In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder.
One GOF variant was identifed (de novo) in a patient with ASD but no seizures.
Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.
Early onset or syndromic epilepsy v2.452 GABRD Helen Lord reviewed gene: GABRD: Rating: GREEN; Mode of pathogenicity: None; Publications: 34633442; Phenotypes: Neurodevelopmental disorders, generalised epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.481 PI4KA Ivone Leong commented on gene: PI4KA: There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

Review by Sophie Hambleton (Newcastle University):

"The immunological abnormalities in PI4KA def are obviously rather variable and a slight side-show to the primary GI and neurologic pathology – however that is a detail that should come out when any putative case is reviewed in detail so I would include this as a “CID with associated or syndromic features” on the same basis as TTC7A"
Primary immunodeficiency or monogenic inflammatory bowel disease v2.481 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.243
Primary immunodeficiency or monogenic inflammatory bowel disease v2.481 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Primary immunodeficiency. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
DDG2P v2.50 ATG7 Dmitrijs Rots gene: ATG7 was added
gene: ATG7 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to PMID:34161705
Phenotypes for gene: ATG7 were set to developmental delay; ataxia
Review for gene: ATG7 was set to GREEN
Added comment: Zornitsa Stark wrote for this gene in Ataxia panel:
"12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model. "

Should be also on ID panel.
Sources: Literature
DDG2P v2.50 RAP1GDS1 Dmitrijs Rots gene: RAP1GDS1 was added
gene: RAP1GDS1 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAP1GDS1 were set to PMID: 33875846
Phenotypes for gene: RAP1GDS1 were set to Intellectual disability, developmental delay
Review for gene: RAP1GDS1 was set to GREEN
Added comment: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846. Cases seem to overlap ones reported in PMID: 32431071.
Sources: Literature
Intellectual disability v3.1396 RAP1GDS1 Dmitrijs Rots changed review comment from: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846; to: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846. Cases seem to overlap those reported in PMID: 32431071.
Intellectual disability v3.1396 RAP1GDS1 Dmitrijs Rots reviewed gene: RAP1GDS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1396 PLK1 Dmitrijs Rots gene: PLK1 was added
gene: PLK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK1 were set to PMID: 33875846
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: >5 cases with epileptic encephalopathy with homozygous variants in PMID: 33875846
Sources: Literature
Early onset or syndromic epilepsy v2.452 PLK1 Dmitrijs Rots gene: PLK1 was added
gene: PLK1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: >5 cases with epileptic encephalopathy with homozygous variants in PMID: 33875846
Sources: Literature
Intellectual disability v3.1396 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.50 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.749 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.50 TAF4 Dmitrijs Rots gene: TAF4 was added
gene: TAF4 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: TAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF4 were set to 33875846
Phenotypes for gene: TAF4 were set to Developmental delay
Penetrance for gene: TAF4 were set to unknown
Review for gene: TAF4 was set to GREEN
Added comment: From the literature:
"A heterozygous de novo variant (frameshift) was reported in TAF4 by Kosmicki et al., in a patient with autism.36 The gene has no phenotypic association in OMIM (accessed 12 October 2020). Within this study, we identified two additional de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and NDD. TAF4 is highly intolerant to LoF as documented in gnomAD (pLi = 1). Expression of TAF4 varies during development and in the processes of cell differentiation; TAF4 is detected in various regions of the human brain, and it is believed to control the differentiation of human neural progenitor cells having a role in the regulation of neural development and brain function.37 The current data suggests that TAF4 haploinsufficiency leads to NDD in humans."
Sources: Literature
IUGR and IGF abnormalities v1.41 PAPPA2 Dmitrijs Rots reviewed gene: PAPPA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: Short stature, dysmorphism, mild microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 MMP15 Dmitrijs Rots gene: MMP15 was added
gene: MMP15 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MMP15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP15 were set to PMID: 33875846
Phenotypes for gene: MMP15 were set to Cholestasis; congenital heart disease
Review for gene: MMP15 was set to AMBER
Added comment: Three cases from two families with biallelic variants and very similar phenotype including rare combination of symtoms (allagile-like) cholestasis with hepatomegaly and congenital heart disease. Phenotype could be important for fetal panel.
Sources: Literature
Cholestasis v1.88 MMP15 Dmitrijs Rots gene: MMP15 was added
gene: MMP15 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: MMP15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP15 were set to PMID: 33875846
Phenotypes for gene: MMP15 were set to Cholestasis; congenital heart disease
Penetrance for gene: MMP15 were set to unknown
Review for gene: MMP15 was set to GREEN
Added comment: Three cases from two families with biallelic variants and very similar phenotype including rare combination of symtoms (allagile-like) cholestasis and congenital heart disease.
Sources: Literature
Fetal anomalies v1.749 PRRX1 Rhiannon Mellis gene: PRRX1 was added
gene: PRRX1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PRRX1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PRRX1 were set to 21294718; 22211708; 22674740; 23444262
Phenotypes for gene: PRRX1 were set to Agnathia-otocephaly complex
Review for gene: PRRX1 was set to GREEN
Added comment: At least 4 unrelated cases reported with agnathia-otocephaly complex
Sources: Literature
Fetal anomalies v1.749 POLR1B Rhiannon Mellis gene: POLR1B was added
gene: POLR1B was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR1B were set to PMID: 31649276
Phenotypes for gene: POLR1B were set to Treacher-Collins syndrome 4
Review for gene: POLR1B was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already flagged for upgrade to Green on the following other PanelApp panel(s): Clefting, Skeletal dysplasias

Details of review:
PMID: 31649276 - Sanchez et al 2020 - using exome sequencing identified 6 patients (5 unrelated families) with Treacher Collins syndrome with heterozygous missense variants in POLR1B.
Sources: Expert Review, Literature
Fetal anomalies v1.749 CSF1R Rhiannon Mellis gene: CSF1R was added
gene: CSF1R was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: CSF1R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSF1R were set to PMID: 30982608
Phenotypes for gene: CSF1R were set to Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS)
Review for gene: CSF1R was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Details of review:
Homozygous variants cause Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). Skeletal phenotype is osteopetrosis, dysosteosclerosis, platyspondyly, widened metaphyses. Brain anomalies include ACC and Dandy walker. At least one reported case of prenatal presentation with multiple brain anomalies - PubMed: 30982608

NB Bilallelic LOF variants cause this condition with fetally relevant phenotype but Monoallelic variants with dominant-negative effect cause an adult-onset neurodegenerative disease. Only for fetal reporting in BIALLELIC form
Sources: Expert Review
Fetal anomalies v1.749 LMNB2 Rhiannon Mellis gene: LMNB2 was added
gene: LMNB2 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB2 were set to PMID: 33033404
Phenotypes for gene: LMNB2 were set to Microcephaly 27, primary, autosomal dominant
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending)

Details of review:
Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic).
Sources: Expert Review, Literature
Fetal anomalies v1.749 LMNB1 Rhiannon Mellis gene: LMNB1 was added
gene: LMNB1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB1 were set to PMID: 33033404
Phenotypes for gene: LMNB1 were set to Microcephaly 26, primary, autosomal dominant
Review for gene: LMNB1 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending)

Details of review:
Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic).
Sources: Literature, Expert Review
Fetal anomalies v1.749 EIF5A Rhiannon Mellis gene: EIF5A was added
gene: EIF5A was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to PMID: 33547280
Phenotypes for gene: EIF5A were set to Faundes-Banka syndrome
Review for gene: EIF5A was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Details of review:
Faundes et al 2021 (PMID: 33547280) report this as a novel disease gene associated with micrognathia, microcephaly, IUGR and Kabuki-like phenotype. Now on OMIM as of August 2021. 7 unrelated patients in this publication.
Sources: Literature, Expert Review
Fetal anomalies v1.749 PRIM1 Rhiannon Mellis gene: PRIM1 was added
gene: PRIM1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to PMID: 33060134
Phenotypes for gene: PRIM1 were set to Primordial dwarfism
Review for gene: PRIM1 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Details of review:
Parry et al 2020 (PMID: 33060134) report this as a novel disease gene - biallelic LOF mutations in 5 patients (from 4 families) with primordial dwarfism phenotype, including prenatal features of IUGR and extreme microcephaly with simplified gyri.
Sources: Literature, Expert Review
Fetal anomalies v1.749 MN1 Rhiannon Mellis commented on gene: MN1: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Agreed that the phenotype is fetally relevant (structural brain abnormalities e.g. polymicrogyria, cerebellar hypoplasia, craniofacial features etc.) support adding to the Fetal anomalies panel as a Green gene.
Fetal anomalies v1.749 EXTL3 Rhiannon Mellis gene: EXTL3 was added
gene: EXTL3 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: EXTL3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: EXTL3 were set to Immunoskeletal dysplasia with neurodevelopmental abnormalities
Review for gene: EXTL3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott.

Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Skeletal dysplasia
Sources: Expert Review
Fetal anomalies v1.749 GREB1L Rhiannon Mellis commented on gene: GREB1L: This gene and phenotype were re-reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene as per previous reviews (unclear on reason for change from Green to Amber previously)
Fetal anomalies v1.749 EXOC3L2 Rhiannon Mellis reviewed gene: EXOC3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30327448, 28749478, 27894351; Phenotypes: Dandy Walker malformation, Meckel-Gruber like phenotype; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 FLNC Rhiannon Mellis changed review comment from: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Distal myopathies

Details of review:
In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth.
Sources: Literature, Expert Review; to: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Distal myopathies; Neuromuscular disorders; flagged for upgrade to Green on Arthrogryposis panel

Details of review:
In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth.
Sources: Literature, Expert Review
Fetal anomalies v1.749 FLNC Rhiannon Mellis gene: FLNC was added
gene: FLNC was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: FLNC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FLNC were set to PMID: 33060286; 29858533
Phenotypes for gene: FLNC were set to Arthrogryposis
Review for gene: FLNC was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Distal myopathies

Details of review:
In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth.
Sources: Literature, Expert Review
Fetal anomalies v1.749 SMARCE1 Rhiannon Mellis reviewed gene: SMARCE1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32732226, 32436246, 32410215; Phenotypes: Coffin Siris syndrome 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.749 SMARCC1 Rhiannon Mellis reviewed gene: SMARCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32732226; Phenotypes: Congenital hydrocephalus, Aqueduct stenosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arthrogryposis v3.137 SLC6A9 Rhiannon Mellis reviewed gene: SLC6A9: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31875334, 27773429, 32712301, 33269555; Phenotypes: Arthrogryposis multiplex congenita, Glycine encephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 SLC6A9 Rhiannon Mellis reviewed gene: SLC6A9: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31875334, 27773429, 32712301, 33269555; Phenotypes: Glycine encephalopathy with Arthrogryposis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 CRADD Rhiannon Mellis reviewed gene: CRADD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29947050, 27773430; Phenotypes: Mental retardation, autosomal recessive 34, with variant lissencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 CDK8 Rhiannon Mellis gene: CDK8 was added
gene: CDK8 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDK8 were set to PMID: 31742715; 30905399
Phenotypes for gene: CDK8 were set to Syndromic developmental disorder with hypotonia and behavioural abnormalities
Review for gene: CDK8 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Intellectual disability; Severe paediatric disorders

Details of review:
Aggarwal et al 2020 report a heterozygous nonsense variant in a fetus with ventriculomegaly and Ebstein anomaly resulting in IUFD. Post-mortem found additionally congenital diaphragmatic hernia, common atrium and facial dysmorphism. This nonsense variant is at the same position as a hotspot for missense variants reported in a paediatric cohort (Calpena et al 2019, PMID: 30905399) with overlapping but milder phenotype: half of the 12 children in that cohort had cardiac defects, most had dysmorphic features - hence Aggarwal et al propose that this is a more severe (prenatal) presentation of the same multiple malformation syndrome, caused here by a nonsense rather than missense mutation.
Sources: Literature, Expert Review
Fetal anomalies v1.749 ENPP1 Rhiannon Mellis reviewed gene: ENPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31742715, 19521093, 19813208; Phenotypes: Generalised arterial calcification of infancy (GACI); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.452 SNIP1 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SNIP1.
Early onset or syndromic epilepsy v2.452 SNIP1 Sarah Leigh commented on gene: SNIP1: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, to decide whether this gene could be green, as the disease association has only been associated with a the founder variant.
Intellectual disability v3.1396 SNIP1 Sarah Leigh commented on gene: SNIP1: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, to decide whether this gene could be green, as the disease association has only been associated with a the founder variant.
Intellectual disability v3.1396 SNIP1 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SNIP1.
CAKUT v1.165 TMEM260 Sarah Leigh edited their review of gene: TMEM260: Changed rating: AMBER
CAKUT v1.165 TMEM260 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517). Renal features were seen in patients as follows: elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12)(PMID 34612517).
Ataxia and cerebellar anomalies - childhood onset v2.243 DHDDS Arina Puzriakova Classified gene: DHDDS as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.243 DHDDS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Ataxia and cerebellar anomalies - childhood onset v2.243 DHDDS Arina Puzriakova Gene: dhdds has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.242 DHDDS Arina Puzriakova gene: DHDDS was added
gene: DHDDS was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q4_21_rating tags were added to gene: DHDDS.
Mode of inheritance for gene: DHDDS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHDDS were set to 29100083; 33798445; 34182312; 34382076
Phenotypes for gene: DHDDS were set to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Review for gene: DHDDS was set to GREEN
Added comment: Monoallelic variants are associated with a neurodevelopmental disorder comprising infantile or childhood-onset DD/ID, epilepsy and a variable movement phenotype which typically initially manifests as action myoclonus/cortical tremor and in some cases ataxia - at least 11 unrelated cases of ataxia reported in literature.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.166 DHDDS Arina Puzriakova Classified gene: DHDDS as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.166 DHDDS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Dystonia, chorea or related movement disorder, childhood onset v1.166 DHDDS Arina Puzriakova Gene: dhdds has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.165 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Dystonia, chorea or related movement disorder, childhood onset v1.164 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to
Dystonia, chorea or related movement disorder, childhood onset v1.163 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dystonia, chorea or related movement disorder, childhood onset v1.162 DHDDS Arina Puzriakova Tag Q4_21_rating tag was added to gene: DHDDS.
Dystonia, chorea or related movement disorder, childhood onset v1.162 DHDDS Arina Puzriakova reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100083, 32654954, 33798445, 34182312, 34382076, 34504728; Phenotypes: Developmental delay and seizures with or without movement abnormalities, OMIM:617836; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Long QT syndrome v2.28 ALG10 Sarah Leigh Mode of inheritance for gene: ALG10 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Long QT syndrome v2.27 ALG10 Sarah Leigh Publications for gene: ALG10 were set to 15280551
Long QT syndrome v2.26 ALG10 Sarah Leigh reviewed gene: ALG10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Long QT syndrome v2.26 ALG10 Sarah Leigh Phenotypes for gene: ALG10 were changed from {Acquired long QT syndrome, reduced susceptibility to}, 613688 to Progressive myoclonus epilepsy; CDG
Long QT syndrome v2.25 ALG10 Sarah Leigh Tag new-gene-name was removed from gene: ALG10.
Short QT syndrome v2.9 Sarah Leigh removed gene:ALG10 from the panel
Short QT syndrome v2.8 ALG10B Sarah Leigh Entity copied from Cardiac arrhythmias - previous panel v1.5
Short QT syndrome v2.8 ALG10B Sarah Leigh gene: ALG10B was added
gene: ALG10B was added to Short QT syndrome. Sources: Other
Mode of inheritance for gene: ALG10B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ALG10B were set to 15280551
Phenotypes for gene: ALG10B were set to {Acquired long QT syndrome, reduced susceptibility to} OMIM:613688
Long QT syndrome v2.25 ALG10B Sarah Leigh Entity copied from Cardiac arrhythmias - previous panel v1.5
Long QT syndrome v2.25 ALG10B Sarah Leigh gene: ALG10B was added
gene: ALG10B was added to Long QT syndrome. Sources: Other
Mode of inheritance for gene: ALG10B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ALG10B were set to 15280551
Phenotypes for gene: ALG10B were set to {Acquired long QT syndrome, reduced susceptibility to} OMIM:613688
Intellectual disability v3.1396 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to 29100083; 27343064
Early onset or syndromic epilepsy v2.452 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to 27343064; 29100083
Intellectual disability v3.1395 DHDDS Arina Puzriakova Tag Q4_21_MOI tag was added to gene: DHDDS.
Intellectual disability v3.1395 DHDDS Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Monoallelic' at the next GMS panel update. Monoallelic variants are associated with a neurodevelopmental disorder comprising DD/ID, epilepsy and a variable movement disorder phenotype - >3 unrelated individuals reported in literature. To date, only one individual with biallelic variants and ID has been reported (PMID: 27343064). This patient presented with glycosylation defects but no corroborating cases have been reported since.
As only one patient has been described with biallelic inheritance and this phenotype, MOI should be set to 'Monoallelic' until evidence of additional cases emerges - biallelic variants would still be picked up by the Genomics England pipeline under this MOI.
Intellectual disability v3.1395 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Tag Q4_21_MOI tag was added to gene: DHDDS.
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Monoallelic' at the next GMS panel update. Monoallelic variants are associated with a neurodevelopmental disorder comprising DD/ID, epilepsy and a variable movement disorder phenotype - >3 unrelated individuals reported in literature. To date, only one individual with biallelic variants and epilepsy has been reported (PMID: 27343064). This patient presented with glycosylation defects but no corroborating cases have been reported since.
As only one patient has been described with biallelic inheritance and this phenotype, MOI should be set to 'Monoallelic' until evidence of additional cases emerges - biallelic variants would still be picked up by the Genomics England pipeline under this MOI.
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.190 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861
Undiagnosed metabolic disorders v1.488 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861
Intellectual disability v3.1394 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836; ?Congenital disorder of glycosylation, type 1bb, 613861 to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Early onset or syndromic epilepsy v2.450 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836; developmental and epileptic encephalopathy (DEE); ?Congenital disorder of glycosylation, type 1bb,613861 to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
CAKUT v1.165 TMEM260 Sarah Leigh Deleted their comment
CAKUT v1.165 TMEM260 Sarah Leigh Entity copied from Fetal anomalies v1.749
CAKUT v1.165 TMEM260 Sarah Leigh gene: TMEM260 was added
gene: TMEM260 was added to CAKUT. Sources: Expert Review Amber,PAGE DD-Gene2Phenotype
Q4_21_rating tags were added to gene: TMEM260.
Mode of inheritance for gene: TMEM260 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM260 were set to 28318500; 34612517
Phenotypes for gene: TMEM260 were set to Structural heart defects and renal anomalies syndrome, OMIM:617478; Structural heart defects and renal anomalies syndrome, MONDO:0044321
Likely inborn error of metabolism v2.189 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59 613861; ?Congenital disorder of glycosylation, type 1bb 613861 to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities
Undiagnosed metabolic disorders v1.487 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa (other congenital disorders of glycosylation); Posterior segment abnormalities to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities
Congenital disorders of glycosylation v2.78 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59 613861; ?Congenital disorder of glycosylation, type 1bb 613861 to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861
Glaucoma (developmental) v1.41 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Eye Disorders to Retinitis pigmentosa 59, OMIM:613861
Glaucoma (developmental) v1.40 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.88 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59, 613861; Eye Disorders to Retinitis pigmentosa 59, OMIM:613861
Retinal disorders v2.228 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Eye Disorders; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa 59, 613861 to Retinitis pigmentosa 59, OMIM:613861
Rhabdomyolysis and metabolic muscle disorders v1.57 FKTN Sarah Leigh commented on gene: FKTN: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, in response to Zornitza Stark's Red review, that Rhabdomyolysis is not a significant feature of this muscle disorder.
Rhabdomyolysis and metabolic muscle disorders v1.57 FKTN Sarah Leigh Tag Q4_21_expert_review tag was added to gene: FKTN.
Neurodegenerative disorders, adult onset v2.201 FIG4 Sarah Leigh changed review comment from: In with respect to Ian Berry's proposed demotion of FIG4, after reviewing PMID:19118816. Helen Brittain (Genomics England Clinical Fellow) has suggested the rating of this gene should be considered by TEWG oversight committee, as there is a lack of evidence for ALS.; to: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, in response to Ian Berry's proposed demotion of FIG4, after reviewing PMID:19118816, which shows a lack of evidence for ALS.
Neurodegenerative disorders, adult onset v2.201 FIG4 Sarah Leigh edited their review of gene: FIG4: Added comment: In with respect to Ian Berry's proposed demotion of FIG4, after reviewing PMID:19118816. Helen Brittain (Genomics England Clinical Fellow) has suggested the rating of this gene should be considered by TEWG oversight committee, as there is a lack of evidence for ALS.; Changed rating: AMBER
Neurodegenerative disorders, adult onset v2.201 FIG4 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: FIG4.
Short QT syndrome v2.7 ALG10 Sarah Leigh changed review comment from: Not associated with Short QT phenotype in OMIM or in Gen2Phen.; to: ALG10 OMIM:618355 is not associated with Short QT phenotype in OMIM or in Gen2Phen. However, ALG10B OMIM:603313 is associated with Long QT syndrome, acquired, reduced susceptibility to OMIM:613688 (PMID:15280551).
Long QT syndrome v2.24 ALG10 Sarah Leigh Publications for gene: ALG10 were set to
Short QT syndrome v2.7 ALG10 Sarah Leigh commented on gene: ALG10: The correct gene name is: ALG10B OMIM:603313
Fetal anomalies v1.749 ACAN Zornitza Stark reviewed gene: ACAN: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia, aggrecan type, MIM# 612813; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 CYP19A1 Arina Puzriakova Phenotypes for gene: CYP19A1 were changed from Aromatase deficiency 613546; Aromatase excess syndrome 139300 to Aromatase deficiency, OMIM:613546; Aromatase excess syndrome, OMIM:139300
Fetal anomalies v1.748 CYP19A1 Arina Puzriakova Mode of inheritance for gene: CYP19A1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.747 CYP19A1 Arina Puzriakova Mode of inheritance for gene: CYP19A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary ovarian insufficiency v1.52 CYP19A1 Arina Puzriakova Phenotypes for gene: CYP19A1 were changed from Aromatase deficiency 613546 to Aromatase deficiency, OMIM:613546
Differences in sex development v2.51 CYP19A1 Arina Puzriakova Phenotypes for gene: CYP19A1 were changed from Gender Assignment Gene Panel (UKGTN); Endocrine disorders including disorders of sexual development; Aromatase deficiency, 613546 to Aromatase deficiency, OMIM:613546
Differences in sex development v2.50 CYP11A1 Arina Puzriakova Phenotypes for gene: CYP11A1 were changed from Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743 to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743
Congenital adrenal hypoplasia v2.7 CYP11A1 Arina Puzriakova Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743; Congenital Adrenal Insufficiency to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743
Fetal anomalies v1.746 CYP11A1 Arina Puzriakova Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete 613743 to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743
Fetal anomalies v1.745 CRYBB3 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS panel update. CRYBB3 is associated with congenital cataract (MIM# 609741) which can have monoallelic or biallelic inheritance. Both MOIs for this phenotype are listed in OMIM and G2P.
Fetal anomalies v1.745 CRYBB3 Arina Puzriakova Mode of inheritance for gene: CRYBB3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.744 CRYBB3 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CRYBB3.
Fetal anomalies v1.744 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from CATARACT, CONGENITAL NUCLEAR, AUTOSOMAL RECESSIVE 2 to Cataract 22, OMIM:609741
Intellectual disability v3.1393 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Structural eye disease v1.87 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Intellectual disability v3.1392 CRYBB3 Arina Puzriakova Mode of inheritance for gene: CRYBB3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.88 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Congenital Nuclear Cataract; Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Structural eye disease v1.86 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from CATARACT 16, MULTIPLE TYPES, 613763 to Cataract 16, multiple types, OMIM:613763
Congenital myopathy v2.64 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Arthrogryposis v3.137 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Paediatric or syndromic cardiomyopathy v1.59 CRYAB Arina Puzriakova Mode of inheritance for gene: CRYAB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric or syndromic cardiomyopathy v1.58 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, fatal infantile hypertrophy, alpha B crystallin related, 613869; Cardiomyopathy, dilated, 1II, to Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810
Dilated and arrhythmogenic cardiomyopathy v1.26 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from to Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810
Congenital myopathy v2.63 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2 608810; Myopathy, myofibrillar, fatal infantile hypertrophy, alpha-B crystallin-related 613869 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386
Arthrogryposis v3.136 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, 608810Cataract 16, multiple types, 613763Myopathy, myofibrillar, fatal infantile hypertrophy, alpha-B crystallin-related, 613869Cardiomyopathy, dilated, 1II, 615184; Myofibrillar Myopathy, Dominant to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386
Dilated Cardiomyopathy and conduction defects v1.72 CRYAB Arina Puzriakova Mode of inheritance for gene: CRYAB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.71 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Cardiomyopathy, dilated, 1II, to Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810
Hypertrophic cardiomyopathy v2.31 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from "Myopathy, myofibrillar, fatal infantile hypertrophy, alpha ‐ B crystallin ‐ related, 613869" to Myopathy, myofibrillar, 2, OMIM:608810
Distal myopathies v1.33 CRYAB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CRYAB.
Distal myopathies v1.33 CRYAB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. Predominantly monoallelic inheritance, though there are rare cases with biallelic variants where individuals tend to be more severely affected.
Distal myopathies v1.33 CRYAB Arina Puzriakova Mode of inheritance for gene: CRYAB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Distal myopathies v1.32 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar 2, 608810 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.32 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Cataract 16, multiple types, 613763; myofibrillar myopathy to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Rare multisystem ciliopathy disorders v1.149 EVC Ivone Leong Added comment: Comment on phenotypes: It is also associated with ?Weyers acrofacial dysostosis, OMIM:193530.
Rare multisystem ciliopathy disorders v1.149 EVC Ivone Leong Phenotypes for gene: EVC were changed from Ellis-van Creveld syndrome, 225500; Weyers acrodental dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500
Neurological ciliopathies v1.21 EVC Ivone Leong Added comment: Comment on phenotypes: It is also associated with ?Weyers acrofacial dysostosis, OMIM:193530.
Neurological ciliopathies v1.21 EVC Ivone Leong Phenotypes for gene: EVC were changed from Ellis-van Creveld syndrome, 225500; Weyers acrodental dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500
Skeletal ciliopathies v1.11 EVC Ivone Leong Added comment: Comment on phenotypes: It is also associated with ?Weyers acrofacial dysostosis, OMIM:193530.
Skeletal ciliopathies v1.11 EVC Ivone Leong Phenotypes for gene: EVC were changed from Ellis-van Creveld syndrome, 225500; Weyers acrodental dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500
DDG2P v2.50 CRYBB1 Ivone Leong Tag Q4_21_MOI tag was added to gene: CRYBB1.
DDG2P v2.50 CRYBB1 Ivone Leong reviewed gene: CRYBB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 COL7A1 Sophie Hambleton reviewed gene: COL7A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32084423; Phenotypes: epidermolysis bullosa, bloody diarrhoea; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 RNU7-1 Sophie Hambleton reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.87 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, 608810; Posterior Polar Cataract to Cataract 16, multiple types, OMIM:613763; Myopathy, myofibrillar, 2, OMIM:608810
Intellectual disability v3.1391 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, 600969; Epiphyseal dysplasia, multiple, with myopathy; {Intervertebral disc disease, susceptibility to}, 603932 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Monogenic hearing loss v2.206 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Stickler syndrome to Stickler syndrome, MONDO:0019354
Fetal anomalies v1.743 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 3 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Skeletal dysplasia v2.145 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from MED; multiple epiphyseal dysplasia; Epiphyseal dysplasia, multiple, with myopathy; Stickler syndrome type VI; multiple epiphyseal dysplasia 3, with or without myopathy - 600969; Multiple Epiphyseal Dysplasia, Dominant; Mutiple Epiphyseal Dysplasia to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Congenital myopathy v2.62 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, with or without myopathy 600969 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Arthrogryposis v3.135 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, 600969Epiphyseal dysplasia, multiple, with myopathy{Intervertebral disc disease, susceptibility to}, 603932 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Arthrogryposis v3.134 COL9A3 Arina Puzriakova Mode of inheritance for gene: COL9A3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Multiple Epiphyseal Dysplasia v1.6 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from multiple epiphyseal dysplasia; Multiple Epiphyseal Dysplasia, Dominant; Epiphyseal dysplasia, multiple, with myopathy to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Multiple Epiphyseal Dysplasia v1.5 COL9A3 Arina Puzriakova Publications for gene: COL9A3 were set to PMID: 21922596; 20301302; 20301479
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 CARS Michael Yau gene: CARS was added
gene: CARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Expert list
Mode of inheritance for gene: CARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CARS were set to PMID 30824121
Phenotypes for gene: CARS were set to Microcephaly; Developmental Delay; Brittle Hair
Penetrance for gene: CARS were set to Complete
Review for gene: CARS was set to GREEN
Added comment: Name: cysteinyl-tRNA synthetase 1; Symbol: CARS1 ; HGNC ID: 1493

Current Status: Not in R227 Panel. This gene was added to the DDG2P panel in March 2019 as a amber gene and the reviewer noted the following: "Microcephaly Developmental Delay and Brittle Hair and Nails. DDG2P Disease confidence: probable. DDG2P mode of pathogenicity/mutation consequence: loss of function. DDG2P mode of inheritance: biallelic." Proposed change: GREEN

The CARS1 genes was added to the DDG2P panel in March 2019 as an amber gene and the reviewer noted the following: "Microcephaly Developmental Delay and Brittle Hair and Nails. DDG2P Disease confidence: probable. DDG2P mode of pathogenicity/mutation consequence: loss of function. DDG2P mode of inheritance: biallelic."

In Kuo et al (2019) reported the identification of bi-allelic CARS1 variants in four affected individuals from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails.

Case 1: CARS1 c.1138C>T p.(Gln380Ter) and CARS1 c.1022G>A p.(Arg341His) Case 2 and 3 (related): CARS1 c.1076C>T p.(Ser359Leu) and CARS1 c.1199T>A p. (Leu400Gln)
Case 4: Homozygous CARS1 c.2061dup p.(Ser688fs).

In-silico analysis predict that the variants result in a truncated protein or affect a highly conserved amino acid. Immunoblot analysis using CARS antibodies on protein isolated from the patient’s fibroblast confirmed the presence of a stable truncated protein for c.1138C>T nonsense variant, while the amount of full-length CARS protein was significantly reduced for the c.2061dup frameshifting variant. A possible explanation for this result is the extreme 3’ location of the variant which could allow it to escape nonsense mediated decay. Analysis of the CARS protein from Case 4 showed no change in the level of full-length CARS protein. Yeast complementation studies indicate that the p.(Gln380Ter), p. (Leu400Gln) and p.(Ser688fs) variants prevented yeast cell growth, consistent with a loss-of-function effect. Severely reduced cell growth was observed with the p.(Arg341His) and p.(Ser359Leu) variants, aminoacylation assays showed that these variants reduce enzyme activity. These results all support that each variant results in loss of function.

This report confirms that individuals with two loss of function CARS1 variants are involved in multi-system, recessive disorder that includes microcephaly, developmental delay, and brittle hair and nails. Clinical phenotypes that overlap with TTD individuals.

References: Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails. Kuo ME, et al. Am J Hum Genet, 2019 Mar 7. PMID 30824121
Sources: Expert list
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 TARS Michael Yau gene: TARS was added
gene: TARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Expert list
Mode of inheritance for gene: TARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS were set to PMID 31374204
Phenotypes for gene: TARS were set to Trichothiodystrophy 7, nonphotosensitive
Penetrance for gene: TARS were set to Complete
Mode of pathogenicity for gene: TARS 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: TARS was set to GREEN
Added comment: Name: threonyl-tRNA synthetase 1; Symbol: TARS1; HGNC ID: 11572

Current Status: Not in R227 Panel. This gene was added to the DDG2P panel in Sept 2019 as a amber gene and the reviwer noted the following: "Non-photosensitive trichothiodystrophy. Disease confidence rating in DDG2P: probable. DDG2P mutation consequence: loss of function. DDG2P allelic requirement: biallelic." Proposed change: GREEN

Supporting Evidence:
Theil et al (2021) published a multi-centre WES/WGS sequencing study which screened in a group of 24 NPS-TTD individuals with no molecular diagnosis. TTD18PV and TTD5VI are unrelated individuals initially diagnosed with TTD were found to have the following predicted pathogenic variants in the TARS1 gene:

TTD18PV: TARS1 c.826A>G p.(Lys276Glu) and TARS1 c.1912C>T p.(Arg638Ter)
TTD5VI: Homozygous TARS1 c.680T>C (p.Leu227Pro).

Testing of additional individuals with unresolved NPS-TTD by the authors did not identify any further bi-allelic variants suggesting in their cohort of 47, TARS1 variants account for 4% of NPS-TTD cases.

In-silico analysis suggest that missense variants result in amino acid substitutions that are close to the core catalytic domain of the protein which may affect its catalytic activity. Quantitative RT-PCR analysis showed only a slight reduction in total TARS mRNA levels in TTD18PV’s primary fibroblasts, while allelic-specific qRT-PCR analysis showed that 90% of the total TARS mRNA molecules are from the missense p.(Lys276Glu) TARS variant with the remaining only 10% from the c.1912C>T variant allele. Immunoblot analysis of whole-cell extracts from both patient’s fibroblasts revealed an approximate 20% reduction in the total cellular amount of full-length TARS. This is consistent with these missense variants causing protein instability.

Based on a total of 47 NPS-TTD individuals for bi-allelic TARS1 variants, the authors suggest that TARS1 variants account for 4% of NPS-TTD cases.

References: Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Theil AF et al. Am J Hum Genet, 2019 Aug 1. PMID 31374204
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 IKZF3 Boaz Palterer edited their review of gene: IKZF3: Changed publications to: 34694366, 34155405
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 IKZF3 Boaz Palterer edited their review of gene: IKZF3: Added comment: New kindred with 4 affected subjects reported with autosomal dominant IKZF3 variant ( p.N160S ) by Kuehn et al.; Changed publications to: 34694366; Changed phenotypes to: B cell deficiency, EBV inefctions suspectibility, hypogammaglobulinemia, T and B cell abnormalities, pneumocystis pneumonia, chronic lymphocytic leukemia
Intellectual disability v3.1390 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Intellectual disability v3.1389 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Intellectual disability v3.1389 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2, 600204; {Intervertebral; disc disease, susceptibility to}, 603932; ?Stickler syndrome, type V, 614284 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Retinal disorders v2.227 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Eye Disorders to Stickler syndrome, type V, OMIM:614284
Retinal disorders v2.226 COL9A2 Arina Puzriakova Mode of inheritance for gene: COL9A2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Multiple Epiphyseal Dysplasia v1.4 COL9A2 Arina Puzriakova Publications for gene: COL9A2 were set to PMID: 20358595, PMID: 21922596, PMID: 20301302
Multiple Epiphyseal Dysplasia v1.3 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from multiple epiphyseal dysplasia; Multiple Epiphyseal Dysplasia, Dominant; Epiphyseal dysplasia, multiple, 2, 600204; {Intervertebral disc disease, susceptibility to}, 603932; Stickler syndrome, type V, 614284 to Epiphyseal dysplasia, multiple, 2, OMIM:600204
Skeletal dysplasia v2.144 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2 600204; Stickler syndrome, type V 614284; Stickler syndrome, type V, 614284; {Intervertebral disc disease, susceptibility to}, 603932 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Structural eye disease v1.85 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from STICKLER SYNDROME, TYPE V, 614284; Eye Disorders to Stickler syndrome, type V, OMIM:614284
Clefting v2.60 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from ?Stickler syndrome type V, 614284; Orofacial Clefting with skeletal features; Stickler syndrome; Cleft palate to Stickler syndrome, type V, OMIM:614284
Monogenic hearing loss v2.205 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from ?Stickler syndrome, type V, 614284 to Stickler syndrome, type V, OMIM:614284
Stickler syndrome v2.23 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from ?Stickler syndrome, type V, OMIM:614284 to Stickler syndrome, type V, OMIM:614284
Clefting v2.59 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV (ophthalmological: myopia, retinal detachment and cataracts, orofacial: micrognathia, midface hypoplasia and cleft palate, auditory:sensorineural hearing loss and articular: epiphyseal dysplasia) symptoms; Autosomal recessive Stickler syndrome; Orofacial Clefting with skeletal features; Cleft palate to Stickler syndrome, type IV, OMIM:614134
Retinal disorders v2.225 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Eye Disorders to Stickler syndrome, type IV, OMIM:614134
Structural eye disease v1.84 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV, 614134; Eye Disorders to Stickler syndrome, type IV, OMIM:614134
Retinal disorders v2.224 COL9A1 Arina Puzriakova Mode of inheritance for gene: COL9A1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1388 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from ?Epiphyseal dysplasia, multiple, 6, 614135; Stickler syndrome, type IV, 614134 to Stickler syndrome, type IV, OMIM:614134; Epiphyseal dysplasia, multiple, 6, OMIM:614135
Long QT syndrome v2.23 ALG10 Sarah Leigh Tag new-gene-name tag was added to gene: ALG10.
Short QT syndrome v2.7 ALG10 Sarah Leigh Tag new-gene-name tag was added to gene: ALG10.
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh commented on gene: ALG10: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least one terminating variant reported.
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh Classified gene: ALG10 as Red List (low evidence)
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh Added comment: Comment on list classification: Homozygous null ALG10 variant (NM_032834.4) c.1170_1171delAA (p.Lys391Valfs∗35) was found in a Turkish female, with frequent myoclonus (reported at 13 years), rare tonic-clonic seizure, ataxia, mild cognitive dysfunction (reported at 16 years) and scoliosis (PMID 33798445). PMID 33798445 also reports that a yeast alg10 deletion strain was used to re-express human wild-type and the variant ALG10 proteins for functional complementation. They found that while the yeast or human wild type strains resulted in mature reported protein, the variant strain resulted in hypo-glycosylated reporter protein.
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh Gene: alg10 has been classified as Red List (Low Evidence).
Skeletal dysplasia v2.143 COL9A1 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL9A1.
Skeletal dysplasia v2.143 COL9A1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL9A1 is associated with two relevant disorders as they both include epiphyseal dysplasia - one of which shows biallelic inheritance (Stickler syndrome, type IV, OMIM:614134) while the other is associated with monoallelic inheritance (Epiphyseal dysplasia, multiple, 6, OMIM:614135)
Skeletal dysplasia v2.143 COL9A1 Arina Puzriakova Mode of inheritance for gene: COL9A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.204 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV, 614134; hearing loss to Stickler syndrome, type IV, OMIM:614134; Hearing loss
Monogenic hearing loss v2.203 COL9A1 Arina Puzriakova Mode of inheritance for gene: COL9A1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.142 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV 614134; Epiphyseal dysplasia, multiple, 6 614135 to Stickler syndrome, type IV, OMIM:614134; Epiphyseal dysplasia, multiple, 6, OMIM:614135
Infantile enterocolitis & monogenic inflammatory bowel disease v1.27 COL7A1 Arina Puzriakova Mode of inheritance for gene: COL7A1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Infantile enterocolitis & monogenic inflammatory bowel disease v1.26 COL7A1 Arina Puzriakova Classified gene: COL7A1 as Amber List (moderate evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.26 COL7A1 Arina Puzriakova Added comment: Comment on list classification: Internal review from the Genomics England clinical team has advised this gene be made Amber, as although there is evidence for gastrointestinal phenotypes in patients who are homozygous for variants in this gene, the skin phenotype more commonly associated with Epidermolysis bullosa is severe and would likely be picked up elsewhere.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.26 COL7A1 Arina Puzriakova Gene: col7a1 has been classified as Amber List (Moderate Evidence).
Epidermolysis bullosa v1.7 COL7A1 Arina Puzriakova Phenotypes for gene: COL7A1 were changed from Dystrophic Epidermolysis Bullosa; Epidermolysis bullosa dystrophica (AD), 131750; Epidermolysis bullosa dystrophica (AR), 226600; Epidermolysis bullosa, pretibial (AR,AD), 131850; EBD, Bart type (AD), 132000; EBD inversa (AR), 226600; Transient bullous of the newborn (AR,AD), 131705 to Epidermolysis bullosa dystrophica (AD), OMIM:131750; Epidermolysis bullosa, pretibial (AR,AD), OMIM:131850; Epidermolysis bullosa dystrophica (AR), OMIM:226600; EBD, Bart type (AD), OMIM:132000; Epidermolysis bullosa pruriginosa, OMIM:604129; Transient bullous of the newborn (AR,AD), OMIM:131705; EBD inversa (AR), OMIM:226600
Hereditary neuropathy v1.418 CPOX Ivone Leong Mode of inheritance for gene: CPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.417 CPOX Ivone Leong Tag Q4_21_MOI was removed from gene: CPOX.
Early onset or syndromic epilepsy v2.449 DEAF1 Ivone Leong Tag Q4_21_MOI tag was added to gene: DEAF1.
Early onset or syndromic epilepsy v2.449 DEAF1 Ivone Leong reviewed gene: DEAF1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1387 COL6A3 Arina Puzriakova Mode of inheritance for gene: COL6A3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.742 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1; DYSTONIA 27 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Fetal anomalies v1.741 COL6A3 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL6A3 is associated with two relevant disorders, both of which show biallelic and monoallelic inheritance (Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090).
Fetal anomalies v1.741 COL6A3 Arina Puzriakova Mode of inheritance for gene: COL6A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.740 COL6A3 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL6A3.
Dystonia, chorea or related movement disorder, childhood onset v1.162 COL6A3 Arina Puzriakova Publications for gene: COL6A3 were set to
Dystonia, chorea or related movement disorder, childhood onset v1.161 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Dystonia 27, 616411 to Dystonia 27, OMIM:616411
Skeletal dysplasia v2.141 ZNF687 Adrienne Flanagan gene: ZNF687 was added
gene: ZNF687 was added to Skeletal dysplasia. Sources: Other,Research
Mode of inheritance for gene: ZNF687 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110
Phenotypes for gene: ZNF687 were set to Paget Disease of Bone with associated Giant Cell Tumour.
Penetrance for gene: ZNF687 were set to unknown
Mode of pathogenicity for gene: ZNF687 was set to Other
Review for gene: ZNF687 was set to GREEN
Added comment: Missense mutation c.2810C>G (p.Pro937Arg) alters the nuclear-ctyoplasmic balance of ZNF687 by generating a stronger nuclear localisation signal thereby acting as a gain-of-function mutation.
Sources: Other, Research
Intellectual disability v3.1386 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Gene2Phenotype confirmed gene with ID HPO to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.31 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Congenital myopathy v2.61 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Arthrogryposis v3.133 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Ullrich congenital muscular dystrophy 1 254090; Bethlem myopathy, 158810Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Congenital muscular dystrophy v2.20 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Fetal anomalies v1.740 COL6A1 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL6A1.
Fetal anomalies v1.740 COL6A1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL6A1 is associated with two relevant disorders, both of which show biallelic and monoallelic inheritance (Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090).
Fetal anomalies v1.740 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.739 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from COL6A1 associated myopathy to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Arthrogryposis v3.132 COL6A1 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL6A1.
Arthrogryposis v3.132 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Ullrich congenital muscular dystrophy 1 254090; Bethlem myopathy 1 158810; Bethlem myopathy, 158810Ullrich congenital muscular dystrophy, 254090{Ossification of the posterior longitudinal spinal ligaments}, 602475 (2); Bethlem myopathy; Ullrich Congenital Muscular Dystrophy to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Arthrogryposis v3.131 COL6A1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL6A1 is associated with two relevant disorders which include multiple joint contractures, both of which show biallelic and monoallelic inheritance (Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090).
Arthrogryposis v3.131 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.738 IFT122 Sarah Leigh reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.738 IFT122 Sarah Leigh Publications for gene: IFT122 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.55 IFT122 Sarah Leigh Publications for gene: IFT122 were set to 24689072; 20493458
Fetal anomalies v1.737 IFT122 Sarah Leigh Phenotypes for gene: IFT122 were changed from CRANIOECTODERMAL DYSPLASIA to Cranioectodermal dysplasia type 1 OMIM:218330; cranioectodermal dysplasia 1 MONDO:0021093
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.54 IFT122 Sarah Leigh Phenotypes for gene: IFT122 were changed from cranioectodermal dysplasia; Cranioectodermal dysplasia type 1 218330 to Cranioectodermal dysplasia type 1 OMIM:218330; cranioectodermal dysplasia 1 MONDO:0021093
Intellectual disability v3.1385 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1384 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v2.64 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy 1,OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.30 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Congenital myopathy v2.60 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Congenital muscular dystrophy v2.19 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1383 COL4A4 Arina Puzriakova Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Proteinuric renal disease v2.61 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Intellectual disability v3.1382 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780; Hematuria, familial benign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Monogenic hearing loss v2.202 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780Hematuria,familial benign; Alportsyndrome,autosomalrecessive,203780Hematuria,familialbenign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Unexplained young onset end-stage renal disease v1.23 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Hematuria,familial benign; Alport syndrome, autosomal recessive, 203780 to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Unexplained kidney failure in young people v1.99 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780; Hematuria,familial benign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Cystic kidney disease v2.27 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Cystic kidney disease, MONDO:0002473 to Cystic kidney disease, MONDO:0002473
Cystic kidney disease v2.27 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from cystic kidney disease MONDO:0002473 to Cystic kidney disease, MONDO:0002473
Unexplained kidney failure in young people v1.98 COL4A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Changing to BOTH monoallelic and biallelic, autosomal or pseudoautosomal because it is associated with two relevant disorders one which shows biallelic and one which shows monoallelic inheritance ( Alport syndrome 2, autosomal recessive is AR and Hematuria, familial benign is AD).
Unexplained kidney failure in young people v1.98 COL4A4 Arina Puzriakova Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.417 CPOX Ivone Leong Tag Q4_21_MOI tag was added to gene: CPOX.
Hereditary neuropathy v1.417 CPOX Ivone Leong reviewed gene: CPOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.64 CPOX Ivone Leong Tag Q4_21_MOI tag was added to gene: CPOX.
Hereditary neuropathy or pain disorder v1.64 CPOX Ivone Leong reviewed gene: CPOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.141 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II 604841; Marshall syndrome 154780; Fibrochondrogenesis 1 228520 to Stickler syndrome, type II, OMIM:604841; Marshall syndrome, OMIM:154780; Fibrochondrogenesis 1, OMIM:228520
Clefting v2.58 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Orofacial Clefting with skeletal features; Stickler Syndrome; Cleft palate to Marshall Syndrome, OMIM:154780; Stickler syndrome, type II, OMIM:604841
Bilateral congenital or childhood onset cataracts v2.86 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Marshall Syndrome; Stickler syndrome to Marshall Syndrome, OMIM:154780; Stickler syndrome, type II, OMIM:604841
Monogenic hearing loss v2.201 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II, MIM#604841; Deafness, autosomal dominant 37, MIM#618533 to Deafness, autosomal dominant 37, OMIM:618533; Stickler syndrome, type II, OMIM:604841
Retinal disorders v2.223 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Eye Disorders to Stickler syndrome, type II, OMIM:604841
Cytopenia - NOT Fanconi anaemia v1.43 CLPB Dmitrijs Rots reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1381 CLPB Dmitrijs Rots reviewed gene: CLPB: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v2.267 DPP6 Ivone Leong Tag Q4_21_expert_review tag was added to gene: DPP6.
Proteinuric renal disease v2.60 TRIM8 Ivone Leong Classified gene: TRIM8 as Amber List (moderate evidence)
Proteinuric renal disease v2.60 TRIM8 Ivone Leong Gene: trim8 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.59 TRIM8 Ivone Leong Tag Q4_21_rating tag was added to gene: TRIM8.
Proteinuric renal disease v2.59 TRIM8 Ivone Leong changed review comment from: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.; to: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Unexplained young onset end-stage renal disease v1.22 TRIM8 Ivone Leong Tag Q4_21_rating tag was added to gene: TRIM8.
Unexplained young onset end-stage renal disease v1.22 TRIM8 Ivone Leong Classified gene: TRIM8 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v1.22 TRIM8 Ivone Leong Gene: trim8 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v1.21 TRIM8 Ivone Leong changed review comment from: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.; to: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Unexplained young onset end-stage renal disease v1.21 TRIM8 Ivone Leong Entity copied from Unexplained kidney failure in young people v1.97
Unexplained young onset end-stage renal disease v1.21 TRIM8 Ivone Leong gene: TRIM8 was added
gene: TRIM8 was added to Unexplained paediatric onset end-stage renal disease. Sources: Expert Review Green,Literature
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM8 were set to 33508234; 32531461; 32193649; 33508234
Phenotypes for gene: TRIM8 were set to nephrotic syndrome; epilepsy; Focal segmental glomerulosclerosis and neurodevelopmental syndrome, OMIM:619428
Mode of pathogenicity for gene: TRIM8 was set to Other
Proteinuric renal disease v2.59 TRIM8 Ivone Leong Entity copied from Unexplained kidney failure in young people v1.97
Proteinuric renal disease v2.59 TRIM8 Ivone Leong gene: TRIM8 was added
gene: TRIM8 was added to Proteinuric renal disease. Sources: Expert Review Green,Literature
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM8 were set to 33508234; 32531461; 32193649; 33508234
Phenotypes for gene: TRIM8 were set to nephrotic syndrome; epilepsy; Focal segmental glomerulosclerosis and neurodevelopmental syndrome, OMIM:619428
Mode of pathogenicity for gene: TRIM8 was set to Other
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong Tag watchlist tag was added to gene: PI4KA.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong edited their review of gene: PI4KA: Changed rating: AMBER
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong commented on gene: PI4KA: This gene is rated Amber as not all affected individuals have IBD. Until more evidence is available this gene has been given an Amber rating.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong Tag Q3_21_rating was removed from gene: PI4KA.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.241
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Intellectual disability v3.1381 CDH15 Arina Puzriakova Tag Q4_21_rating tag was added to gene: CDH15.
Intellectual disability v3.1381 CDH15 Arina Puzriakova Classified gene: CDH15 as Green List (high evidence)
Intellectual disability v3.1381 CDH15 Arina Puzriakova Added comment: Comment on list classification: Gene should be demoted to Red as there is limited evidence supporting this gene-disease association. The only cases reported to date with SNVs were discovered by targeted sequencing of CDH15. Clinical information was limited, describing only mild ID in some cases. There are also multiple benign LOF variants in population databases. Asymptomatic carriers lead authors to suggest incomplete penetrance but all identified variants are in gnomAD so are unlikely to be causal.
Intellectual disability v3.1381 CDH15 Arina Puzriakova Gene: cdh15 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.60 PI4KA Ivone Leong Classified gene: PI4KA as Green List (high evidence)
Cerebellar hypoplasia v1.60 PI4KA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is now enough evidence to support a gene-disease association.
Cerebellar hypoplasia v1.60 PI4KA Ivone Leong Gene: pi4ka has been classified as Green List (High Evidence).
Intellectual disability v3.1380 CDH15 Arina Puzriakova Publications for gene: CDH15 were set to
Hereditary spastic paraplegia, childhood onset v2.87 PI4KA Ivone Leong edited their review of gene: PI4KA: Added comment: After consulting with the Genomics England Clinical Team it was decided that this gene should be added to the Hereditary spastic paraplegia - childhood onset panel with an Amber rating.

Helen Brittain:
"I think the spasticity is likely to be secondary to the CNS findings and therefore might opt for amber at this stage, as it is perhaps unlikely to be clearly relevant to the more typical cohort with isolated spasticity that will be targeted by that panel."; Changed rating: AMBER
Intellectual disability v3.1379 CDH15 Arina Puzriakova Phenotypes for gene: CDH15 were changed from Mental retardation, autosomal dominant 3, 612580; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 3 (MRD3) to Mental retardation, autosomal dominant 3, OMIM:612580
Hereditary spastic paraplegia, childhood onset v2.87 PI4KA Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.
Hereditary spastic paraplegia, childhood onset v2.87 PI4KA Ivone Leong Tag Q3_21_rating was removed from gene: PI4KA.
Hereditary spastic paraplegia, childhood onset v2.87 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.241
Hereditary spastic paraplegia, childhood onset v2.87 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Hereditary spastic paraplegia, childhood onset v2.86 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to 18660473; 22214631; 29927410; 31023660; 33190326; 33612672
Hereditary spastic paraplegia, childhood onset v2.85 GJA1 Arina Puzriakova commented on gene: GJA1: Regarding inclusion of this gene on the childhood-onset panel, Helen Brittain (Genomics England Clinical Team) suggests - "As you say, there are sufficient cases albeit seemingly edge cases. I would be inclined to include it on the paediatric panel, as they are outlining the spasticity as a feature of ODDD, rather than a separate clinical entity. ODDD would be a paediatric-age diagnosis to make and the fact that it is clinically recognisable could aid in interpretation of variants of uncertain significance"
Malformations of cortical development v2.94 PI4KA Ivone Leong Tag watchlist was removed from gene: PI4KA.
Tag Q4_21_rating tag was added to gene: PI4KA.
Malformations of cortical development v2.94 PI4KA Ivone Leong Publications for gene: PI4KA were set to 25855803
Malformations of cortical development v2.93 PI4KA Ivone Leong edited their review of gene: PI4KA: Added comment: There is now enough evidence to support this gene-disease association. This gene should be rated Green at the next review.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.; Changed rating: GREEN; Changed publications to: 25855803, 34415322, 34415310
Hereditary spastic paraplegia, childhood onset v2.85 GJA1 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - adult onset v1.73
Hereditary spastic paraplegia, childhood onset v2.85 GJA1 Arina Puzriakova gene: GJA1 was added
gene: GJA1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: GJA1.
Mode of inheritance for gene: GJA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GJA1 were set to 18660473; 22214631; 29927410; 31023660; 33190326; 33612672
Phenotypes for gene: GJA1 were set to Oculodentodigital dysplasia, OMIM:164200; Spastic paraplegia
Malformations of cortical development v2.93 PI4KA Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Classified gene: DYNC1I2 as Amber List (moderate evidence)
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Gene: dync1i2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.266 DYNC1I2 Ivone Leong Tag Q4_21_rating tag was added to gene: DYNC1I2.
IUGR and IGF abnormalities v1.41 ARCN1 Ivone Leong Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, OMIM:617164
IUGR and IGF abnormalities v1.40 ARCN1 Ivone Leong Publications for gene: ARCN1 were set to PMID: 27476655; PMID: 33154040
IUGR and IGF abnormalities v1.39 ARCN1 Ivone Leong Classified gene: ARCN1 as Amber List (moderate evidence)
IUGR and IGF abnormalities v1.39 ARCN1 Ivone Leong Added comment: Comment on list classification: New gene added by Andžela Lazdāne (Children's Clinical University Hospital of Latvia). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). After consulting the Genomics England Clinical Team it was thought that this gene should be Amber on this panel for now as the skeletal phenotype in association with short stature makes the gene better suited to a skeletal panel.
IUGR and IGF abnormalities v1.39 ARCN1 Ivone Leong Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.266 ARCN1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences was given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences were given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Tag Q4_21_expert_review tag was added to gene: GYG1.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Tag watchlist tag was added to gene: GYG1.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Classified gene: GYG1 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Added comment: Comment on list classification: New gene added by Oliver Watkinson (NHS). THis gene is associated with a phenotype in OMIM but not Gene2Phenotype. While there are >3 unrelated cases of affected patients with HCM there are other patients with variants in this gene who do not have any cardiomyopathy phenotype. As indicated by Oliver Watkinson, the sister of an affected patient had the same genotype but was unaffected. Based on the available evidence this gene has been given an Amber rating until more cases are available.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Gene: gyg1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.736 LRIT3 Zornitza Stark reviewed gene: LRIT3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Night blindness, congenital stationary (complete), 1F, autosomal recessive 615058; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.50 KPNA3 Dmitrijs Rots gene: KPNA3 was added
gene: KPNA3 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to PMID: 34564892
Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay
Penetrance for gene: KPNA3 were set to unknown
Mode of pathogenicity for gene: KPNA3 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: KPNA3 was set to GREEN
Added comment: 8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.84 KPNA3 Dmitrijs Rots gene: KPNA3 was added
gene: KPNA3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to PMID: 34564892
Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay
Penetrance for gene: KPNA3 were set to unknown
Mode of pathogenicity for gene: KPNA3 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: KPNA3 was set to GREEN
Added comment: 8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: Literature
Fetal anomalies v1.736 AAAS Zornitza Stark edited their review of gene: AAAS: Changed rating: RED
Fetal anomalies v1.736 AAAS Zornitza Stark reviewed gene: AAAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Achalasia-addisonianism-alacrimia syndrome, MIM#231550; Mode of inheritance: None
Early onset or syndromic epilepsy v2.449 CELF2 Dmitrijs Rots reviewed gene: CELF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: DEE; Mode of inheritance: None
Hereditary neuropathy or pain disorder v1.64 GBF1 Dmitrijs Rots reviewed gene: GBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial dysautonomia v1.15 DST Dmitrijs Rots reviewed gene: DST: Rating: AMBER; Mode of pathogenicity: None; Publications: PubMed: 30371979; Phenotypes: Neuropathy, hereditary sensory and autonomic; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.64 TECPR2 Dmitrijs Rots gene: TECPR2 was added
gene: TECPR2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: TECPR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TECPR2 were set to PubMed: 33847017
Phenotypes for gene: TECPR2 were set to Hereditary sensory and autonomic neuropathy
Penetrance for gene: TECPR2 were set to unknown
Review for gene: TECPR2 was set to GREEN
Added comment: Neuser et al. (2021) reported clinical findings in 17 patients, including 2 sib pairs, from 15 families segregating HSAN9.
Sources: Literature
Familial dysautonomia v1.15 TECPR2 Dmitrijs Rots reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 33847017; Phenotypes: Sensory neuropathy, autonomic neuropathy; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 DEF6 Dmitrijs Rots reviewed gene: DEF6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32562707; Phenotypes: ; Mode of inheritance: None
Cutaneous photosensitivity with a likely genetic cause v1.8 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.16 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.26 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.26 AXIN2 Tom Cullup gene: AXIN2 was added
gene: AXIN2 was added to Ectodermal dysplasia. Sources: Other
Mode of inheritance for gene: AXIN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXIN2 were set to 15042511
Phenotypes for gene: AXIN2 were set to OLIGODONTIA-COLORECTAL CANCER SYNDROME
Penetrance for gene: AXIN2 were set to unknown
Review for gene: AXIN2 was set to GREEN
Added comment: Sources: Other
Rare genetic inflammatory skin disorders v1.40 ECM1 Tom Cullup gene: ECM1 was added
gene: ECM1 was added to Rare genetic inflammatory skin disorders. Sources: Other
Mode of inheritance for gene: ECM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ECM1 were set to 11929856
Phenotypes for gene: ECM1 were set to Urbach-Wiethe disease
Penetrance for gene: ECM1 were set to Complete
Review for gene: ECM1 was set to GREEN
Added comment: Sources: Other
Neurological ciliopathies v1.20 TMEM218 Tom Cullup reviewed gene: TMEM218: Rating: GREEN; Mode of pathogenicity: None; Publications: 33791682; Phenotypes: JOUBERT SYNDROME 39; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Multiple monogenic benign skin tumours v1.12 NOTCH3 Tom Cullup gene: NOTCH3 was added
gene: NOTCH3 was added to Multiple monogenic benign skin tumours. Sources: Other
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 23731542
Phenotypes for gene: NOTCH3 were set to MYOFIBROMATOSIS, INFANTILE, 2
Penetrance for gene: NOTCH3 were set to unknown
Review for gene: NOTCH3 was set to AMBER
Added comment: Request to add PDGFRB and NOTCH3 to MMBST panel - phenotype appropriate, but may need to broaden eligibility criteria simultaneously.
Sources: Other
Multiple monogenic benign skin tumours v1.12 PDGFRB Tom Cullup reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23731537, 23731542; Phenotypes: MYOFIBROMATOSIS, INFANTILE, 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v1.68 ASPRV1 Tom Cullup reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32516568; Phenotypes: ICHTHYOSIS, LAMELLAR, AUTOSOMAL DOMINANT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pigmentary skin disorders v1.16 NDUFB11 Tom Cullup gene: NDUFB11 was added
gene: NDUFB11 was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: NDUFB11 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: NDUFB11 were set to 33670341
Phenotypes for gene: NDUFB11 were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: NDUFB11 were set to unknown
Review for gene: NDUFB11 was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Pigmentary skin disorders v1.16 COX7B Tom Cullup gene: COX7B was added
gene: COX7B was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: COX7B was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: COX7B were set to 33670341
Phenotypes for gene: COX7B were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: COX7B were set to unknown
Review for gene: COX7B was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Pigmentary skin disorders v1.16 HCCS Tom Cullup gene: HCCS was added
gene: HCCS was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: HCCS was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: HCCS were set to 33670341
Phenotypes for gene: HCCS were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: HCCS were set to unknown
Review for gene: HCCS was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Structural eye disease v1.83 ASPH Tom Cullup reviewed gene: ASPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24768550; Phenotypes: Traboulsi syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.16 SMARCAL1 Tom Cullup gene: SMARCAL1 was added
gene: SMARCAL1 was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: SMARCAL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCAL1 were set to 11799392
Phenotypes for gene: SMARCAL1 were set to SCHIMKE IMMUNOOSSEOUS DYSPLASIA
Penetrance for gene: SMARCAL1 were set to Complete
Review for gene: SMARCAL1 was set to GREEN
Added comment: Sources: Other
Pigmentary skin disorders v1.16 DDX3X Tom Cullup gene: DDX3X was added
gene: DDX3X was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: DDX3X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: DDX3X were set to 30349862
Phenotypes for gene: DDX3X were set to INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNIJDERS BLOK TYPE
Penetrance for gene: DDX3X were set to unknown
Review for gene: DDX3X was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 USP9X Tom Cullup gene: USP9X was added
gene: USP9X was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: USP9X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: USP9X were set to 26833328
Phenotypes for gene: USP9X were set to INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 99, SYNDROMIC, FEMALE-RESTRICTED
Penetrance for gene: USP9X were set to unknown
Review for gene: USP9X was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 PHF6 Tom Cullup gene: PHF6 was added
gene: PHF6 was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: PHF6 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: PHF6 were set to 24092917
Phenotypes for gene: PHF6 were set to BORJESON-FORSSMAN-LEHMANN SYNDROME; Fine and whorled Blaschko-linear hypo or hyperpigmentation
Penetrance for gene: PHF6 were set to unknown
Review for gene: PHF6 was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 TFE3 Tom Cullup gene: TFE3 was added
gene: TFE3 was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: TFE3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TFE3 were set to 32409512
Phenotypes for gene: TFE3 were set to Intellectual disability with pigmentary mosaicism and storage disorder-like features
Penetrance for gene: TFE3 were set to unknown
Review for gene: TFE3 was set to GREEN
Added comment: Sources: Expert list
Mosaic skin disorders - Deep sequencing v1.5 PTPN11 Tom Cullup edited their review of gene: PTPN11: Added comment: Request upgrade to green in order that panel updates can be made in preparation for publication of case series, without delay waiting for next PanelApp update cycle.; Changed rating: GREEN; Changed publications to: Mosaic case series currently under publication review - expected to be published by end of 2021; Changed phenotypes to: Phakomatosis pigmentovascularis (PPV), Noonan syndrome with lentigines (LEOPARD)(151100), Speckled lentiginous naevus syndrome (deletion)
DDG2P v2.50 PLCB4 Kate Downes reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 22560091, PMID: 23315542, PMID: 28328130, PMID: 23913798; Phenotypes: Auriculocondylar syndrome 2 (OMIM: 614669); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Classified gene: CLCN7 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis.
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Classified gene: CLCN7 as Amber List (moderate evidence)
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis.
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Lysosomal storage disorder v1.75 CLCN7 Arina Puzriakova gene: CLCN7 was added
gene: CLCN7 was added to Lysosomal storage disorder. Sources: Literature
watchlist tags were added to gene: CLCN7.
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Mode of pathogenicity for gene: CLCN7 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: CLCN7 was set to AMBER
Added comment: Nicoli et al., 2019 (PMID: 31155284) reported on two unrelated individuals from different ethnic backgrounds with the same de novo gain-of-function missense variant (c.2144A>G, p.Tyr715Cys) in the CLCN7 gene. Both children had generalised cutaneous hypopigmentation without ocular involvement, delayed myelination and motor development, and organomegaly. Biopsies showed that both probands had cytoplasmic inclusions, characteristic of those seen in lysosomal-storage disorders. Human phenotypes were recapitulated by a mouse model harbouring the knock-in Clcn7 variant.

This gene-disease relationship is listed in OMIM (MIM# 618541) but is not yet in G2P.
Sources: Literature
Albinism or congenital nystagmus v1.18 CLCN7 Arina Puzriakova gene: CLCN7 was added
gene: CLCN7 was added to Albinism or congenital nystagmus. Sources: Literature
watchlist tags were added to gene: CLCN7.
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Mode of pathogenicity for gene: CLCN7 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: CLCN7 was set to AMBER
Added comment: Nicoli et al., 2019 (PMID: 31155284) reported on two unrelated individuals from different ethnic backgrounds with the same de novo gain-of-function missense variant (c.2144A>G, p.Tyr715Cys) in the CLCN7 gene. Both children had generalised cutaneous hypopigmentation without ocular involvement, delayed myelination and motor development, and organomegaly. Biopsies showed that both probands had cytoplasmic inclusions, characteristic of those seen in lysosomal-storage disorders. Human phenotypes were recapitulated by a mouse model harbouring the knock-in Clcn7 variant.

This gene-disease relationship is listed in OMIM (MIM# 618541) but is not yet in G2P.
Sources: Literature
Fetal anomalies v1.736 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600 to CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600; Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Severe microcephaly v2.266 BRD4 Ivone Leong Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome to Cornelia de Lange-like syndrome, MONDO:0016033
Severe microcephaly v2.265 BRD4 Ivone Leong Classified gene: BRD4 as Amber List (moderate evidence)
Severe microcephaly v2.265 BRD4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not OMIM. Based on the available evidence this gene has been given an Amber rating.
Severe microcephaly v2.265 BRD4 Ivone Leong Gene: brd4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.264 BRD4 Ivone Leong Tag watchlist tag was added to gene: BRD4.
Hydrocephalus v2.123 HYLS1 Ivone Leong Tag Q4_21_expert_review tag was added to gene: HYLS1.
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Classified gene: TNFRSF11A as Amber List (moderate evidence)
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. Based on the expert review there is enough evidnece for this gene to be Green on this panel.
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Gene: tnfrsf11a has been classified as Amber List (Moderate Evidence).
Hydrocephalus v2.122 TNFRSF11A Ivone Leong Tag Q4_21_rating tag was added to gene: TNFRSF11A.
Intellectual disability v3.1378 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4, 611490; Osteopetrosis, autosomal dominant 2, 166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Intellectual disability v3.1377 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.479 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Primary immunodeficiency or monogenic inflammatory bowel disease v2.479 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Defects in Intrinsic and Innate Immunity; Osteopetrosis with hypocalcemia, neurologic features to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Fetal anomalies v1.735 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from CLCN7-RELATED OSTEOPETROSIS to CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Fetal anomalies v1.734 CLCN7 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Biallelic' to 'Both mono- and biallelic' at the next review. At least 2 recessive cases and >3 dominant cases reported with osteopetrosis.
Fetal anomalies v1.734 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.733 CLCN7 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN7.
Skeletal dysplasia v2.140 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4 611490; Osteopetrosis, autosomal dominant 2 166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Osteopetrosis v1.27 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4 OMIM:611490; Osteopetrosis, autosomal dominant 2 OMIM:166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Intellectual disability v3.1376 BLOC1S1 Ivone Leong Tag watchlist tag was added to gene: BLOC1S1.
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong Entity copied from Intellectual disability v3.1376
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong gene: ARFGEF1 was added
gene: ARFGEF1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: ARFGEF1.
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1376 ARFGEF1 Ivone Leong Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Classified gene: ARFGEF1 as Amber List (moderate evidence)
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Gene: arfgef1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1374 ARFGEF1 Ivone Leong Tag Q4_21_rating tag was added to gene: ARFGEF1.
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Classified gene: TMEM251 as Amber List (moderate evidence)
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases reported.
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.138 TMEM251 Eleanor Williams Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex‐like skeletal dysplasia; severe short stature to Dysostosis multiplex, Ain-Naz type, OMIM:19345; severe short stature
Skeletal dysplasia v2.137 TMEM251 Eleanor Williams reviewed gene: TMEM251: Rating: AMBER; Mode of pathogenicity: None; Publications: 33252156; Phenotypes: Dysostosis multiplex, Ain-Naz type, OMIM:19345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.50 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from HEREDITARY SENSORY & AUTONOMIC NEUROPATHY TYPE VIII 616488 to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Hereditary neuropathy v1.417 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from hereditary sensory & autonomic neuropathy type VIII to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Hereditary neuropathy or pain disorder v1.64 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from hereditary sensory & autonomic neuropathy type VIII to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1374 PRDM12 Sarah Leigh Mode of inheritance for gene: PRDM12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1373 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from NA to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1372 PRDM12 Sarah Leigh Publications for gene: PRDM12 were set to
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh Tag Q4_21_rating tag was added to gene: EHBP1L1.
Likely inborn error of metabolism v2.188 EHBP1L1 Sarah Leigh Tag Q4_21_rating tag was added to gene: EHBP1L1.
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh Entity copied from Fetal hydrops v1.39
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh gene: EHBP1L1 was added
gene: EHBP1L1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to 34645488; 26833786; https://dmdd.org.uk/mutants/Ehbp1l1
Phenotypes for gene: EHBP1L1 were set to non-immune hydrops fetalis MONDO:0009369
Penetrance for gene: EHBP1L1 were set to unknown
Likely inborn error of metabolism v2.188 EHBP1L1 Sarah Leigh Entity copied from Fetal hydrops v1.39
Likely inborn error of metabolism v2.188 EHBP1L1 Sarah Leigh gene: EHBP1L1 was added
gene: EHBP1L1 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to 34645488; 26833786; https://dmdd.org.uk/mutants/Ehbp1l1
Phenotypes for gene: EHBP1L1 were set to non-immune hydrops fetalis MONDO:0009369
Penetrance for gene: EHBP1L1 were set to unknown
Fetal hydrops v1.39 EHBP1L1 Sarah Leigh Publications for gene: EHBP1L1 were set to 34645488
Fetal hydrops v1.38 EHBP1L1 Sarah Leigh edited their review of gene: EHBP1L1: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least two variants reported in two unrelated families with non-immune hydrops fetalis (NIHF) resulting in recurrent fetal loss. Two Ehbp1l1−/− mouse models shared phenotypic features with the affected patients, including early death, abnormal intestinal microvilli, subcutaneous edema, perimembraneous ventricular septic defect, and thin myocardium (PMID 26833786, https://dmdd.org.uk/mutants/Ehbp1l1).; Changed rating: GREEN
Fetal hydrops v1.38 EHBP1L1 Sarah Leigh Publications for gene: EHBP1L1 were set to PMID: 34645488
Fetal hydrops v1.37 EHBP1L1 Sarah Leigh Phenotypes for gene: EHBP1L1 were changed from Non immune hydrops to non-immune hydrops fetalis MONDO:0009369
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Classified gene: EHBP1L1 as Amber List (moderate evidence)
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Gene: ehbp1l1 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.29 GYG1 Ivone Leong Phenotypes for gene: GYG1 were changed from to ?Glycogen storage disease XV, OMIM:613507; hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v2.28 GYG1 Ivone Leong Publications for gene: GYG1 were set to 27718144
Hypertrophic cardiomyopathy v2.27 GYG1 Oliver Watkinson reviewed gene: GYG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27718144, 20357282, 31628455; Phenotypes: Hypertrophic Cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v2.27 GYG1 Oliver Watkinson gene: GYG1 was added
gene: GYG1 was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Literature
Mode of inheritance for gene: GYG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GYG1 were set to 27718144
Penetrance for gene: GYG1 were set to Incomplete
DDG2P v2.49 ATN1 Dmitrijs Rots Deleted their review
DDG2P v2.49 ATN1 Dmitrijs Rots Deleted their comment
DDG2P v2.49 ATN1 Dmitrijs Rots reviewed gene: ATN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.50 IFT140 Sarah Leigh changed review comment from: Two IFT140 variants reported in a case of primary ciliary dyskinesia (PMID 34556108).
Sources: Literature; to: Two rare missense IFT140 variants (p.Leu693Phe & p.Lys390Arg) reported in a case of primary ciliary dyskinesia, both variats predicted to be benign by Polyphen & SIFT (PMID 34556108).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.50 IFT140 Sarah Leigh gene: IFT140 was added
gene: IFT140 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: IFT140 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT140 were set to 34556108
Phenotypes for gene: IFT140 were set to Short-rib thoracic dysplasia 9 with or without polydactyly OMIM:266920
Review for gene: IFT140 was set to RED
Added comment: Two IFT140 variants reported in a case of primary ciliary dyskinesia (PMID 34556108).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.49 PLK4 Sarah Leigh Publications for gene: PLK4 were set to 22503633; 34556108
Respiratory ciliopathies including non-CF bronchiectasis v1.48 PLK4 Sarah Leigh gene: PLK4 was added
gene: PLK4 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: PLK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK4 were set to 22503633; 34556108
Phenotypes for gene: PLK4 were set to Microcephaly and chorioretinopathy, autosomal recessive 2 OMIM:616171; microcephaly and chorioretinopathy 2 MONDO:0014516
Review for gene: PLK4 was set to RED
Added comment: Two PLK4 variants reported in a case of primary ciliary dyskinesia (PMID: 34556108).
Sources: Literature
Intellectual disability v3.1371 ZC4H2 Ivone Leong reviewed gene: ZC4H2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1371 ZC4H2 Ivone Leong Tag Q4_21_MOI tag was added to gene: ZC4H2.
Fetal anomalies v1.732 ZC4H2 Ivone Leong Publications for gene: ZC4H2 were set to
Fetal anomalies v1.731 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Arthrogryposis v3.130 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from Wieacker-Wolff syndrome 314580 to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Intellectual disability v3.1371 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Infantile enterocolitis & monogenic inflammatory bowel disease v1.24 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease; 32686289; 25943627; 24942515; 29501442
Infantile enterocolitis & monogenic inflammatory bowel disease v1.23 XIAP Ivone Leong Added comment: Comment on publications: Previously: 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease
Infantile enterocolitis & monogenic inflammatory bowel disease v1.23 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Gastrointestinal epithelial barrier disorders v1.61 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055
Gastrointestinal epithelial barrier disorders v1.60 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Infantile enterocolitis & monogenic inflammatory bowel disease v1.22 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.478 XIAP Ivone Leong Publications for gene: XIAP were set to 26581487; 21119115; 23973892; 17080092; 21173700; 22228567; 23131490; 25943627; 31754776
Primary immunodeficiency or monogenic inflammatory bowel disease v2.477 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Intracerebral calcification disorders v1.30 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17617514 - identification of AP1S2 variants in a large 4-generation French family, and a Scottish family, marked calcifications of the basal ganglia were reported in affected individuals in both families; 18428203 - an additional two families reported "Studying four patients in two unrelated families in which AP1S2 nonsense and splicesite
mutations segregated, we found that affected individuals presented, in addition to previously described features,
with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that
the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be
progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically
recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive
behavior, brain calcifications, and elevated CSF protein levels."
Structural basal ganglia disorders v1.22 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 23756445; 17617514; 18428203
White matter disorders and cerebral calcification - childhood onset v1.208 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17617514; 1842820
Dystonia, chorea or related movement disorder, childhood onset v1.160 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 23756445; 17617514; 18428203
Intellectual disability v3.1370 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to
Hydrocephalus v2.122 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17186471
Fetal anomalies v1.730 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Fetal anomalies v1.730 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from MENTAL RETARDATION X-LINKED TYPE 59 to Pettigrew syndrome, OMIM:304340
Fetal anomalies v1.729 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Fetal anomalies v1.729 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Dystonia, chorea or related movement disorder, childhood onset v1.159 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Intellectual disability v3.1369 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Intellectual disability v3.1369 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Dystonia, chorea or related movement disorder, childhood onset v1.159 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Dystonia, chorea or related movement disorder, childhood onset v1.159 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Structural basal ganglia disorders v1.21 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'XL, biallelic in females' to 'XL, monoallelic in females'.

Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Structural basal ganglia disorders v1.21 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Dystonia, chorea or related movement disorder, adult onset v1.125 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'XL, biallelic in females' to 'XL, monoallelic in females'.

Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females.
Dystonia, chorea or related movement disorder, adult onset v1.125 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Hydrocephalus v2.121 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Hydrocephalus v2.121 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Hydrocephalus v2.121 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare multisystem ciliopathy disorders v1.148 TBC1D32 Ivone Leong Classified gene: TBC1D32 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.148 TBC1D32 Ivone Leong Gene: tbc1d32 has been classified as Green List (High Evidence).
Malformations of cortical development v2.93 TBC1D32 Ivone Leong Tag Q3_21_rating tag was added to gene: TBC1D32.
Malformations of cortical development v2.93 TBC1D32 Ivone Leong Entity copied from Rare multisystem ciliopathy disorders v1.147
Malformations of cortical development v2.93 TBC1D32 Ivone Leong gene: TBC1D32 was added
gene: TBC1D32 was added to Malformations of cortical development. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Amber
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Phenotypes for gene: TBC1D32 were set to Orofaciodigital syndrome, MONDO:0015375
Penetrance for gene: TBC1D32 were set to Complete
Ophthalmological ciliopathies v1.25 TBC1D32 Ivone Leong Tag Q3_21_rating tag was added to gene: TBC1D32.
Ophthalmological ciliopathies v1.25 TBC1D32 Ivone Leong Phenotypes for gene: TBC1D32 were changed from No OMIM phenotype; Oro-facio-digital syndrome type IX (Adly (2014) Hum Mutat 35, 36) to Orofaciodigital syndrome, MONDO:0015375
Ophthalmological ciliopathies v1.24 TBC1D32 Ivone Leong Publications for gene: TBC1D32 were set to
Ophthalmological ciliopathies v1.23 TBC1D32 Ivone Leong Classified gene: TBC1D32 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.23 TBC1D32 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with Ciliopathy syndrome in Gene2Phenotype (possible) but not a phenotype in OMIM. There is enough evidence for this gene to be Green.

Green review from Rhiannon Mellis (Great Ormond Street Hospital) on the Rare multisystem ciliopathy disorders panel (ID: 150):

"The same group who reported the first individual with a ciliopathy phenotype (Adly et al 2014) now report two further unrelated fetal cases (Alsahan 2020, Monies et al 2019) with OFD/ciliopathy phenotype:

- One had polyhydramnios, hydrocephaly with enlarged biparietal diameter and dilated lateral ventricles, single nostril, anophthalmia, short long bones and echogenic lungs
- The other had holoprosencephaly, cyclops, cleft lip, ventricular septal defect, agenesis of corpus callosum, and club feet

- There are also two sib pairs (one Finnish, one Pakistani) reported by Hietamaki et al 2020 with TBC1D32 variants and a variable phenotype of pituitary hypoplasia +/- other midline defects, hydrocephalus, short limbs, polydactyly
Created: 6 Oct 2020, 3:14 p.m. | Last Modified: 6 Oct 2020, 3:14 p.m.
Panel Version: 1.129

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
OFD IX

Publications

PMID: 32573025
31130284
32060556"
Ophthalmological ciliopathies v1.23 TBC1D32 Ivone Leong Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Hydrocephalus v2.120 TBC1D32 Ivone Leong Tag Q4_21_rating tag was added to gene: TBC1D32.
Hydrocephalus v2.120 TBC1D32 Ivone Leong Entity copied from Rare multisystem ciliopathy disorders v1.147
Hydrocephalus v2.120 TBC1D32 Ivone Leong gene: TBC1D32 was added
gene: TBC1D32 was added to Hydrocephalus. Sources: Expert list,Radboud University Medical Center, Nijmegen,Expert Review Amber
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Phenotypes for gene: TBC1D32 were set to Orofaciodigital syndrome, MONDO:0015375
Penetrance for gene: TBC1D32 were set to Complete
Rare multisystem ciliopathy disorders v1.147 TBC1D32 Ivone Leong Classified gene: TBC1D32 as Amber List (moderate evidence)
Rare multisystem ciliopathy disorders v1.147 TBC1D32 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with Ciliopathy syndrome in Gene2Phenotype (possible) but not a phenotype in OMIM. There is enough evidence for this gene to be Green.
Rare multisystem ciliopathy disorders v1.147 TBC1D32 Ivone Leong Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.241 B4GAT1 Ivone Leong reviewed gene: B4GAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.241 B4GAT1 Ivone Leong Publications for gene: B4GAT1 were set to 23359570
Ataxia and cerebellar anomalies - childhood onset v2.240 B4GAT1 Ivone Leong Tag Q3_21_rating tag was added to gene: B4GAT1.
Hereditary ataxia, adult onset v2.90 B4GAT1 Ivone Leong reviewed gene: B4GAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v2.90 B4GAT1 Ivone Leong Publications for gene: B4GAT1 were set to
Retinal disorders v2.222 ARL3 Ivone Leong edited their review of gene: ARL3: Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype (possible - RP, and probable - Joubert syndrome). There is enough evidence to support a gene-disease association for both MOIs. This gene should be rated as Green at the next review.; Changed rating: GREEN
Retinal disorders v2.222 ARL3 Ivone Leong Tag Q4_21_rating tag was added to gene: ARL3.
Retinal disorders v2.222 ARL3 Ivone Leong Mode of inheritance for gene: ARL3 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.221 ARL3 Ivone Leong Phenotypes for gene: ARL3 were changed from to Joubert syndrome 35, OMIM:61816; cone-rod dystrophy, MONDO:0015993; Retinitis pigmentosa 83, OMIM:618173
Retinal disorders v2.220 ARL3 Ivone Leong Added comment: Comment on publications: PMID:30269812 describes 2 unrelated consanguineous families (Saudi and Pakistani). Both have phenotype resembling Joubert syndrome (night blindness, rod-cone dystrophy, mild dysmorphic features, hypotonia (only in 1 family), ataxia, cerebellar vernis hypoplasia). Both are homozygous missense for the same amino acid residue (R149C, R149H). The authors performed some in vitro functional analysis.

PMID:16565502 describes a knockout mouse model of Arl3. The homozygous knockouts developed ciliary disease affecting kidney, biliary tract, pancreas and retina. However, there was no mention of a brain phenotype.

PMID:31743939 describes 2 large consanguineous Pakastani families with the same homozygous variant (Arg99Ile). There are 8 affected individuals in total and 7/8 had cone-rod dystrophy and no features of Joubert syndrome.

PMID:33748123 describes a Chinese family. Proband is compound het (c.91A>G, p.T31A; c.353G>T, p.C118F) and has retinal dystrophy. Heterozygous father has late onset and mild rode-cone dystrophy. Mother and sister (het) are normal. All family members did not have any other phenotypes.

PMID:26964041 describes a family with affected mother, son and daughter with retinitis pigmentosa. Affected patients were heterozygosity for Y90C. The mother's parents do not have the variant suggesting that it is a de novo event in the mother. No functional studies of the variant were performed.

PMID:30932721 reports a case where a patient has a de novo Y90C variant and has RP.

PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.
Retinal disorders v2.220 ARL3 Ivone Leong Publications for gene: ARL3 were set to
Ophthalmological ciliopathies v1.22 ARL3 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from Biallelic to Both monoallelic and biallelic as eye phenotype is seen for both MOIs.
Ophthalmological ciliopathies v1.22 ARL3 Ivone Leong Mode of inheritance for gene: ARL3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ophthalmological ciliopathies v1.21 ARL3 Ivone Leong Phenotypes for gene: ARL3 were changed from Joubert syndrome 35, OMIM:61816 to Joubert syndrome 35, OMIM:61816; cone-rod dystrophy, MONDO:0015993; Retinitis pigmentosa 83, OMIM:618173
Ophthalmological ciliopathies v1.20 ARL3 Ivone Leong Tag watchlist was removed from gene: ARL3.
Tag Q4_21_rating tag was added to gene: ARL3.
Ophthalmological ciliopathies v1.20 ARL3 Ivone Leong Entity copied from Neurological ciliopathies v1.20
Ophthalmological ciliopathies v1.20 ARL3 Ivone Leong gene: ARL3 was added
gene: ARL3 was added to Ophthalmological ciliopathies. Sources: Expert list,Expert Review Amber
watchlist tags were added to gene: ARL3.
Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL3 were set to 30269812; 16565502; 33748123; 31743939; 26964041; 30932721; 34485303
Phenotypes for gene: ARL3 were set to Joubert syndrome 35, OMIM:61816
Neurological ciliopathies v1.20 ARL3 Ivone Leong Classified gene: ARL3 as Amber List (moderate evidence)
Neurological ciliopathies v1.20 ARL3 Ivone Leong Added comment: Comment on list classification: New gene submitted by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (possible - RP, and probable - Joubert syndrome).

As there are only 2 cases that have been associated with Joubert syndrome (PMID:30269812) and the knockout mouse model does not appear to have a neurological phenotype (PMID:16565502) this gene has been given an Amber rating until further evidence is available.
Neurological ciliopathies v1.20 ARL3 Ivone Leong Gene: arl3 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v1.19 ARL3 Ivone Leong Tag watchlist tag was added to gene: ARL3.
Neurological ciliopathies v1.19 ARL3 Ivone Leong Added comment: Comment on publications: PMID:30269812 describes 2 unrelated consanguineous families (Saudi and Pakistani). Both have phenotype resembling Joubert syndrome (night blindness, rod-cone dystrophy, mild dysmorphic features, hypotonia (only in 1 family), ataxia, cerebellar vernis hypoplasia). Both are homozygous missense for the same amino acid residue (R149C, R149H). The authors performed some in vitro functional analysis.

PMID:16565502 describes a knockout mouse model of Arl3. The homozygous knockouts developed ciliary disease affecting kidney, biliary tract, pancreas and retina. However, there was no mention of a brain phenotype.

PMID:31743939 describes 2 large consanguineous Pakastani families with the same homozygous variant (Arg99Ile). There are 8 affected individuals in total and 7/8 had cone-rod dystrophy and no features of Joubert syndrome.

PMID:33748123 describes a Chinese family. Proband is compound het (c.91A>G, p.T31A; c.353G>T, p.C118F) and has retinal dystrophy. Heterozygous father has late onset and mild rode-cone dystrophy. Mother and sister (het) are normal. All family members did not have any other phenotypes.

PMID:26964041 describes a family with affected mother, son and daughter with retinitis pigmentosa. Affected patients were heterozygosity for Y90C. The mother's parents do not have the variant suggesting that it is a de novo event in the mother. No functional studies of the variant were performed.

PMID:30932721 reports a case where a patient has a de novo Y90C variant and has RP.

PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.
Neurological ciliopathies v1.19 ARL3 Ivone Leong Publications for gene: ARL3 were set to 30269812; 16565502
Dystonia, chorea or related movement disorder, adult onset v1.124 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 304340; Dystonia to Pettigrew syndrome, OMIM:304340
Neurodegenerative disorders, adult onset v2.201 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Dystonia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
Hereditary ataxia, adult onset v2.89 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 OMIM:304340; syndromic X-linked intellectual disability 5 MONDO:0010574 to Pettigrew syndrome, OMIM:304340
Intracerebral calcification disorders v1.29 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Calcifications in basal ganglia to Pettigrew syndrome, OMIM:304340; Calcifications in basal ganglia
Hereditary ataxia v1.245 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
Ataxia and cerebellar anomalies - childhood onset v2.240 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
White matter disorders and cerebral calcification - childhood onset v1.207 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Calcifications in basal ganglia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340; Calcifications in basal ganglia
Dystonia, chorea or related movement disorder, childhood onset v1.158 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Dystonia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340; Dystonia
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic, Fried type, 300630; MENTAL RETARDATION X-LINKED TYPE 59 (MRX59) to Pettigrew syndrome, OMIM:304340
Structural basal ganglia disorders v1.20 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 304340 to Pettigrew syndrome, OMIM:304340
Hydrocephalus v2.119 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, OMIM:304340 to Pettigrew syndrome, OMIM:304340
Congenital muscular dystrophy v2.18 MYMK Ivone Leong commented on gene: MYMK
Congenital muscular dystrophy v2.18 MYMK Ivone Leong Tag Q3_21_expert_review tag was added to gene: MYMK.
Tag Q3_21_phenotype tag was added to gene: MYMK.
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Classified gene: GGPS1 as Green List (high evidence)
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green according to my previous review.
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Gene: ggps1 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

PMID:32403198 all 6 unrelated families are from different ethnic backgrounds and all had missense variants (hom or compound het). All have muscle dystrophy, contractures were noted in the more severe patients (4/11), 10/11 hearing loss, 3/3 affected females have ovariant insufficiency (other 3 females are undetermined due to age), 8/10 failure to thrive/short stature.

There is enough evidence to support a gene-disease association. This gene should be Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

PMID:32403198 all 6 unrelated families are from different ethnic backgrounds and all had missense variants (hom or compound het). All have muscle dystrophy, contractures were noted in the more severe patients (4/11), 10/11 hearing loss, 3/3 affected females have ovariant insufficiency (other 3 females are undetermined due to age), 8/10 failure to thrive/short stature.

There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong Tag Q4_21_rating was removed from gene: GGPS1.
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong Entity copied from Congenital muscular dystrophy v2.18
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong gene: GGPS1 was added
gene: GGPS1 was added to Primary ovarian insufficiency. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: GGPS1.
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Monogenic hearing loss v2.200 GGPS1 Ivone Leong Entity copied from Congenital muscular dystrophy v2.18
Monogenic hearing loss v2.200 GGPS1 Ivone Leong gene: GGPS1 was added
gene: GGPS1 was added to Hearing loss. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: GGPS1.
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Tag Q4_21_rating tag was added to gene: GGPS1.
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Classified gene: GGPS1 as Amber List (moderate evidence)
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

PMID:32403198 all 6 unrelated families are from different ethnic backgrounds and all had missense variants (hom or compound het). All have muscle dystrophy, contractures were noted in the more severe patients (4/11), 10/11 hearing loss, 3/3 affected females have ovariant insufficiency (other 3 females are undetermined due to age), 8/10 failure to thrive/short stature.

There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Gene: ggps1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v2.17 GGPS1 Ivone Leong Phenotypes for gene: GGPS1 were changed from Muscular dystrophy; Deafness; Ovarian insufficiency to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Paediatric or syndromic cardiomyopathy v1.57 GSN Ivone Leong Classified gene: GSN as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.57 GSN Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM and Gene2Phenotype.

PMID: 26339870 found that 12/227 patients had cardiomyopathy and previous case reports and publications show that cardiomyopathy is only present in some cases and the age of diagnosis (or when pacemakers were implants into patients) is >50 years. Cardiomyopathy does not appear to be a presenting feature.

Therefore, this gene has been given an Amber rating.
Paediatric or syndromic cardiomyopathy v1.57 GSN Ivone Leong Gene: gsn has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1367 BLOC1S1 Dmitrijs Rots gene: BLOC1S1 was added
gene: BLOC1S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to PMID: 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Review for gene: BLOC1S1 was set to GREEN
Added comment: 4 cases with similar phenotype and inheritance reported
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v1.57 MYH1 Dmitrijs Rots gene: MYH1 was added
gene: MYH1 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: MYH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYH1 were set to PMID: 33755318
Phenotypes for gene: MYH1 were set to Rhabdomyolysis
Penetrance for gene: MYH1 were set to unknown
Mode of pathogenicity for gene: MYH1 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: MYH1 was set to AMBER
Added comment: One patient reported with some statistical evidence and known horse "model" with same phenotype.
Sources: Literature
Fetal hydrops v1.35 EHBP1L1 Dmitrijs Rots gene: EHBP1L1 was added
gene: EHBP1L1 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to PMID: 34645488
Phenotypes for gene: EHBP1L1 were set to Non immune hydrops
Penetrance for gene: EHBP1L1 were set to unknown
Review for gene: EHBP1L1 was set to GREEN
Added comment: 2 families with confirming mouse data
Sources: Literature
Intellectual disability v3.1367 FAAH2 Dmitrijs Rots reviewed gene: FAAH2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34645488; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Mild cognitive impairment has been reported in some patients with CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ID. There is also controversy regarding any link between CLCN2 and epilepsy.
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.448 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628
Intellectual disability v3.1366 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Intellectual disability v3.1365 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Early onset or syndromic epilepsy v2.447 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Monoallelic' only. Seizures have been linked with monoallelic variants (MIM# 607628) although there is debate regarding this gene-disease relationship, hence the current Red rating on this panel. Autosomal recessive pathogenic variants are also associated with Leukoencephalopathy (MIM# 615651) which does not include epilepsy.
Early onset or syndromic epilepsy v2.447 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v2.200 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Features of neurodegeneration are seen in CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes are relevant to this panel.
Neurodegenerative disorders, adult onset v2.200 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.199 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; Leukoencephalopathy with ataxia, OMIM:615651 to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary ataxia, adult onset v2.88 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628; Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary ataxia v1.244 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Neurodegenerative disorders, adult onset v2.198 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 19191339; 23707145
Neurodegenerative disorders, adult onset v2.197 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Familial Meniere Disease v1.1 AQP6 Eldar Dedic reviewed gene: AQP6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Familial Meniere Disease v1.1 AQP5 Eldar Dedic reviewed gene: AQP5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Hereditary ataxia, adult onset v2.87 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Hereditary ataxia v1.243 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Ataxia and cerebellar anomalies - childhood onset v2.239 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 19191339; 23707145
Ataxia and cerebellar anomalies - childhood onset v2.238 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Hereditary ataxia, adult onset v2.86 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Hereditary ataxia, adult onset v2.86 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Hereditary ataxia, adult onset v2.86 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.242 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Hereditary ataxia v1.242 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.238 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Ataxia and cerebellar anomalies - childhood onset v2.238 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.237 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; Leukoencephalopathy with ataxia, 615651 to Leukoencephalopathy with ataxia, OMIM:615651
Inherited white matter disorders v1.141 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Chloride Ion Channel 2(ClC-2) related leukoencephalopathy with intramyelinic oedema; Leukoencephalopathy with ataxia; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukoencephalopathy with ataxia, OMIM:615651
Leukodystrophy, adult onset v1.31 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651 to Leukoencephalopathy with ataxia, OMIM:615651
White matter disorders and cerebral calcification - childhood onset v1.206 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Chloride Ion Channel 2(ClC-2) related leukoencephalopathy with intramyelinic oedema to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary spastic paraplegia, adult onset v1.73 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, OMIM:270685 to Silver spastic paraplegia syndrome, OMIM:270685; Neuropathy, distal hereditary motor, type VC, OMIM:619112
Hereditary spastic paraplegia, childhood onset v2.84 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, OMIM:270685 to Silver spastic paraplegia syndrome, OMIM:270685; Neuropathy, distal hereditary motor, type VC, OMIM:619112
Familial Meniere Disease v1.1 AQP3 Eldar Dedic reviewed gene: AQP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Monogenic nephrogenic diabetes insipidus v1.8 AVPR2 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: AVPR2.
Renal tubulopathies v2.30 AVPR2 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: AVPR2.
Renal tubulopathies v2.30 AVPR2 Eleanor Williams Phenotypes for gene: AVPR2 were changed from Diabetes insipidus, nephrogenic, 304800; Nephrogenic Diabetes Insipidus; Diabetes Insipidus, Nephrogenic, X-Linked; nephrogenic diabetes insipidus (commonest cause, affected females also reported often with a milder and later presentation); Nephrogenic syndrome of inappropriate antidiuresis, 300539 to Diabetes insipidus, nephrogenic, OMIM:304800; Nephrogenic syndrome of inappropriate antidiuresis, OMIM:300539
Renal tubulopathies v2.29 AVPR2 Eleanor Williams Added comment: Comment on mode of pathogenicity: Gain of function variants
Renal tubulopathies v2.29 AVPR2 Eleanor Williams Mode of pathogenicity for gene: AVPR2 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Neurodegenerative disorders, adult onset v2.197 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, to Silver spastic paraplegia syndrome, OMIM:270685
Hydrocephalus v2.118 MYMK Ivone Leong Tag Q4_21_phenotype tag was added to gene: MYMK.
Hydrocephalus v2.118 MYMK Ivone Leong commented on gene: MYMK
Mosaic skin disorders - Deep sequencing v1.5 BRAF Tom Cullup changed review comment from: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list; to: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list
Fast track form submitted. Note from Prof Kinsler:
We have noticed that BRAF is not included on this panel. As a key player in mosaic diseases of various types this was an error somehow in the preparation of the original list. Without it's inclusion on the panel various conditions cannot be properly tested for. For example 7% of Congenital Melanocytic Naevus syndrome are caused by BRAF mosaicism and approximately 5% of Arteriovenous Malformations.
Hydrocephalus v2.118 MYMK Ivone Leong Tag Q4_21_expert_review tag was added to gene: MYMK.
Mosaic skin disorders - Deep sequencing v1.5 BRAF Tom Cullup gene: BRAF was added
gene: BRAF was added to Mosaic skin disorders - deep sequencing. Sources: Expert list
Mode of inheritance for gene: BRAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAF were set to PMID: 31111470; 31891627; 29461977
Phenotypes for gene: BRAF were set to Melanocytic naevus syndrome (MIM 137550); Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 (MIM 613707); Cardio-facio-cutaneous syndrome 1 (MIM 115150)
Penetrance for gene: BRAF were set to Complete
Mode of pathogenicity for gene: BRAF 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: BRAF was set to GREEN
Added comment: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list
Hydrocephalus v2.118 TCIRG1 Ivone Leong Tag Q4_21_rating tag was added to gene: TCIRG1.
Hydrocephalus v2.118 TCIRG1 Ivone Leong Publications for gene: TCIRG1 were set to
Hydrocephalus v2.117 TCIRG1 Ivone Leong Classified gene: TCIRG1 as Amber List (moderate evidence)
Hydrocephalus v2.117 TCIRG1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hydrocephalus v2.117 TCIRG1 Ivone Leong Gene: tcirg1 has been classified as Amber List (Moderate Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFB Eleanor Williams commented on gene: CFB: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained young onset end-stage renal disease v1.20 CFB Eleanor Williams commented on gene: CFB: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained kidney failure in young people v1.97 CFB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained kidney failure in young people v1.97 CFB Eleanor Williams Mode of inheritance for gene: CFB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Atypical haemolytic uraemic syndrome v2.10 CFB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Atypical haemolytic uraemic syndrome v2.10 CFB Eleanor Williams Mode of inheritance for gene: CFB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Clefting v2.57 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Fetal anomalies v1.728 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Skeletal dysplasia v2.137 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184.
Skeletal dysplasia v2.137 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Limb disorders v2.65 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Clefting v2.56 SCUBE3 Sarah Leigh Deleted their comment
Clefting v2.56 SCUBE3 Sarah Leigh edited their review of gene: SCUBE3: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined.; Changed rating: AMBER
Clefting v2.56 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined.
Clefting v2.56 SCUBE3 Sarah Leigh Deleted their comment
Clefting v2.56 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Clefting v2.56 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SCUBE3.
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Fetal anomalies v1.727 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Prenatal growth retardation was evident in 8/11 relevant cases.
Limb disorders v2.64 SCUBE3 Sarah Leigh Tag Q4_21_rating tag was added to gene: SCUBE3.
Limb disorders v2.64 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Limb disorders v2.64 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Brachydactyly was evident in 12/15 cases examined.
Fetal anomalies v1.727 BMPR1B Arina Puzriakova changed review comment from: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel.; to: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel.
-----
Confirmed with clinical team that this is the appropriate MOI for this panel.
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Added comment: Comment on phenotypes: Previously associated with ?Mental retardation, X-linked 91, OMIM:300577; however, OMIM has removed this
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Phenotypes for gene: ZDHHC15 were changed from ?Mental retardation, X-linked 91, 300577 to cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Added comment: Comment on publications: New publication added PMID:34345675
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Publications for gene: ZDHHC15 were set to 15915161
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Fetal anomalies v1.727 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Fetal anomalies. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Clefting v2.56 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Clefting v2.56 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Clefting. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Limb disorders v2.64 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Limb disorders v2.64 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Limb disorders. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Intellectual disability v3.1362 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Intellectual disability v3.1362 RAD51 Arina Puzriakova Added comment: Comment on list classification: Intellectual disability has been reported in 2/3 individuals with RAD51-associated FA (third patient with mild early DD). However, a syndromic presentation prior to this is expected. Potential for VUSs in pure ID cohort, although there is an allied chromosome breakage test. Upgrading from Red to Amber - which also reflects the rating of other FA genes associated with ID.
Intellectual disability v3.1362 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1361 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2, OMIM:614508 to Fanconi anemia, complementation group R, OMIM:617244
Intellectual disability v3.1360 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 22305526; 21242494
Intellectual disability v3.1359 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial Meniere Disease v1.1 AQP2 Eldar Dedic reviewed gene: AQP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Haematological malignancies cancer susceptibility v2.21 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 28297620
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova edited their review of gene: RAD51: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies for rare disease v1.7 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 28297620
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova edited their review of gene: RAD51: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.264 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Severe microcephaly v2.264 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Severe microcephaly v2.264 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.63 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Limb disorders v2.63 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Limb disorders v2.63 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Fanconi anaemia or Bloom syndrome v1.12 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Confirmed Fanconi anaemia or Bloom syndrome. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Severe microcephaly v2.263 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Severe microcephaly. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Limb disorders v2.62 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Limb disorders. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Hereditary spastic paraplegia v1.259 ABHD16A Ivone Leong Classified gene: ABHD16A as Green List (high evidence)
Hereditary spastic paraplegia v1.259 ABHD16A Ivone Leong Gene: abhd16a has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong Tag Q4_21_rating was removed from gene: ABHD16A.
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to Hereditary spastic paraplegia. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Hereditary spastic paraplegia, childhood onset v2.83 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
Hereditary spastic paraplegia, childhood onset v2.83 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
White matter disorders and cerebral calcification - childhood onset v1.205 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
White matter disorders and cerebral calcification - childhood onset v1.205 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group R, OMIM:617244
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group R, OMIM:617244
Intellectual disability v3.1359 ABHD16A Ivone Leong Tag Q4_21_rating tag was added to gene: ABHD16A.
Intellectual disability v3.1359 ABHD16A Ivone Leong Classified gene: ABHD16A as Amber List (moderate evidence)
Intellectual disability v3.1359 ABHD16A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1359 ABHD16A Ivone Leong Gene: abhd16a has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.80 RAD51 Arina Puzriakova Mode of inheritance for gene: RAD51 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1358 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2,614508 to Mirror movements 2, OMIM:614508
Arthrogryposis v3.129 ERGIC1 Arina Puzriakova Publications for gene: ERGIC1 were set to 28317099; 34037256
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Classified gene: ERGIC1 as Amber List (moderate evidence)
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update - three unrelated families reported to date with arthrogryposis associated with different variants in this gene (PMID: 28317099; 31230720; 34037256).
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Gene: ergic1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Tag watchlist was removed from gene: ERGIC1.
Tag Q3_21_rating tag was added to gene: ERGIC1.
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova reviewed gene: ERGIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230720; Phenotypes: Arthrogryposis multiplex congenita 2, neurogenic type, OMIM:208100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v2.55 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Clefting v2.55 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.726 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Fetal anomalies v1.726 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.136 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Skeletal dysplasia v2.136 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v2.61 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Limb disorders v2.61 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Tag watchlist tag was added to gene: ERGIC1.
Fetal anomalies v1.725 BHLHA9 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic single nucleotide variants in this gene are associated with Syndactyly, mesoaxial synostotic, with phalangeal reduction (OMIM:609432). Monoallelic duplications of the whole gene are associated with split hand/foot malformations, but it is not clear if they are inherited in an Mendelian manner (see review on the Limb disorders panel https://panelapp.genomicsengland.co.uk/panels/384/gene/BHLHA9/)

Therefore the recommendation is that the mode of inheritance should be biallelic only for this gene, with region being eventually represented by a separate entity.
Fetal anomalies v1.725 BHLHA9 Eleanor Williams Mode of inheritance for gene: BHLHA9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1357 DDX23 Ivone Leong Publications for gene: DDX23 were set to 33057194
Monogenic hearing loss v2.199 SARS Ivone Leong Tag watchlist was removed from gene: SARS.
Tag new-gene-name tag was added to gene: SARS.
Monogenic hearing loss v2.199 SARS Ivone Leong Tag new-gene-name was removed from gene: SARS.
Monogenic hearing loss v2.199 SARS Ivone Leong Classified gene: SARS as Red List (low evidence)
Monogenic hearing loss v2.199 SARS Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red as only 1 of the cases had hearing loss.
Monogenic hearing loss v2.199 SARS Ivone Leong Gene: sars has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.198 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Monogenic hearing loss v2.198 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Hearing loss. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Severe microcephaly v2.262 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Severe microcephaly v2.262 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Early onset or syndromic epilepsy v2.446 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Early onset or syndromic epilepsy v2.446 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Intellectual disability v3.1356 SARS Ivone Leong Classified gene: SARS as Amber List (moderate evidence)
Intellectual disability v3.1356 SARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. As there are only 2 cases there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1356 SARS Ivone Leong Gene: sars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1355 SARS Ivone Leong Tag watchlist tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong commented on gene: SARS
Intellectual disability v3.1355 SARS Ivone Leong Tag new-gene-name tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong Phenotypes for gene: SARS were changed from Intellectual disability to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Fetal anomalies v1.724 BHLHA9 Eleanor Williams Phenotypes for gene: BHLHA9 were changed from ?Camptosynpolydactyly, complex, OMIM:607539; Syndactyly, mesoaxial synostotic, with phalangeal reduction, OMIM:609432SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE to ?Camptosynpolydactyly, complex, OMIM:607539; Syndactyly, mesoaxial synostotic, with phalangeal reduction, OMIM:609432; SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE
Fetal anomalies v1.723 BHLHA9 Eleanor Williams Phenotypes for gene: BHLHA9 were changed from SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE to ?Camptosynpolydactyly, complex, OMIM:607539; Syndactyly, mesoaxial synostotic, with phalangeal reduction, OMIM:609432SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE
Fetal anomalies v1.722 BHLHA9 Eleanor Williams Tag Q4_21_MOI tag was added to gene: BHLHA9.
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Phenotypes for gene: ERGIC1 were changed from Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100 to Arthrogryposis multiplex congenita 2, neurogenic type, OMIM:208100
Structural eye disease v1.83 BEST1 Eleanor Williams Phenotypes for gene: BEST1 were changed from Retinitis pigmentosa, concentric, 613194; Vitelliform Macular degeneration 2, 153700; Microcornea, rod-cone dystrophy, cataract, and posterior; Eye Disorders; Bestrophinopathy, autosomal recessive, 611809; staphyloma; 193220 to ?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2, OMIM:193220; Bestrophinopathy, autosomal recessive , OMIM:611809; Macular dystrophy, vitelliform, 2, OMIM:153700; Retinitis pigmentosa, concentric, OMIM:613194; Retinitis pigmentosa-50, OMIM:613194; Vitreoretinochoroidopathy, OMIM:193220
Severe microcephaly v2.261 ATP6V0C Ivone Leong Entity copied from Intellectual disability v3.1354
Severe microcephaly v2.261 ATP6V0C Ivone Leong gene: ATP6V0C was added
gene: ATP6V0C was added to Severe microcephaly. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Early onset or syndromic epilepsy v2.445 ATP6V0C Ivone Leong Entity copied from Intellectual disability v3.1354
Early onset or syndromic epilepsy v2.445 ATP6V0C Ivone Leong gene: ATP6V0C was added
gene: ATP6V0C was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Structural eye disease v1.82 BEST1 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic for now. However two cases with angle closure glaucoma as part of the phenotype have been reported, so adding the watch list tag.
Structural eye disease v1.82 BEST1 Eleanor Williams Mode of inheritance for gene: BEST1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1354 ATP6V0C Ivone Leong Classified gene: ATP6V0C as Amber List (moderate evidence)
Intellectual disability v3.1354 ATP6V0C Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1354 ATP6V0C Ivone Leong Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.81 BEST1 Eleanor Williams Tag watchlist_moi tag was added to gene: BEST1.
Structural eye disease v1.81 BEST1 Eleanor Williams commented on gene: BEST1
Intellectual disability v3.1353 ATP6V0C Ivone Leong Tag watchlist tag was added to gene: ATP6V0C.
Arthrogryposis v3.126 SLC29A3 Arina Puzriakova Publications for gene: SLC29A3 were set to
Severe microcephaly v2.260 ATP11A Ivone Leong Classified gene: ATP11A as Red List (low evidence)
Severe microcephaly v2.260 ATP11A Ivone Leong Gene: atp11a has been classified as Red List (Low Evidence).
Severe microcephaly v2.259 ATP11A Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As the mouse model did not show signs of microcephaly, there is currently not enough evidence to support a gene-disease association, this gene has been given an Red rating.
White matter disorders and cerebral calcification - childhood onset v1.204 ATP11A Ivone Leong Entity copied from Intellectual disability v3.1353
White matter disorders and cerebral calcification - childhood onset v1.204 ATP11A Ivone Leong gene: ATP11A was added
gene: ATP11A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP11A.
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Inherited white matter disorders v1.140 ATP11A Ivone Leong Entity copied from Intellectual disability v3.1353
Inherited white matter disorders v1.140 ATP11A Ivone Leong gene: ATP11A was added
gene: ATP11A was added to Inherited white matter disorders. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ATP11A.
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Severe microcephaly v2.259 ATP11A Ivone Leong Entity copied from Intellectual disability v3.1353
Severe microcephaly v2.259 ATP11A Ivone Leong gene: ATP11A was added
gene: ATP11A was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ATP11A.
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Intellectual disability v3.1353 ATP11A Ivone Leong Tag watchlist tag was added to gene: ATP11A.
Intellectual disability v3.1353 ATP11A Ivone Leong Classified gene: ATP11A as Amber List (moderate evidence)
Intellectual disability v3.1353 ATP11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Intellectual disability v3.1353 ATP11A Ivone Leong Gene: atp11a has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SLC29A3.
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Classified gene: SLC29A3 as Amber List (moderate evidence)
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lucy Jackson (NHS). Fixed flexion contractures of the fingers, toes and elbows have been reported in FHC and H-syndrome. Sufficient unrelated cases of joint contractures which can be a presenting feature to rate as Green at the next GMS panel update.
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Gene: slc29a3 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.219 BEST1 Eleanor Williams changed review comment from: Review of mode of inheritance:
Macular dystrophy, vitelliform, 2 OMIM:153700 - many heterozygous cases reported

OMIM also lists Bestrophinopathy, autosomal recessive OMIM:611809 and Retinitis pigmentosa, concentric and Retinitis pigmentosa-50 OMIM:613194 but with no inheritance pattern listed.

Reports for 11 biallelic cases:

PMID: 18179881 Burgess et al 2008 - report on the analysis of the BEST1 gene in 7 affected individuals from 5 unrelated families of European ethnicity. Clinical electrophysiology of affected individuals showed abnormal full-field ERGs in addition to a severe reduction in the electrooculogram (EOG) light rise analogous to that seen with dominant BEST1 mutations that cause both Best disease and autosomal-dominant vitreoretinochoroidopathy. In all families homozygous or compound het variants in BEST1 were found (6 missense, 1 nonsense). 10 asymptomatic heterozygotes were examined in detail and were found to have a normal retinal examination, ERG responses, and EOG light rise.

PMID: 34327816 - Nowomiejska et al 2021 - in retrospective variant-phenotype analysis they report 6 patients with either homozygous or compound het variants in BEST1, aswell as 24 patients with heterozygous variants.; to: Review of mode of inheritance:
Macular dystrophy, vitelliform, 2 OMIM:153700 - many heterozygous cases reported

OMIM also lists Bestrophinopathy, autosomal recessive OMIM:611809 and Retinitis pigmentosa, concentric and Retinitis pigmentosa-50 OMIM:613194 but with no inheritance pattern listed.

Reports for 11 biallelic cases:

PMID: 18179881 Burgess et al 2008 - report on the analysis of the BEST1 gene in 7 affected individuals from 5 unrelated families of European ethnicity. Clinical electrophysiology of affected individuals showed abnormal full-field ERGs in addition to a severe reduction in the electrooculogram (EOG) light rise analogous to that seen with dominant BEST1 mutations that cause both Best disease and autosomal-dominant vitreoretinochoroidopathy. In all families homozygous or compound het variants in BEST1 were found (6 missense, 1 nonsense). 10 asymptomatic heterozygotes were examined in detail and were found to have a normal retinal examination, ERG responses, and EOG light rise.

PMID: 34327816 - Nowomiejska et al 2021 - in a retrospective variant-phenotype analysis they report 6 patients with either homozygous or compound het variants in BEST1, aswell as 24 patients with heterozygous variants.
Pigmentary skin disorders v1.16 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome/H disease; HISTIOCYTOSIS-LYMPHADENOPATHY PLUS SYNDROME to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782
Monogenic hearing loss v2.197 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome; Hyperpigmentation, Cutaneous, with Hypertrichosis, Hepatosplenomegaly, Heart Anomalies, Hearing Loss, and Hypogonadism to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; Hyperpigmentation, Cutaneous, with Hypertrichosis, Hepatosplenomegaly, Heart Anomalies, Hearing Loss, and Hypogonadism
Skeletal dysplasia v2.135 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome 602782 to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782
Primary immunodeficiency or monogenic inflammatory bowel disease v2.477 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome 602782; Other autoinflammatory diseases with known genetic defect; Hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome; Autoinflammatory Disorders to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; Hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome; Autoinflammatory Disorders
Hypogonadotropic hypogonadism (GMS) v1.47 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome (OMIM 602782) - H syndrome: characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies and hypogonadism to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; H syndrome: characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies and hypogonadism
Familial diabetes v1.63 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome
Arthrogryposis v3.124 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782
Arthrogryposis v3.123 SLC29A3 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: SLC29A3.
Rare anaemia v1.29 HSCB Arina Puzriakova Tag watchlist tag was added to gene: HSCB.
Rare anaemia v1.29 HSCB Arina Puzriakova Classified gene: HSCB as Amber List (moderate evidence)
Rare anaemia v1.29 HSCB Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Amber, awaiting further cases - single individual reported to date (PMID:32634119) but with strong functional support, including in vitro and animal studies (zebrafish and mouse)
Rare anaemia v1.29 HSCB Arina Puzriakova Gene: hscb has been classified as Amber List (Moderate Evidence).
Rare anaemia v1.28 HSCB Arina Puzriakova Phenotypes for gene: HSCB were changed from Anaemia, sideroblastic, 5 619523 to ?Anemia, sideroblastic, 5, OMIM:619523
Arthrogryposis v3.123 CHRND Ivone Leong Phenotypes for gene: CHRND were changed from Myasthenic syndrome, congenital, 3A, slow-channel 616321; ?Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency 616323; Multiple pterygium syndrome, lethal type 253290; Myasthenic syndrome, congenital, 3B, fast-channel 616322 to Multiple pterygium syndrome, lethal type, OMIM:253290
Familial Meniere Disease v1.1 AQP1 Eldar Dedic reviewed gene: AQP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Intellectual disability v3.1352 SNIP1 Sarah Leigh Classified gene: SNIP1 as Amber List (moderate evidence)
Intellectual disability v3.1352 SNIP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.
Intellectual disability v3.1352 SNIP1 Sarah Leigh Gene: snip1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh edited their review of gene: SNIP1: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.; Changed rating: AMBER
Intellectual disability v3.1351 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524
Retinal disorders v2.219 BEST1 Eleanor Williams Added comment: Comment on phenotypes: Was Achromatopsia, Cone, and Cone-rod Dystrophy; Best macular atrophy (AD); Bestrophinopathy (AR); Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (AD); Retinitis pigmentosa, concentric (AD); Retinitis pigmentosa-50 (AD); Vitelliform macular dystrophy, adult-onset (AD); Vitreoretinochoroidopathy (AD); Best macular dystrophy, 153700; Maculopathy, bull's-eye; Vitelliform macular dystrophy, adult-onset, 608161; Bestrophinopathy, 611809; Vitreoretinochoroidopathy, 193220; Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, 1;Best Vitelliform Macular Dystrophy;Eye Disorders;Retinitis pigmentosa;Retinitis Pigmentosa, Recessive;Best macular dystrophy, 153700;Macular Dystrophy/Degeneration/Stargardt Disease;Macular Dystrophy, Vitelliform; VMD;Macular Dystrophy, Vitelliform, Adult-Onset;Best macular dystrophy
Retinal disorders v2.219 BEST1 Eleanor Williams Phenotypes for gene: BEST1 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Best macular atrophy (AD); Bestrophinopathy (AR); Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (AD); Retinitis pigmentosa, concentric (AD); Retinitis pigmentosa-50 (AD); Vitelliform macular dystrophy, adult-onset (AD); Vitreoretinochoroidopathy (AD); Best macular dystrophy, 153700; Maculopathy, bull's-eye; Vitelliform macular dystrophy, adult-onset, 608161; Bestrophinopathy, 611809; Vitreoretinochoroidopathy, 193220; Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, 1; Best Vitelliform Macular Dystrophy; Eye Disorders; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive; Best macular dystrophy, 153700; Macular Dystrophy/Degeneration/Stargardt Disease; Macular Dystrophy, Vitelliform; VMD; Macular Dystrophy, Vitelliform, Adult-Onset; Best macular dystrophy to ?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2, OMIM:193220; Bestrophinopathy, autosomal recessive , OMIM:611809; Macular dystrophy, vitelliform, 2, OMIM:153700; Retinitis pigmentosa, concentric, OMIM:613194; Retinitis pigmentosa-50, OMIM:613194; Vitreoretinochoroidopathy, OMIM:193220
Retinal disorders v2.218 BEST1 Eleanor Williams Publications for gene: BEST1 were set to
Retinal disorders v2.217 BEST1 Eleanor Williams Added comment: Comment on mode of inheritance: Review of mode of inheritance in Oct 2021 - there are cases of both biallelic and monoallelic inheritance related to a retinal disorder.
Retinal disorders v2.217 BEST1 Eleanor Williams Mode of inheritance for gene: BEST1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.216 BEST1 Eleanor Williams reviewed gene: BEST1: Rating: ; Mode of pathogenicity: None; Publications: 18179881, 34327816; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.196 CEACAM16 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving mode of inheritance as monoallelic for now but with recommendation for changing to both mono and biallelic after GMS review. 3 reported cases with homozygous variants.
Monogenic hearing loss v2.196 CEACAM16 Eleanor Williams Mode of inheritance for gene: CEACAM16 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.195 CEACAM16 Eleanor Williams Tag Q4_21_MOI tag was added to gene: CEACAM16.
Monogenic hearing loss v2.195 CEACAM16 Eleanor Williams edited their review of gene: CEACAM16: Added comment: Further heterozygous cases:
PMID: 33040498 - Zhang et al 2020 - a heterozygous missense mutation, c.418A>G/p. Thr140Ala in the CEACAM16 gene, segregating with the deafness in this Chinese family. Abstract only accessed.

Homozygous cases:
PMID: 29703829 - Booth et al 2018 - 2 Iranian families with progressive mild-to-moderate hearing loss reported, in which homozygous splice variants ( c.662-1G>C and c.37G>T) were found in CEACAM16. In both families the variant segregated with the phenotype. Heterozygous carriers had normal hearing. Both variants are absent from gnomAD and ExAC.

PMID: 30514912 - Dias et al 2019 - novel and extremely rare loss-of-function variant c.436 C > T/p.(Arg146Ter) in the CEACAM16 gene segregating with post-lingual progressive autosomal recessive hearing loss in 3 individuals from a Brazilian family. This variant is predicted to significantly reduce the size of the wild type protein.; Changed publications to: 33040498, 29703829, 30514912; Changed phenotypes to: Deafness, autosomal recessive 113, OMIM:618410, deafness, autosomal recessive 113, MONDO:0032732, Deafness, autosomal dominant 4B, OMIM:614614, autosomal dominant nonsyndromic deafness 4B, MONDO:0013823; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Clefting v2.54 GDF11 Eleanor Williams Classified gene: GDF11 as Amber List (moderate evidence)
Clefting v2.54 GDF11 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 2 cases plus mouse model data.
Clefting v2.54 GDF11 Eleanor Williams Gene: gdf11 has been classified as Amber List (Moderate Evidence).
Clefting v2.53 GDF11 Eleanor Williams Phenotypes for gene: GDF11 were changed from Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM #619122 to Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM:619122
Clefting v2.52 GDF11 Eleanor Williams Publications for gene: GDF11 were set to 31215115; 34113007
Clefting v2.51 GDF11 Eleanor Williams Tag Q4_21_rating tag was added to gene: GDF11.
Clefting v2.51 GDF11 Eleanor Williams reviewed gene: GDF11: Rating: ; Mode of pathogenicity: None; Publications: 3411300, 31215115, 10391213; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1350 SNIP1 Sarah Leigh Tag founder-effect tag was added to gene: SNIP1.
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh Tag founder-effect tag was added to gene: SNIP1.
Intellectual disability v3.1350 SNIP1 Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; severe developmental delay to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism 614501 to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787
Early onset or syndromic epilepsy v2.443 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524
DDG2P v2.49 TMEM260 Sarah Leigh Tag Q4_21_rating tag was added to gene: TMEM260.
Fetal anomalies v1.722 TMEM260 Sarah Leigh Tag Q4_21_rating tag was added to gene: TMEM260.
Fetal anomalies v1.722 TMEM260 Sarah Leigh edited their review of gene: TMEM260: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517).; Changed rating: GREEN
DDG2P v2.49 TMEM260 Sarah Leigh edited their review of gene: TMEM260: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517).; Changed rating: GREEN
DDG2P v2.49 TMEM260 Sarah Leigh Publications for gene: TMEM260 were set to 28318500
DDG2P v2.48 TMEM260 Sarah Leigh Phenotypes for gene: TMEM260 were changed from Neurodevelopmental, Cardiac, and Renal Syndrome to Structural heart defects and renal anomalies syndrome OMIM:617478; Structural heart defects and renal anomalies syndrome MONDO:0044321
DDG2P v2.47 TMEM260 Sarah Leigh Classified gene: TMEM260 as Amber List (moderate evidence)
DDG2P v2.47 TMEM260 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
DDG2P v2.47 TMEM260 Sarah Leigh Gene: tmem260 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.722 TMEM260 Sarah Leigh Classified gene: TMEM260 as Amber List (moderate evidence)
Fetal anomalies v1.722 TMEM260 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Fetal anomalies v1.722 TMEM260 Sarah Leigh Gene: tmem260 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.721 TMEM260 Sarah Leigh Publications for gene: TMEM260 were set to 28318500
Primary ciliary disorders v1.33 CFAP221 Ivone Leong Entity copied from Respiratory ciliopathies including non-CF bronchiectasis v1.47
Primary ciliary disorders v1.33 CFAP221 Ivone Leong gene: CFAP221 was added
gene: CFAP221 was added to Primary ciliary disorders. Sources: Expert Review Red,Literature
Mode of inheritance for gene: CFAP221 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP221 were set to 31636325
Phenotypes for gene: CFAP221 were set to Primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v1.47 CFAP221 Ivone Leong Phenotypes for gene: CFAP221 were changed from Primary ciliary dyskinesia to Primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v1.46 CFAP221 Ivone Leong Classified gene: CFAP221 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.46 CFAP221 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is currently not associated with a phenotype in OMIM and Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.46 CFAP221 Ivone Leong Gene: cfap221 has been classified as Red List (Low Evidence).
CAKUT v1.164 DSTYK Zornitza Stark reviewed gene: DSTYK: Rating: RED; Mode of pathogenicity: None; Publications: 23862974; Phenotypes: Congenital anomalies of kidney and urinary tract 1, MIM# 610805; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained kidney failure in young people v1.96 DSTYK Zornitza Stark reviewed gene: DSTYK: Rating: RED; Mode of pathogenicity: None; Publications: 23862974; Phenotypes: Congenital anomalies of kidney and urinary tract 1, MIM# 610805; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypertrophic cardiomyopathy v2.27 ALPK3 Ivone Leong Tag Q3_21_NHS_review tag was added to gene: ALPK3.
Hypertrophic cardiomyopathy v2.27 ALPK3 Ivone Leong Phenotypes for gene: ALPK3 were changed from Cardiomyopathy, familial hypertrophic 27, 618052 to Cardiomyopathy, familial hypertrophic 27, OMIM:618052
Palmoplantar keratodermas v1.9 SPINK5 Ivone Leong reviewed gene: SPINK5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.9 SPINK5 Ivone Leong Tag Q4_21_MOI tag was added to gene: SPINK5.
IUGR and IGF abnormalities v1.38 STAT5B Ivone Leong Publications for gene: STAT5B were set to
IUGR and IGF abnormalities v1.37 STAT5B Ivone Leong Added comment: Comment on mode of inheritance: MOI has been updated from Biallelic to Both monoallelic and biallelic. PMID: 29844444 reported 11 patients from 3 unrelated families with GH insensitivity. Most patients presented in the first or second decades of life with short stature (down to -5.3 SD), delayed bone age, and delayed puberty associated with decreased IGF1 levels.
IUGR and IGF abnormalities v1.37 STAT5B Ivone Leong Mode of inheritance for gene: STAT5B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1349 KIRREL3 Ivone Leong Added comment: Comment on publications: New publication added (PMID:33853164)
Intellectual disability v3.1349 KIRREL3 Ivone Leong Publications for gene: KIRREL3 were set to 22965935; 19012874
Severe microcephaly v2.258 WDR11 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in Gene2Phenotype (probable) but not in OMIM. There is enough evidence to support a gene-disease association; however, the severity of ID in the patients described in PMID:34413497 does not fit the criteria for this panel (panel is for moderate to severe ID, patients have mild ID). Therefore, this gene has been given an Amber rating.

The OFC of patients in PMID: 34413497 ranged from -3.09 SD to -4.93 SD); to: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in Gene2Phenotype (probable) but not in OMIM. The OFC of patients in PMID: 34413497 ranged from -3.09 SD to -4.93 SD). There is enough evidence to support a gene-disease association, this gene should be rated Green at the next review.
Severe microcephaly v2.258 WDR11 Ivone Leong Tag watchlist was removed from gene: WDR11.
Tag Q4_21_rating tag was added to gene: WDR11.
Severe microcephaly v2.258 WDR11 Ivone Leong Entity copied from Intellectual disability v3.1348
Severe microcephaly v2.258 WDR11 Ivone Leong gene: WDR11 was added
gene: WDR11 was added to Severe microcephaly. Sources: Expert Review Amber
watchlist tags were added to gene: WDR11.
Mode of inheritance for gene: WDR11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR11 were set to 26350204; 34413497
Phenotypes for gene: WDR11 were set to Intellectual disability, MONDO:0001071; Microcephaly, MONDO:0001149; Short stature,HP:0004322
Penetrance for gene: WDR11 were set to Complete
Intellectual disability v3.1348 WDR11 Ivone Leong Classified gene: WDR11 as Amber List (moderate evidence)
Intellectual disability v3.1348 WDR11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in Gene2Phenotype (probable) but not in OMIM. There is enough evidence to support a gene-disease association; however, the severity of ID in the patients described in PMID:34413497 does not fit the criteria for this panel (panel is for moderate to severe ID, patients have mild ID). Therefore, this gene has been given an Amber rating.

The OFC of patients in PMID: 34413497 ranged from -3.09 SD to -4.93 SD)
Intellectual disability v3.1348 WDR11 Ivone Leong Gene: wdr11 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1347 WDR11 Ivone Leong Added comment: Comment on phenotypes: Previously associated with Kallmann syndrome.
Intellectual disability v3.1347 WDR11 Ivone Leong Phenotypes for gene: WDR11 were changed from KALLMANN SYNDROME to Intellectual disability, MONDO:0001071; Microcephaly, MONDO:0001149; Short stature,HP:0004322
Intellectual disability v3.1346 WDR11 Ivone Leong Publications for gene: WDR11 were set to 26350204
Intellectual disability v3.1345 WDR11 Ivone Leong Added comment: Comment on mode of inheritance: Changed MOI from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BIALLELIC, autosomal or pseudoautosomal" as biallelic variants in this gene is associated with ID.
Intellectual disability v3.1345 WDR11 Ivone Leong Mode of inheritance for gene: WDR11 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1344 WDR11 Ivone Leong Tag watchlist tag was added to gene: WDR11.
Intellectual disability v3.1344 PRICKLE2 Ivone Leong Phenotypes for gene: PRICKLE2 were changed from Epilepsy, progressive myoclonic 5, 613832 to Neurodevelopmental disorder; global developmental delay
Intellectual disability v3.1344 PRICKLE2 Ivone Leong Publications for gene: PRICKLE2 were set to
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Tag Q4_21_rating tag was added to gene: PRICKLE2.
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Classified gene: PRICKLE2 as Amber List (moderate evidence)
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently enough evidence to support a gene-disease association. Therefore this gene should be rated Green at the next review.
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Gene: prickle2 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.26 ALPK3 Ivone Leong Tag Q3_21_expert_review tag was added to gene: ALPK3.
Hypertrophic cardiomyopathy v2.26 ALPK3 Ivone Leong Tag Q3_21_MOI tag was added to gene: ALPK3.
DDG2P v2.46 GRIK2 Ivone Leong reviewed gene: GRIK2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1342 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant to Mental retardation, autosomal recessive, 6, OMIM:611092; non-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Early onset or syndromic epilepsy v2.442 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant to Mental retardation, autosomal recessive, 6, OMIM:611092; non-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Early onset or syndromic epilepsy v2.441 GRIK2 Ivone Leong Mode of inheritance for gene: GRIK2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.440 GRIK2 Ivone Leong Classified gene: GRIK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.440 GRIK2 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Amber as this gene has not been approved to be on this panel yet. It should be noted that not all patients with variants in this gene develop seizures.
Early onset or syndromic epilepsy v2.440 GRIK2 Ivone Leong Gene: grik2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.439 GRIK2 Ivone Leong Tag Q4_21_MOI was removed from gene: GRIK2.
Tag Q4_21_rating tag was added to gene: GRIK2.
Early onset or syndromic epilepsy v2.439 GRIK2 Ivone Leong Entity copied from Intellectual disability v3.1341
Early onset or syndromic epilepsy v2.439 GRIK2 Ivone Leong gene: GRIK2 was added
gene: GRIK2 was added to Genetic epilepsy syndromes. Sources: Radboud University Medical Center, Nijmegen,Expert Review Green,Victorian Clinical Genetics Services
Q4_21_MOI tags were added to gene: GRIK2.
Mode of inheritance for gene: GRIK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRIK2 were set to 34375587; 17847003; 25039795
Phenotypes for gene: GRIK2 were set to Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Penetrance for gene: GRIK2 were set to Complete
Intellectual disability v3.1341 GRIK2 Ivone Leong Tag Q4_21_MOI tag was added to gene: GRIK2.
Intellectual disability v3.1341 GRIK2 Ivone Leong reviewed gene: GRIK2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1341 GRIK2 Ivone Leong Publications for gene: GRIK2 were set to
Intellectual disability v3.1340 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, 611092; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 6 (MRT6) to Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Early onset or syndromic epilepsy v2.438 CACNA1I Ivone Leong Entity copied from Intellectual disability v3.1339
Early onset or syndromic epilepsy v2.438 CACNA1I Ivone Leong gene: CACNA1I was added
gene: CACNA1I was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: CACNA1I.
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Intellectual disability v3.1339 CACNA1I Ivone Leong Classified gene: CACNA1I as Amber List (moderate evidence)
Intellectual disability v3.1339 CACNA1I Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1339 CACNA1I Ivone Leong Gene: cacna1i has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1338 CACNA1I Ivone Leong Tag Q4_21_rating tag was added to gene: CACNA1I.
Cerebral vascular malformations v2.58 PIK3CA Zornitza Stark reviewed gene: PIK3CA: Rating: GREEN; Mode of pathogenicity: None; Publications: 34496175; Phenotypes: Cerebral cavernous malformations 4, MIM#619538; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1338 SHANK1 Zornitza Stark reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34113010, 22503632, 25188300; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Clefting v2.51 GDF11 Zornitza Stark gene: GDF11 was added
gene: GDF11 was added to Clefting. Sources: Literature
Mode of inheritance for gene: GDF11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GDF11 were set to 31215115; 34113007
Phenotypes for gene: GDF11 were set to Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM #619122
Review for gene: GDF11 was set to GREEN
Added comment: PMID 34113007: Ravenscroft et al. (2021) report 6 probands who presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). They found de novo and inherited variants in GDF11. gdf11 mutant zebrafish showed craniofacial abnormalities and body segmentation defects that matched some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants are partial LOF variants.

PMID 31215115: In 5 affected members over 3 generations of a family segregating vertebral hypersegmentation and orofacial anomalies, Cox et al. (2019) identified heterozygosity for a missense mutation in the GDF11 gene (R298Q) that was not found in unaffected family members or in public variant databases. Functional analysis demonstrated that the R298Q substitution prevents cleavage to the active form of the protein, resulting in loss of function.
Sources: Literature
Early onset or syndromic epilepsy v2.437 CHRM1 Ivone Leong Classified gene: CHRM1 as Red List (low evidence)
Early onset or syndromic epilepsy v2.437 CHRM1 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red to match my review.
Early onset or syndromic epilepsy v2.437 CHRM1 Ivone Leong Gene: chrm1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong Tag watchlist was removed from gene: CHRM1.
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently only 1 case with epilepsy this gene has been given a Red rating.
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong Entity copied from Intellectual disability v3.1338
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong gene: CHRM1 was added
gene: CHRM1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: CHRM1.
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability, MONDO:0001071; autism
Intellectual disability v3.1338 PLXNA1 Zornitza Stark gene: PLXNA1 was added
gene: PLXNA1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature
Intellectual disability v3.1338 CHRM1 Ivone Leong Tag watchlist tag was added to gene: CHRM1.
Intellectual disability v3.1338 CHRM1 Ivone Leong Deleted their comment
Intellectual disability v3.1338 HNRNPD Zornitza Stark edited their review of gene: HNRNPD: Added comment: More individuals reported in PMID 33874999; Changed rating: GREEN; Changed publications to: 33057194, 33874999; Changed phenotypes to: Developmental disorders, Intellectual disability
Intellectual disability v3.1338 CHRM1 Ivone Leong Classified gene: CHRM1 as Amber List (moderate evidence)
Intellectual disability v3.1338 CHRM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.
Intellectual disability v3.1338 CHRM1 Ivone Leong Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1338 CHRM1 Ivone Leong Classified gene: CHRM1 as Amber List (moderate evidence)
Intellectual disability v3.1338 CHRM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.
Intellectual disability v3.1338 CHRM1 Ivone Leong Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.435 UNC13B Zornitza Stark gene: UNC13B was added
gene: UNC13B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UNC13B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC13B were set to 33876820
Phenotypes for gene: UNC13B were set to Epilepsy
Review for gene: UNC13B was set to RED
Added comment: No OMIM human disease association. Gene encodes a presynaptic protein Munc13-2 highly expressed in the brain (predominantly cerebral cortex).

Variant interpretation data in human epilepsy cohort somewhat conflicting and restricted to a single study. Wang et al, Brain, 2021 - trio-based whole-exome sequencing identified UNC13B in 12 individuals affected by partial epilepsy and/or febrile seizures from 8 unrelated families. Identified:
x1 de novo nonsense variant, absent in gnomad, damaging in silicos
x1 de novo splice site, absent in gnomad, damaging in silicos
x1 splice site variant present in unaffected mother (low frequency in gnomad)
x2 compound het in one individual - more severe phenotype postulated (x1 variant present in contro cohortl, the other variant present in low frequency in gnomad)
x1 missense variant - in Han Chinese major depressive disorders study, not in gnomad
x1 missense variant - highly conserved residue, not in gnomad
x2 other missense variant - highly conserved residue, low frequency in gnomad
Latter 4 missense variants cosegregated with affected individuals in the families

In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila

De novo UNC13B variants previously reported in bipolar disorder and autism spectrum disorder
Sources: Literature
Intellectual disability v3.1337 CHRM1 Ivone Leong Phenotypes for gene: CHRM1 were changed from Neurodevelopmental delay; intellectual disability; autism to Neurodevelopmental delay; intellectual disability, MONDO:0001071; autism
Early onset or syndromic epilepsy v2.435 CHD4 Zornitza Stark gene: CHD4 was added
gene: CHD4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CHD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD4 were set to 27479907; 27616479; 34109749
Phenotypes for gene: CHD4 were set to Sifrim-Hitz-Weiss syndrome, MIM# 617159; Childhood idiopathic epilepsy and sinus arrhythmia
Review for gene: CHD4 was set to GREEN
Added comment: PMID 34109749: 8 individuals from 4 families with childhood idiopathic epilepsy and sinus arrhythmia. This may be a distinct gene-disease association as the variants were located outside of the typical domains associated with SHW syndrome (central regions from SNF2-like region to DUF1087 domain).

SHW syndrome: seizures are also reported, though not as a common feature.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.45 CFAP221 Zornitza Stark gene: CFAP221 was added
gene: CFAP221 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: CFAP221 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP221 were set to 31636325
Phenotypes for gene: CFAP221 were set to Primary ciliary dyskinesia
Review for gene: CFAP221 was set to RED
Added comment: WES in 1 family with 3 siblings with clinical symptoms of PCD identified compound heterozygous loss-of-function variants in CFAP221, which segregated with disease. No functional studies. Nasal epithelial cells from 1 of the subjects demonstrated slightly reduced beat frequency, however, waveform analysis revealed that the CFAP221 defective cilia beat in an aberrant circular pattern. A candidate gene in cases where PCD is suspected but cilia structure and beat frequency appear normal.
Sources: Literature
Intellectual disability v3.1336 SARS Zornitza Stark gene: SARS was added
gene: SARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to Intellectual disability
Review for gene: SARS was set to AMBER
Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.

PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature
Intellectual disability v3.1336 ZNF699 Ivone Leong Tag Q4_21_rating tag was added to gene: ZNF699.
Intellectual disability v3.1336 ZNF699 Ivone Leong Classified gene: ZNF699 as Amber List (moderate evidence)
Intellectual disability v3.1336 ZNF699 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1336 ZNF699 Ivone Leong Gene: znf699 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1335 ZDHHC15 Zornitza Stark reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: 34345675; Phenotypes: Mental retardation, X-linked 91, 300577, cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - childhood onset v2.236 RFXANK Zornitza Stark gene: RFXANK was added
gene: RFXANK was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: RFXANK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFXANK were set to 33855173; 23314770; 28676232
Phenotypes for gene: RFXANK were set to Progressive Ataxia and Neurologic Regression; MHC class II deficiency, complementation group B MIM#209920
Review for gene: RFXANK was set to AMBER
Added comment: PMID: 33855173 - 1 family (2 affecteds, 3rd not sequenced) with a homozygous c.271+1G>C splice variant, late-onset immunodeficiency and subacute progressive neurodegenerative disease, including cognition, motor, visual and cerebellar features. MRI demonstrated global cerebral and cerebellar atrophy.

PMID: 23314770 - 1/34 MHCII deficient patients with biallelic variants reported with ataxia. Majority of patients (including patient with ataxia) share a founder variant (c.338-25_338del26).

PMID: 28676232 - single 30 month old patient with ataxic gait and dysarthria and a homozygous PTC.

Summary: 3 patients but uncommon feature of an established immunological disorder, variable expressivity
Sources: Literature
Hereditary ataxia, adult onset v2.85 PRPS1 Zornitza Stark gene: PRPS1 was added
gene: PRPS1 was added to Hereditary ataxia - adult onset. Sources: Literature
Mode of inheritance for gene: PRPS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PRPS1 were set to 33898739; 28967191; 25491489
Phenotypes for gene: PRPS1 were set to Ataxia; deafness; eye disease
Review for gene: PRPS1 was set to AMBER
Added comment: PMID: 25491489:
Heterozygous missense variant, loss of function - PRS enzyme deficiency showed.
Proband and her mother have various degrees of ataxia (examinations at 34yrs and 70yrs, respectively), peripheral neuropathy and hearing loss beyond the ophthalmological symptoms, whereas the phenotype of the affected older sister (36yo) is currently confined to the eye and milder.

PMID: 28967191
in one of the families, heterozygous variants in proband with hearing loss and ataxia developed in the proband in her forties, and ocular manifestations of retinal changes and disc pallor were first confirmed in the two affected daughters in their twenties.

PMID: 33898739:
Heterozygous de novo missense variant in a 30yo female individual, presented with a 5-year history of progressive ataxia. She also had congenital strabismus, infantile-onset hearing loss, and a retinal dystrophy with progressive visual loss for the past 10 years.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.236 DAB1 Zornitza Stark reviewed gene: DAB1: Rating: RED; Mode of pathogenicity: None; Publications: 33928188; Phenotypes: Ataxia, Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.236 TRIP4 Zornitza Stark gene: TRIP4 was added
gene: TRIP4 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: TRIP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIP4 were set to 34075209
Phenotypes for gene: TRIP4 were set to cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures.
Review for gene: TRIP4 was set to AMBER
Added comment: PMID: 34075209:
One patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures, hom PTV. The same PTV had been previously reported in 3 patients from 2 families with prenatal spinal muscular atrophy and congenital bone fractures (PMID: 26924529).

Possible phenotype expansion.
Sources: Literature
Intellectual disability v3.1335 ATP11A Zornitza Stark gene: ATP11A was added
gene: ATP11A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Review for gene: ATP11A was set to AMBER
Added comment: PMID: 34403372:
- Single de novo missense variant reported in a patient with developmental delay and neurological deterioration.
- Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested.
- K/I heterozygous mice died perinatally.
- Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc.

gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets.
Sources: Literature
Hereditary neuropathy or pain disorder v1.63 COX20 Zornitza Stark gene: COX20 was added
gene: COX20 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: COX20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX20 were set to 33751098
Phenotypes for gene: COX20 were set to Neuropathy
Review for gene: COX20 was set to GREEN
gene: COX20 was marked as current diagnostic
Added comment: Well established association with mitochondrial disease, presentation with neuropathy reported PMID 33751098
Sources: Literature
Fetal anomalies v1.720 LONP1 Zornitza Stark reviewed gene: LONP1: Rating: RED; Mode of pathogenicity: None; Publications: 34547244; Phenotypes: Congenital diaphragmatic hernia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1335 ZNF699 Ivone Leong Phenotypes for gene: ZNF699 were changed from DEGCAGS syndrome, MIM# 619488 to DEGCAGS syndrome, OMIM:619488
Early onset or syndromic epilepsy v2.435 JAKMIP1 Ivone Leong Entity copied from Intellectual disability v3.1334
Early onset or syndromic epilepsy v2.435 JAKMIP1 Ivone Leong gene: JAKMIP1 was added
gene: JAKMIP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: JAKMIP1.
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability, MONDO:0001071; seizures
Intellectual disability v3.1334 ABHD16A Zornitza Stark gene: ABHD16A was added
gene: ABHD16A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Review for gene: ABHD16A was set to GREEN
gene: ABHD16A was marked as current diagnostic
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
Sources: Literature
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Tag watchlist tag was added to gene: JAKMIP1.
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Classified gene: JAKMIP1 as Amber List (moderate evidence)
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Currently there are only 2 cases; however, there is very little information about the two cases in the papers. Therefore, this gene has been given an Amber rating until more evidence is available.
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1333 JAKMIP1 Ivone Leong Phenotypes for gene: JAKMIP1 were changed from Intellectual disability; seizures to Intellectual disability, MONDO:0001071; seizures
Fetal anomalies v1.720 WLS Zornitza Stark gene: WLS was added
gene: WLS was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to 34587386
Phenotypes for gene: WLS were set to structural congenital anomalies
Review for gene: WLS was set to GREEN
Added comment: - Homozygous variants in 10 affected persons from 5 unrelated families.
- Affected individuals had multiorgan defects, including microcephaly, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Intellectual disability v3.1332 ATP6V0C Zornitza Stark gene: ATP6V0C was added
gene: ATP6V0C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Review for gene: ATP6V0C was set to AMBER
Added comment: 9 individuals reported with deletions and ID/seizures/microcephaly, minimum overlapping region implicates ATP6V0C as the causative gene. Single case report of de novo SNV and ID/seizures.
Sources: Literature
Intellectual disability v3.1332 ARFGEF1 Zornitza Stark gene: ARFGEF1 was added
gene: ARFGEF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability; Epilepsy
Review for gene: ARFGEF1 was set to GREEN
Added comment: 13 individuals reported with variants in this gene and a neurodevelopmental disorder characterised by variable ID, seizures present in around half. Variants were inherited from mildly affected parents in 40% of families.
Sources: Literature
Congenital disorders of glycosylation v2.76 ALG10 Zornitza Stark gene: ALG10 was added
gene: ALG10 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: ALG10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG10 were set to 33798445
Phenotypes for gene: ALG10 were set to Progressive myoclonus epilepsy; CDG
Review for gene: ALG10 was set to RED
Added comment: Single individual with homozygous variant identified in a progressive myoclonus epilepsy cohort.
Sources: Literature
Intellectual disability v3.1332 KIF4A Zornitza Stark reviewed gene: KIF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24812067, 34346154; Phenotypes: Mental retardation, X-linked 100, MIM# 300923; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Dystonia, chorea or related movement disorder, childhood onset v1.157 SHQ1 Zornitza Stark gene: SHQ1 was added
gene: SHQ1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645
Phenotypes for gene: SHQ1 were set to Dystonia; Neurodegeneration
Review for gene: SHQ1 was set to AMBER
Added comment: Three unrelated families reported. Family 1: isolated dystonia only; Family 2: dystonia, and neurodegeneration; Family 3: neurodegeneration.

Functional data in PMID 34542157

Rated Amber as phenotypes likely represent a continuum but currently unclear.
Sources: Literature
Rare anaemia v1.27 HSCB Zornitza Stark gene: HSCB was added
gene: HSCB was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: HSCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSCB were set to 32634119
Phenotypes for gene: HSCB were set to Anaemia, sideroblastic, 5 619523
Review for gene: HSCB was set to AMBER
Added comment: Single individual reported with compound heterozygous variants in this gene. Good functional data including animal model.
Sources: Literature
Fetal anomalies v1.720 WNT9B Zornitza Stark gene: WNT9B was added
gene: WNT9B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WNT9B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT9B were set to 34145744
Phenotypes for gene: WNT9B were set to Renal agenesis/hypoplasia/dysplasia
Review for gene: WNT9B was set to AMBER
Added comment: WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. WNT9B−/− mice have renal agenesis/hypoplasia and reproductive tract abnormalities.

Lemire et al. (2021) report 4 individuals from 2 unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 had bilateral renal cystic dysplasia and chronic kidney disease, with 2 deceased siblings with bilateral renal hypoplasia/agenesis. The 3 affected family members were homozygous for a Gly317Arg missense variant in WNT9B. Proband from Family 2 had renal hypoplasia/dysplasia, chronic kidney disease, and was homozygous for a Pro5Alafs*52 nonsense variant in WNT9B. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance.

I wasn't sure which panel this is more pertinent to: we have added this gene to our CAKUT panel.
Sources: Literature
Familial Meniere Disease v1.1 ADD3 Eldar Dedic reviewed gene: ADD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Limb disorders v2.60 UBA2 Eleanor Williams Classified gene: UBA2 as Amber List (moderate evidence)
Limb disorders v2.60 UBA2 Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber for now, but with a recommendation for green rating following GMS review. There are now 5 cases reported with split hand malformation and plausible disease causing variants in this gene.
Limb disorders v2.60 UBA2 Eleanor Williams Gene: uba2 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.59 UBA2 Eleanor Williams Publications for gene: UBA2 were set to 31332306; 24243649; 29988626; 31587267
Limb disorders v2.58 UBA2 Eleanor Williams Tag Q4_21_rating tag was added to gene: UBA2.
Limb disorders v2.58 UBA2 Eleanor Williams edited their review of gene: UBA2: Added comment: As reviewer notes, in PMID: 34159400 (Elsner et al 2021) they report 3 unrelated cases where a variant in UBA2 are reported in individuals with split hand malformation.; Changed rating: GREEN; Changed publications to: 31332306, 24243649, 29988626, 31587267, 34159400
Limb disorders v2.58 HMGB1 Eleanor Williams Classified gene: HMGB1 as Red List (low evidence)
Limb disorders v2.58 HMGB1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red based on 1 case, plus some supportive animal model data.
Limb disorders v2.58 HMGB1 Eleanor Williams Gene: hmgb1 has been classified as Red List (Low Evidence).
Clefting v2.51 SF3B2 Eleanor Williams Classified gene: SF3B2 as Amber List (moderate evidence)
Clefting v2.51 SF3B2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a green recommendation following GMS review. 4 families reported in which lateral oral clefting is part of the phenotype. Supportive Xenopus data.
Clefting v2.51 SF3B2 Eleanor Williams Gene: sf3b2 has been classified as Amber List (Moderate Evidence).
Clefting v2.50 SF3B2 Eleanor Williams Tag Q4_21_rating tag was added to gene: SF3B2.
Clefting v2.50 SF3B2 Eleanor Williams commented on gene: SF3B2
Monogenic hearing loss v2.195 CLDN9 Eleanor Williams Classified gene: CLDN9 as Amber List (moderate evidence)
Monogenic hearing loss v2.195 CLDN9 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a green rating recommendation following GMS review. 3 unrelated cases plus mouse model and some functional data.
Monogenic hearing loss v2.195 CLDN9 Eleanor Williams Gene: cldn9 has been classified as Amber List (Moderate Evidence).
Familial Meniere Disease v1.1 ADD2 Eldar Dedic reviewed gene: ADD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Monogenic hearing loss v2.194 CLDN9 Eleanor Williams Phenotypes for gene: CLDN9 were changed from to Deafness, autosomal recessive 116, OMIM:619093; deafness, autosomal recessive 116, MONDO:0033670
Monogenic hearing loss v2.193 CLDN9 Eleanor Williams Publications for gene: CLDN9 were set to
Monogenic hearing loss v2.192 CLDN9 Eleanor Williams Mode of inheritance for gene: CLDN9 was changed from to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.191 CLDN9 Eleanor Williams Tag Q4_21_rating tag was added to gene: CLDN9.
Monogenic hearing loss v2.191 CLDN9 Eleanor Williams reviewed gene: CLDN9: Rating: GREEN; Mode of pathogenicity: None; Publications: 31175426, 34265170; Phenotypes: Deafness, autosomal recessive 116, OMIM:619093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1332 TAF2 Zornitza Stark reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34474177, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40, OMIM # 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1332 DDX23 Zornitza Stark edited their review of gene: DDX23: Added comment: PMID 34050707: 9 unrelated individuals (gathered through GeneMatcher) with de novo missense alterations in DDX23. Clinical features include: tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA.; Changed rating: GREEN; Changed publications to: 33057194, 34050707
Arthrogryposis v3.122 ERGIC1 Zornitza Stark gene: ERGIC1 was added
gene: ERGIC1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: ERGIC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC1 were set to 28317099; 34037256
Phenotypes for gene: ERGIC1 were set to Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100
Review for gene: ERGIC1 was set to AMBER
Added comment: Reinstein et al. (2018) used WES in a large consanguineous Israeli Arab kindred consisting of 16 patients affected with the neurogenic type of arthrogryposis multiplex congenita. They identified a homozygous missense (V98E) mutation in ERGIC1 gene, which segregated with the disorder in the kindred, and was not found in the ExAC database or in 212 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi.

Marconi et al (2021) used genome sequencing in a consanguineous family with 2 affected siblings presenting congenital arthrogryposis and some facial dysmorphism. They identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents.
Sources: Literature
Intellectual disability v3.1332 HMGB1 Zornitza Stark gene: HMGB1 was added
gene: HMGB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGB1 were set to 34164801
Phenotypes for gene: HMGB1 were set to Developmental delay and microcephaly
Review for gene: HMGB1 was set to GREEN
gene: HMGB1 was marked as current diagnostic
Added comment: 13q12.3 microdeletion syndrome is a rare cause of syndromic ID. Previous studies identified four genes within the ~300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1.

Uguen et al. (2021) report 6 patients with LOF variants involving HMGB1 with features similar to 13q12.3 microdeletion syndrome (i.e. developmental delay, language delay, microcephaly, obesity and dysmorphic features). In silico analyses suggest that HMGB1 is likely to be intolerant to LOF, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. They suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
Sources: Literature
Intellectual disability v3.1332 WIPI2 Zornitza Stark edited their review of gene: WIPI2: Added comment: PMID: 34557665 (2021)
- two novel homozygous variants were identified in four individuals of two consanguineous families.
- one family presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia.
- second family (similar to initial publication) presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait.
- functional studies showed dysregulation of the early steps of the autophagy pathway.; Changed rating: GREEN; Changed publications to: 30968111, 34557665; Set current diagnostic: yes
Hypertrophic cardiomyopathy v2.26 ALPK3 Oliver Watkinson reviewed gene: ALPK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32480058; Phenotypes: Hypertrophic Cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Arthrogryposis v3.122 SLC29A3 Lucy Jackson gene: SLC29A3 was added
gene: SLC29A3 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: SLC29A3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC29A3 were set to Histiocytosis-lymphadenopathy plus syndrome
Review for gene: SLC29A3 was set to GREEN
gene: SLC29A3 was marked as current diagnostic
Added comment: Sources: Literature
Familial Meniere Disease v1.1 ADD1 Eleanor Williams changed review comment from: As noted by the expert reviewer Eldar Dedic, PMID: 30828346 - Gallego-Martinez, et al. (2019) reports a family in which two members have a rare variant of unknown signficance in ADD1 (chr4:2900221 A>G). In addition, two other rare variants in candidate genes are reported in 2 family members (KCNQ4) and in all cases within the famile (DPT). See Table 5, family 2.

This adds some weight to ADD1 being associated with Familial Meniere disease, and so the watchlist tag has been added to this gene.; to: As noted by the expert reviewer Eldar Dedic, PMID: 30828346 - Gallego-Martinez, et al. (2019) reports a family in which two members have a rare missense variant of unknown signficance in ADD1 (chr4:2900221 A>G (grch37, rs372777117). In addition, two other rare variants in candidate genes are reported in 2 members of the same family (variant in KCNQ4) and in all cases within the family (variant in DPT). See Table 5, family 2.

This adds some weight to ADD1 being associated with Familial Meniere disease, and so the watchlist tag has been added to this gene.
Familial Meniere Disease v1.1 ADD1 Eleanor Williams reviewed gene: ADD1: Rating: ; Mode of pathogenicity: None; Publications: 30828346; Phenotypes: ; Mode of inheritance: None
Familial Meniere Disease v1.1 ADD1 Eleanor Williams Tag watchlist tag was added to gene: ADD1.
Proteinuric renal disease v2.58 LCAT Eleanor Williams Classified gene: LCAT as Amber List (moderate evidence)
Proteinuric renal disease v2.58 LCAT Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber for now, but with a green rating recommendation following GMS review. There are several reported cases where proteinuria is a prominent feature, plus a green expert review reporting a case of a family presenting with proteinuric kidney disease
Proteinuric renal disease v2.58 LCAT Eleanor Williams Gene: lcat has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.57 LCAT Eleanor Williams Phenotypes for gene: LCAT were changed from Norum disease #245900 to Norum disease, OMIM:245900; Norum disease, MONDO:0009515; LCAT DEFICIENCY
Proteinuric renal disease v2.56 LCAT Eleanor Williams Publications for gene: LCAT were set to 6078131
Proteinuric renal disease v2.55 LCAT Eleanor Williams edited their review of gene: LCAT: Changed publications to: 21315357, 30201532, 29535099, 22108153, 28508023, 25657982, 9884427
Proteinuric renal disease v2.55 LCAT Eleanor Williams Tag Q4_21_rating tag was added to gene: LCAT.
Proteinuric renal disease v2.55 LCAT Eleanor Williams edited their review of gene: LCAT: Added comment: Several cases in which proteinuria was noted in patients with LCAT deficiency are reported, including:

PMID: 21315357 - Holleboom et al 2011 - report 3 siblings (age 17, 12 and 3 years) in a family with HDL deficency. The 17-year-old was referred for renal pathology compatible with a metabolic disorder, including FLD. Corneal opacification and proteinuria were observed in all three and they were found to be homozygous for a missense variant in LCAT which disrupted the second disulfide. LCAT protein and activity were undetectable in the patients' plasma. The parents and an unaffected brother were heterozygous for the variant.

PMID: 30201532 - Hanna et al 2018 - report a 29-year-old female who initially presented with discomfort, photophobia, and decreased vision in both eyes. Bilateral corneal clouding, severely reduced HDL cholesterol, and proteinuria were noted. Two heterozygous mutations of the LCAT gene were identified: c.321C>A (p.Tyr107 *) and c.1034C>T (p.Thr345Met)

PMID: 29535099 - Morales et al 2018 - report 44-year-old woman diagnosed with corneal dystrophy and anaemia. Analysis showed proteinuria between 1 and 2 g/day. A missense homozygous variant in the LCAT gene c.368G>C (p (R123p)) was identified.

PMID: 22108153 - Roshan et al 2011 - report a 50-year-old man with uncontrolled hypertension, hemolytic anemia, and renal insufficiency. He had a long history of proteinuria (3+ for at least 30 years). He was found to have diffuse marked corneal opacification. Sequencing the LCAT gene showed a homozygous missense mutation. His parents were first cousins.


Cases presenting with proteinuria with a LCAT deficiency diagnosis but no molecular analyses:

PMID: 28508023 - Balwani et al 2016 - a patient with nephrotic syndrome, which renal biopsy revealed classic features of LCAT deficiency. There was no obvious family history and the patient was without any corneal deposits and normal HDL-C levels. NOTE NO MOLECULAR DIAGNOSIS.

PMID: 25657982 - Mahdi Althaf et al 2015 - 30-year-old male was referred for persistent proteinuria. Bilateral corneal ring opacities were noted. Renal biopsy findings were consistent with LCAT deficiency.; Changed phenotypes to: Norum disease, OMIM:245900, Norum disease, MONDO:0009515, LCAT DEFICIENCY
Fetal anomalies v1.720 TMEM260 Alistair Pagnamenta reviewed gene: TMEM260: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28318500, 34612517; Phenotypes: ventricular septal defects, truncus arteriosus, elevated creatinine levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.191 USP48 Eleanor Williams Tag watchlist was removed from gene: USP48.
Tag Q4_21_rating tag was added to gene: USP48.
Monogenic hearing loss v2.191 USP48 Eleanor Williams Classified gene: USP48 as Amber List (moderate evidence)
Monogenic hearing loss v2.191 USP48 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, with a recommendation for green rating following GMS review. 3 cases, 1 with segregation data (incomplete penetrance), plus supportive zebrafish model.
Monogenic hearing loss v2.191 USP48 Eleanor Williams Gene: usp48 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.190 USP48 Eleanor Williams Phenotypes for gene: USP48 were changed from non-syndromic hearing loss to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497
Monogenic hearing loss v2.189 USP48 Eleanor Williams Publications for gene: USP48 were set to
Monogenic hearing loss v2.188 USP48 Eleanor Williams Mode of inheritance for gene: USP48 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.187 USP48 Eleanor Williams edited their review of gene: USP48: Added comment: PMID: 34059922 - Bassani et al 2021 - 3 cases reported with variants in USP48 and non syndromic hearing loss. They first analysed 4-generation Italian family with 6 individuals with hearing loss. The only rare variant segregating with the disease was a missense variant in USP48 (NM_032234.7:c.1216G > A, NP_115612.4:p.(Gly406Arg)). The variant is present in GnomAD v2.1.1 with a minor allele frequency (MAF) of 6.7 × 10−5 (17 allele out of 251 304 with no homozygotes). They also observed one hearing individual in the family who was heterozygous for the variant, suggesting incomplete penetrance.
In a Dutch family the found by exome sequencing a missense variant in USP48 (NM_032236.7:c.2215_2216delinsTT, NP_115612.4:p.(Thr739Leu)). The probands mother and uncle were also affected by no sequence data was available for analysis.
In a French family a proband is reported with right profound sensorineural hearing impairment (at 12 months), but normal left hearing (at 6 years old). The patient is heterozygote for a de novo splice variant in USP48 (NM_032236.7:c.3058 + 2 T > C, NP_115612.4:p.?;) which is not found in GnomAD and is predicted to result in a frameshift resulting in either NMD or a truncated protein.
In functional experiments they showed that the two missense variants found in the Italian and Dutch families, and a shortened protein as predicted for the variant found in the French variant, showed an impaired ability to cleave tetra-ubiquitin into tri-, di- and mono-ubiquitin. Using immunohistology, they show that the human USP48 protein is present in fetal inner ear specimens.
In addition zebrafish lacking usp48 showed a significant decrease of auditory response in acoustic startle response assays at 600 and 800 Hz wavelengths.; Changed rating: GREEN; Changed publications to: 34059922; Changed phenotypes to: nonsyndromic genetic deafness, MONDO:0019497; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 MARS Eleanor Williams gene: MARS was added
gene: MARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Literature
new-gene-name tags were added to gene: MARS.
Mode of inheritance for gene: MARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MARS were set to 33909043
Phenotypes for gene: MARS were set to trichothiodystrophy, MONDO:0018053
Review for gene: MARS was set to RED
Added comment: PMID: 33909043 - Botta et al 2021 - using WES/WGS analysis of 34 unsolved cases with multi-system phenotypes, but with hair alterations that are typical of trichothiodystrophy but no reported photosensitivity, they identified a homozygous variant in one Italian patient (c.1201G > A (p.Val401Me) that is very rare (gnomAD frequency 0.00001414). Functional studies suggest that the variant affects gene product stability.
Sources: Literature
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.17 AARS Eleanor Williams Classified gene: AARS as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.17 AARS Eleanor Williams Added comment: Comment on list classification: Promoting to amber as 2 cases with plausible disease causing variants in the AARS gene reported.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.17 AARS Eleanor Williams Gene: aars has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.16 AARS Eleanor Williams gene: AARS was added
gene: AARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Literature
new-gene-name tags were added to gene: AARS.
Mode of inheritance for gene: AARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS were set to 33909043
Phenotypes for gene: AARS were set to trichothiodystrophy, MONDO:0018053
Review for gene: AARS was set to AMBER
Added comment: PMID: 33909043 - Botta et al 2021 - using WES or WGS analysis of 34 unsolved cases with multi-system phenotypes, but with hair alterations that are typical of trichothiodystrophy but no reported photosensitivity, they identified 2 unrelated cases carrying 4 potentially pathogenic variants in the AARS1 gene (previously known as AARSB. Both patients had very rare compound heterozygous missense variants. In one family there was an older affected sibling but segregation data was not available for either family.
Sources: Literature
Severe microcephaly v2.257 ZNF668 Ivone Leong Entity copied from Intellectual disability v3.1332
Severe microcephaly v2.257 ZNF668 Ivone Leong gene: ZNF668 was added
gene: ZNF668 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ZNF668.
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Intellectual disability v3.1332 ZNF668 Ivone Leong Tag watchlist tag was added to gene: ZNF668.
Intellectual disability v3.1332 ZNF668 Ivone Leong Classified gene: ZNF668 as Amber List (moderate evidence)
Intellectual disability v3.1332 ZNF668 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently no phenotypes associated with this gene in OMIM or Gene2Phenotype. As there are only 2 cases there is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1332 ZNF668 Ivone Leong Gene: znf668 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.85 UBE2U Ivone Leong Entity copied from Intellectual disability v3.1331
Bilateral congenital or childhood onset cataracts v2.85 UBE2U Ivone Leong gene: UBE2U was added
gene: UBE2U was added to Cataracts. Sources: Expert Review Red,Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis, MONDO:0004579; cataracts; learning disability, MONDO:0004681; developmental delay
Intellectual disability v3.1331 UBE2U Ivone Leong Classified gene: UBE2U as Red List (low evidence)
Intellectual disability v3.1331 UBE2U Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a disease in Gene2Phenotype (there is currently no entry for this gene in OMIM). As there is currently only 1 case this gene has been given a Red rating.
Intellectual disability v3.1331 UBE2U Ivone Leong Gene: ube2u has been classified as Red List (Low Evidence).
Intellectual disability v3.1330 UBE2U Ivone Leong Phenotypes for gene: UBE2U were changed from Retinoschisis; cataracts; learning disabilities; developmental delay to Retinoschisis, MONDO:0004579; cataracts; learning disability, MONDO:0004681; developmental delay
Paediatric or syndromic cardiomyopathy v1.56 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Intellectual disability, MONDO:0001071 to Dilated cardiomyopathy,MONDO:0005021
Monogenic hearing loss v2.187 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Intellectual disability, MONDO:0001071 to Sensorineural hearing impairment, HP:0000407
Ataxia and cerebellar anomalies - childhood onset v2.236 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Intellectual disability, MONDO:0001071 to Ataxia, HP:0001251
Paediatric or syndromic cardiomyopathy v1.55 RNF220 Ivone Leong Tag Q4_21_rating tag was added to gene: RNF220.
Paediatric or syndromic cardiomyopathy v1.55 RNF220 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association. Therefore, this gene should be Green at the next review.
Monogenic hearing loss v2.186 RNF220 Ivone Leong Tag Q4_21_rating tag was added to gene: RNF220.
Monogenic hearing loss v2.186 RNF220 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association. Therefore, this gene should be Green at the next review.
Ataxia and cerebellar anomalies - childhood onset v2.235 RNF220 Ivone Leong Tag Q4_21_rating tag was added to gene: RNF220.
Ataxia and cerebellar anomalies - childhood onset v2.235 RNF220 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association. Therefore, this gene should be Green at the next review.
White matter disorders and cerebral calcification - childhood onset v1.203 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum to Leukodystrophy, MONDO:0019046; Abnormal corpus callosum morphology, HP:0001273
White matter disorders and cerebral calcification - childhood onset v1.202 RNF220 Ivone Leong Tag Q4_21_rating tag was added to gene: RNF220.
White matter disorders and cerebral calcification - childhood onset v1.202 RNF220 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association. Therefore, this gene should be Green at the next review.
Paediatric or syndromic cardiomyopathy v1.55 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1329
Paediatric or syndromic cardiomyopathy v1.55 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to Cardiomyopathies - including childhood onset. Sources: Literature,Expert Review Amber,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 Intellectual disability, MONDO:0001071
Penetrance for gene: RNF220 were set to Complete
Monogenic hearing loss v2.186 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1329
Monogenic hearing loss v2.186 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to Hearing loss. Sources: Literature,Expert Review Amber,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 Intellectual disability, MONDO:0001071
Penetrance for gene: RNF220 were set to Complete
Ataxia and cerebellar anomalies - childhood onset v2.235 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1329
Ataxia and cerebellar anomalies - childhood onset v2.235 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature,Expert Review Amber,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 Intellectual disability, MONDO:0001071
Penetrance for gene: RNF220 were set to Complete
Intellectual disability v3.1329 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum to Intellectual disability, MONDO:0001071
White matter disorders and cerebral calcification - childhood onset v1.202 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1328
White matter disorders and cerebral calcification - childhood onset v1.202 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Other,Expert Review Amber,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
Penetrance for gene: RNF220 were set to Complete
Intellectual disability v3.1328 RNF220 Ivone Leong Classified gene: RNF220 as Amber List (moderate evidence)
Intellectual disability v3.1328 RNF220 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1328 RNF220 Ivone Leong Gene: rnf220 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1327 TCF7L2 Ivone Leong Tag Q4_21_rating tag was added to gene: TCF7L2.
Intellectual disability v3.1327 TCF7L2 Ivone Leong edited their review of gene: TCF7L2: Added comment: This gene is now associated with a relevant phenotype in Gene2Phenotype (confirmed). There is now enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: GREEN
Intellectual disability v3.1327 TCF7L2 Ivone Leong Phenotypes for gene: TCF7L2 were changed from Developmental disorders to Developmental disorders; Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system
Intellectual disability v3.1326 TCF7L2 Ivone Leong Publications for gene: TCF7L2 were set to 33057194
Intellectual disability v3.1325 PLXNA2 Ivone Leong Classified gene: PLXNA2 as Amber List (moderate evidence)
Intellectual disability v3.1325 PLXNA2 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there are currently only 2 cases there is not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1325 PLXNA2 Ivone Leong Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1324 PLXNA2 Ivone Leong Phenotypes for gene: PLXNA2 were changed from Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology to Intellectual disability, MONDO:0001071; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Intellectual disability v3.1323 PLXNA2 Ivone Leong Tag watchlist tag was added to gene: PLXNA2.
Rhabdomyolysis and metabolic muscle disorders v1.57 CAV3 Ivone Leong Publications for gene: CAV3 were set to
Rhabdomyolysis and metabolic muscle disorders v1.56 CAV3 Ivone Leong Tag Q3_21_MOI tag was added to gene: CAV3.
Rhabdomyolysis and metabolic muscle disorders v1.56 CAV3 Ivone Leong edited their review of gene: CAV3: Added comment: MOI should be changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown".

PMID: 9536092, reported one patient with homozygous G56S. The patient was the only member of the family to be affected by disease (proximal muscle weakness in the first decade of life). The variant was not found in 200 controls. The patient's skeletal muscle biopsy looked normal and expression of dystrophin, sarcoglycans and caveolin-3 was normal. This variant was later reclassified as a VUS as PMID:11251997 identified 2 Brazilian patients with LGMD with heterozygous G55S. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening 200 normal controls showed 4 controls also had this variant.
In OMIM: "Hamosh (2018) found that the G55S variant was present in heterozygous state in 3,142 of 277,064 alleles and in 184 homozygotes in the gnomAD database (January 24, 2018), calling into question the pathogenicity of the variant."

PMID: 12666119, reported an Italian patient with severe rippling muscle disease (A92T) who was AR. Actually A93T.

PMID: 15668980, the same authors of PMID: 12666119 reported 1 family with 2 affected sibs who have AR rippling muscle disease (same variant as above A92T). Unaffected parents were both heterozygous for the variant. The authors note that the parents were not known to be consanguineous but they are from the same small village in Germany. The authors also did a haplotype analysis and showed that this variant arose separately from the Italian case, suggesting that A92 might be a mutation hot spot. According to ClinVar, this variant has conflicting interpretations of pathogenicity (https://www.ncbi.nlm.nih.gov/clinvar/variation/8285/).

PMID: 16730439, reports on 1 patient (AR) with mild proximal muscle weakness of the lower limbs. No other family members were available for further analysis. Patient is homozygous for a splice variant (IVS1+2T>C).

While there are cases of biallelic variants causing disease there are currently no new cases reporting of this (newest report was in 2006). There is currently not enough evidence to support biallelic cause of disease, I suggest changing the MOI to Monoallelic until more evidence is available.; Changed publications to: 15668980, 12666119, 9536092, 11251997, 16730439; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.29 CAV3 Ivone Leong commented on gene: CAV3
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.29 CAV3 Ivone Leong Deleted their review
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.29 CAV3 Ivone Leong Tag Q3_21_MOI was removed from gene: CAV3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.29 CAV3 Ivone Leong Deleted their comment
Hereditary neuropathy or pain disorder v1.63 AIFM1 Arina Puzriakova commented on gene: AIFM1
Intellectual disability v3.1323 AIFM1 Arina Puzriakova Phenotypes for gene: AIFM1 were changed from Combined oxidative phosphorylation deficiency 6, 300816Cowchock syndrome, 310490; COWCHOCK SYNDROME to Cowchock syndrome, OMIM:310490; Combined oxidative phosphorylation deficiency 6, OMIM:300816; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, OMIM:300232
Hereditary neuropathy v1.416 AIFM1 Arina Puzriakova Phenotypes for gene: AIFM1 were changed from Cowchock syndrome; Combined oxidative phosphorylation deficiency 6 to Cowchock syndrome, OMIM:310490; Combined oxidative phosphorylation deficiency 6, OMIM:300816
Hereditary neuropathy or pain disorder v1.63 AIFM1 Arina Puzriakova Phenotypes for gene: AIFM1 were changed from Combined oxidative phosphorylation deficiency 6; Cowchock syndrome to Cowchock syndrome, OMIM:310490; Combined oxidative phosphorylation deficiency 6, OMIM:300816
Hereditary neuropathy or pain disorder v1.62 ABCA1 Arina Puzriakova commented on gene: ABCA1
Dystonia, chorea or related movement disorder, adult onset v1.123 GBA Arina Puzriakova changed review comment from: GBA included on this panel to capture association with Parkinson disease (PD). However, GBA is only a risk factor and variants do not cause highly penetrant forms of PD. For these reasons, GBA was given an Amber rating on the 'Neurodegenerative disorders - adult onset' (R58) panel (https://panelapp.genomicsengland.co.uk/panels/474/gene/GBA/). Furthermore, issues regarding interpretation a GBA variant in the context of PD have been highlighted in the 100K (see Alison Callaway review on 100K PD panel - https://panelapp.genomicsengland.co.uk/panels/39/gene/GBA/). Given the potential carrier implications, inclusion of this gene will be flagged for review at the next GMS panel update.; to: GBA included on this panel to capture association with Parkinson disease (PD). However, variants do not cause highly penetrant forms of PD and for these reasons, GBA was given an Amber rating on the 'Neurodegenerative disorders - adult onset' (R58) panel (https://panelapp.genomicsengland.co.uk/panels/474/gene/GBA/). Furthermore, issues regarding interpretation a GBA variant in the context of PD have been highlighted in the 100K (see Alison Callaway review on 100K PD panel - https://panelapp.genomicsengland.co.uk/panels/39/gene/GBA/). Given that GBA is only a PD risk factor and the potential carrier implications, inclusion of this gene will be flagged for review at the next GMS panel update.
Dystonia, chorea or related movement disorder, adult onset v1.123 GBA Arina Puzriakova commented on gene: GBA
Dystonia, chorea or related movement disorder, adult onset v1.123 GBA Arina Puzriakova Tag Q4_21_MOI was removed from gene: GBA.
Dystonia, chorea or related movement disorder, adult onset v1.123 GBA Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: GBA.
Tag Q4_21_MOI tag was added to gene: GBA.
Retinal disorders v2.216 MED12 Eleanor Williams Tag Q3_21_MOI tag was added to gene: MED12.
Early onset or syndromic epilepsy v2.434 MED12 Eleanor Williams Tag Q3_21_MOI tag was added to gene: MED12.
Tag Q3_21_expert_review tag was added to gene: MED12.
Early onset or syndromic epilepsy v2.434 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct although consideration should be given to the carrier implications for the predominantly male-only phenotypes associated with this gene.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Clefting v2.50 MED12 Eleanor Williams Tag Q3_21_MOI tag was added to gene: MED12.
Fetal anomalies v1.720 MED12 Eleanor Williams changed review comment from: Comment on mode of inheritance: Variants in this gene have also been reported in females with Hardikar syndrome (Li et al 2021, PMID: 33244166). The phenotype includes facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation.

In addition Polla et al 2021 (PMID: 33244165) and Riccardi et al 2021 (PMID: 34079076) report 22 females in total with de novo variants in MED12. Some physical features such as syndactyly (10/22) and anteriorly placed anus (4/22) are noted. 12/22 have severe intellectual disability.

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the predominantly male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases. ; to: Comment on mode of inheritance: Variants in this gene have also been reported in females with Hardikar syndrome (Li et al 2021, PMID: 33244166). The phenotype includes facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation.

In addition Polla et al 2021 (PMID: 33244165) and Riccardi et al 2021 (PMID: 34079076) report 22 females in total with de novo variants in MED12. Some physical features such as syndactyly (10/22) and anteriorly placed anus (4/22) are noted. 12/22 have severe intellectual disability.

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the predominantly male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases, therefore waiting for GMS review before considering changing the mode of inheritance.
Non-syndromic familial congenital anorectal malformations v1.7 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as biallelic in females just now but noting that a few female cases have been reported, mainly with skewed x-chromosome inactivation.
Non-syndromic familial congenital anorectal malformations v1.7 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Non-syndromic familial congenital anorectal malformations v1.6 MED12 Eleanor Williams changed review comment from: De novo variants in this gene gene have also been linked to disease in females (many of who show skewed X inactivation):

PMID: 33244166 - Li et al 2021 - report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing. All five tested patients showed evidence of skewed x chromosome inactivation. 1 patient had imperforate anus and constipation.

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 3/22 have anteriorly placed anus and 1 additionally presented with anal stenosis . Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. Two patients had chronic constipation, one of whom also presented an anteriorly placed anus.; to: De novo variants in this gene gene have also been linked to disease in females (many of who show skewed X inactivation):

PMID: 33244166 - Li et al 2021 - report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing. All five tested patients showed evidence of skewed x chromosome inactivation. 1 patient had imperforate anus and constipation.

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 3/22 have anteriorly placed anus and one of the three additionally presented with anal stenosis . Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. Two patients had chronic constipation, one of whom also presented an anteriorly placed anus.
Familial Chylomicronaemia Syndrome v1.19 APOB Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: APOB.
Tag Q3_21_expert_review tag was added to gene: APOB.
Likely inborn error of metabolism v2.187 EHHADH Arina Puzriakova Classified gene: EHHADH as Amber List (moderate evidence)
Likely inborn error of metabolism v2.187 EHHADH Arina Puzriakova Added comment: Comment on list classification: Single family reported with additional functional data which is sufficient evidence to rate as Amber, awaiting further evidence.
Likely inborn error of metabolism v2.187 EHHADH Arina Puzriakova Gene: ehhadh has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.186 EHHADH Arina Puzriakova Phenotypes for gene: EHHADH were changed from L-bifunctional protein deficiency; Metabolic acidosis; Increased amino acids in urine to ?Fanconi renotubular syndrome 3, OMIM:615605; L-bifunctional protein deficiency; Metabolic acidosis; Increased amino acids in urine
Renal tubulopathies v2.28 EHHADH Arina Puzriakova Phenotypes for gene: EHHADH were changed from metabolic acidosis, glucosuria, phosphaturia, aminoaciduria, and proteinuria; ?Fanconi renotubular syndrome 3, 605615 to ?Fanconi renotubular syndrome 3, OMIM:615605; L-bifunctional protein deficiency; Metabolic acidosis; Increased amino acids in urine
Likely inborn error of metabolism v2.185 EHHADH Arina Puzriakova Publications for gene: EHHADH were set to PMID: 33340416
Likely inborn error of metabolism v2.184 EHHADH Arina Puzriakova Mode of inheritance for gene: EHHADH was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Likely inborn error of metabolism v2.183 EHHADH Arina Puzriakova reviewed gene: EHHADH: Rating: ; Mode of pathogenicity: None; Publications: 24401050, 27160910; Phenotypes: ?Fanconi renotubular syndrome 3, OMIM:615605; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Non-syndromic familial congenital anorectal malformations v1.6 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Non-syndromic familial congenital anorectal malformations v1.6 MED12 Eleanor Williams commented on gene: MED12: De novo variants in this gene gene have also been linked to disease in females (many of who show skewed X inactivation):

PMID: 33244166 - Li et al 2021 - report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing. All five tested patients showed evidence of skewed x chromosome inactivation. 1 patient had imperforate anus and constipation.

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 3/22 have anteriorly placed anus and 1 additionally presented with anal stenosis . Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. Two patients had chronic constipation, one of whom also presented an anteriorly placed anus.
Fetal anomalies v1.720 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Early onset or syndromic epilepsy v2.434 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Fetal anomalies v1.720 MED12 Eleanor Williams changed review comment from: Comment on mode of inheritance: Variants in this gene have also been reported in females with Hardikar syndrome (the phenotype that includes facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation).

In addition Polla et al 2021 (PMID: 33244165) and Riccardi et al 2021 (PMID: 34079076) report 22 females in total with de novo variants in MED12. Some physical features such as syndactyly (10/22) and anteriorly placed anus (4/22) also noted. 12/22 have severe intellectual disability.

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the predominantly male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases. ; to: Comment on mode of inheritance: Variants in this gene have also been reported in females with Hardikar syndrome (Li et al 2021, PMID: 33244166). The phenotype includes facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation.

In addition Polla et al 2021 (PMID: 33244165) and Riccardi et al 2021 (PMID: 34079076) report 22 females in total with de novo variants in MED12. Some physical features such as syndactyly (10/22) and anteriorly placed anus (4/22) are noted. 12/22 have severe intellectual disability.

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the predominantly male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases.
Familial Meniere Disease v1.1 ADD1 Eldar Dedic reviewed gene: ADD1: Rating: RED; Mode of pathogenicity: None; Publications: PMID:30828346; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Malformations of cortical development v2.92 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Malformations of cortical development v2.92 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Malformations of cortical development. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: VPS50.
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
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.256 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1322 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Cholestasis v1.88 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Cholestasis v1.88 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Cholestasis. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: VPS50.
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
Severe microcephaly v2.256 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Severe microcephaly v2.256 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: VPS50.
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
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Tag watchlist tag was added to gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag watchlist tag was added to gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag Q3_21_rating was removed from gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag Q3_21_rating tag was added to gene: VPS50.
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Classified gene: VPS50 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Gene: vps50 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1322 VPS50 Ivone Leong Classified gene: VPS50 as Amber List (moderate evidence)
Intellectual disability v3.1322 VPS50 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1322 VPS50 Ivone Leong Gene: vps50 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.255 ARF3 Ivone Leong Tag watchlist was removed from gene: ARF3.
Severe microcephaly v2.255 ARF3 Ivone Leong Classified gene: ARF3 as Red List (low evidence)
Severe microcephaly v2.255 ARF3 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red as per my review.
Severe microcephaly v2.255 ARF3 Ivone Leong Gene: arf3 has been classified as Red List (Low Evidence).
Severe microcephaly v2.254 ARF3 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

As only 1 patient has severe microcephaly. This gene has been given a Red rating.
Severe microcephaly v2.254 ARF3 Ivone Leong Entity copied from Intellectual disability v3.1321
Severe microcephaly v2.254 ARF3 Ivone Leong gene: ARF3 was added
gene: ARF3 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ARF3.
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, MONDO:0001071; Seizures; Morphological abnormality of the central nervous system; microcephaly, MONDO:0001149
Penetrance for gene: ARF3 were set to unknown
Early onset or syndromic epilepsy v2.433 ARF3 Ivone Leong Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.433 ARF3 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia. Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.
Early onset or syndromic epilepsy v2.433 ARF3 Ivone Leong Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.432 ARF3 Ivone Leong Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Global developmental delay; Intellectual disability, MONDO:0001071; Seizures; Morphological abnormality of the central nervous system; microcephaly, MONDO:0001149
Intellectual disability v3.1321 ARF3 Ivone Leong Tag watchlist tag was added to gene: ARF3.
Early onset or syndromic epilepsy v2.431 ARF3 Ivone Leong Tag watchlist tag was added to gene: ARF3.
Intellectual disability v3.1321 ARF3 Ivone Leong Classified gene: ARF3 as Amber List (moderate evidence)
Intellectual disability v3.1321 ARF3 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.
Intellectual disability v3.1321 ARF3 Ivone Leong Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1320 ARF3 Ivone Leong Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Global developmental delay; Intellectual disability, MONDO:0001071; Seizures; Morphological abnormality of the central nervous system; microcephaly, MONDO:0001149
Rare anaemia v1.27 RPS27 Arina Puzriakova commented on gene: RPS27
Rare anaemia v1.27 RPS27 Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: RPS27.
Haematological malignancies for rare disease v1.5 RPS27 Arina Puzriakova Phenotypes for gene: RPS27 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML; Osteosarcoma, soft tissue sarcomas to ?Diamond-Blackfan anemia 17, OMIM:617409; Class: BM failure syndrome (typ AR); MDS, AML; Osteosarcoma, soft tissue sarcomas
Haematological malignancies cancer susceptibility v2.19 RPS27 Arina Puzriakova Phenotypes for gene: RPS27 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML; Osteosarcoma, soft tissue sarcomas to ?Diamond-Blackfan anemia 17, OMIM:617409; Class: BM failure syndrome (typ AR); MDS, AML; Osteosarcoma, soft tissue sarcomas
Cytopenia - NOT Fanconi anaemia v1.43 RPS27 Arina Puzriakova Phenotypes for gene: RPS27 were changed from Diamond-Blackfan anemia; ?Diamond-Blackfan anemia 17, 617409 to ?Diamond-Blackfan anemia 17, OMIM:617409
Cytopenias and congenital anaemias v1.88 RPS27 Arina Puzriakova Phenotypes for gene: RPS27 were changed from Diamond-Blackfan anemia; ?Diamond-Blackfan anemia 17, 617409 to ?Diamond-Blackfan anemia 17, OMIM:617409
Rare anaemia v1.27 RPS27 Arina Puzriakova Phenotypes for gene: RPS27 were changed from Diamond-Blackfan anemia; ?Diamond-Blackfan anemia 17, 617409; 617409 ?Diamond-Blackfan anemia 17, to ?Diamond-Blackfan anemia 17, OMIM:617409
Arthrogryposis v3.122 MED12 Eleanor Williams reviewed gene: MED12: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases seizures with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases seizures with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Likely inborn error of metabolism v2.183 ACAT2 Arina Puzriakova Publications for gene: ACAT2 were set to PMID:33340416
Likely inborn error of metabolism v2.182 ACAT2 Arina Puzriakova Phenotypes for gene: ACAT2 were changed from Developmental delay to ?ACAT2 deficiency, OMIM:614055; Increased serum lactate and pyruvate; High levels of ketones; Low levels of cytosolic acetoacetyl-CoA thiolase; Hypotonia; Severe developmental delay
Mitochondrial disorders v2.54 ACAT2 Arina Puzriakova Phenotypes for gene: ACAT2 were changed from Increased serum lactate and pyruvate; high levels of ketones to ?ACAT2 deficiency, OMIM:614055; Increased serum lactate and pyruvate; High levels of ketones; Low levels of cytosolic acetoacetyl-CoA thiolase; Hypotonia; Severe developmental delay
Mitochondrial disorders v2.53 ACAT2 Arina Puzriakova Mode of inheritance for gene: ACAT2 was changed from Other to Unknown
Likely inborn error of metabolism v2.181 ACAT2 Arina Puzriakova Classified gene: ACAT2 as Red List (low evidence)
Likely inborn error of metabolism v2.181 ACAT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Andžela Lazdāne. Currently associated with a provisional phenotype in OMIM (?ACAT2 deficiency, OMIM:614055) and not yet listed in G2P. In the 2 cases reported to date (PMIDs: 20597, 6150136), diagnoses were made based on molecular rather than genetic findings. Rating Red as at present there is no published evidence of deleterious variants in the ACAT2 gene leading to this phenotype.
Likely inborn error of metabolism v2.181 ACAT2 Arina Puzriakova Gene: acat2 has been classified as Red List (Low Evidence).
Mitochondrial disorders v2.52 ACAT2 Arina Puzriakova Classified gene: ACAT2 as Red List (low evidence)
Mitochondrial disorders v2.52 ACAT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Andžela Lazdāne. Currently associated with a provisional phenotype in OMIM (?ACAT2 deficiency, OMIM:614055) and not yet listed in G2P. In the 2 cases reported to date (PMIDs: 20597, 6150136), diagnoses were made based on molecular rather than genetic findings. Rating Red as at present there is no published evidence of deleterious variants in the ACAT2 gene leading to this phenotype.
Mitochondrial disorders v2.52 ACAT2 Arina Puzriakova Gene: acat2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams commented on gene: MED12
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.15 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.15 RNF113A Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM (MIM# 300953) and as possible Gen2Phen gene for X-linked trichothiodystrophy. At least 3 terminating variants reported in unrelated cases. Supportive functional studies also reported. Upgraded from Red to Amber but this gene should be promoted to Green at the next review.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.15 RNF113A Arina Puzriakova Gene: rnf113a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.431 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from ?Trichothiodystrophy 5, nonphotosensitive, 300953 to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.14 RNF113A Arina Puzriakova Publications for gene: RNF113A were set to 25612912
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.13 RNF113A Arina Puzriakova Tag Q3_21_rating tag was added to gene: RNF113A.
White matter disorders and cerebral calcification - childhood onset v1.201 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from ?Trichothiodystrophy 5, nonphotosensitive to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Intellectual disability v3.1319 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from X-linked trichothiodystrophy; Trichothiodystrophy 5, nonphotosensitive, 300953; Intellectual disability to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.13 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from ?Trichothiodystrophy 5, nonphotosensitive to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - two distinct homozygous variants identified in 5 individuals from 4 families who all had microcephaly among other features. Supportive in vitro studies that demonstrate functional impairment.
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v1.68 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v1.68 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - two distinct homozygous variants identified in 5 individuals from 4 families who all had ichthyosis among other features. Supportive in vitro studies that demonstrate functional impairment.
Ichthyosis and erythrokeratoderma v1.68 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v1.67 GTF2E2 Arina Puzriakova gene: GTF2E2 was added
gene: GTF2E2 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Q3_21_rating tags were added to gene: GTF2E2.
Mode of inheritance for gene: GTF2E2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF2E2 were set to 26996949; 28973399
Phenotypes for gene: GTF2E2 were set to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Review for gene: GTF2E2 was set to GREEN
Added comment: Four individuals from 3 different Moroccan families with the same homozygous variant (c.C559T) in the GTF2E2 gene have been identified, as well as an additional patient from Asian origin with a distinct homozygous variant (c.448G>C). Predominant phenotype was that of trichothiodystrophy; however, all 5 individuals also had ID/DD, microcephaly and ichthyosis - and therefore adding GTF2E2 to these relevant panel.
Sources: Literature
Severe microcephaly v2.252 GTF2E2 Arina Puzriakova gene: GTF2E2 was added
gene: GTF2E2 was added to Severe microcephaly. Sources: Literature
Q3_21_rating tags were added to gene: GTF2E2.
Mode of inheritance for gene: GTF2E2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF2E2 were set to 26996949; 28973399
Phenotypes for gene: GTF2E2 were set to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Review for gene: GTF2E2 was set to GREEN
Added comment: Four individuals from 3 different Moroccan families with the same homozygous variant (c.C559T) in the GTF2E2 gene have been identified, as well as an additional patient from Asian origin with a distinct homozygous variant (c.448G>C). Predominant phenotype was that of trichothiodystrophy; however, all 5 individuals also had ID/DD, microcephaly and ichthyosis - and therefore adding GTF2E2 to these relevant panel.
Sources: Literature
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova changed review comment from: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID. Despite indication that one of these represents a founder variants, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive functional studies.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.; to: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID among other features. Despite indication that one of these represents a founder variant, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive in vitro studies that demonstrate functional impairment.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID. Despite indication that one of these represents a founder variants, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive functional studies.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1317 GTF2E2 Arina Puzriakova Tag watchlist was removed from gene: GTF2E2.
Tag Q3_21_rating tag was added to gene: GTF2E2.
Intellectual disability v3.1317 GTF2E2 Arina Puzriakova reviewed gene: GTF2E2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26996949, 28973399; Phenotypes: Trichothiodystrophy 6, nonphotosensitive, OMIM:616943; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1317 GTF2E2 Arina Puzriakova Publications for gene: GTF2E2 were set to 30914295; 26996949
Fetal anomalies v1.720 MED12 Eleanor Williams changed review comment from: Comment on mode of inheritance: Variants in this gene have also been reported in females with Hardikar syndrome and phenotype that includes facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation.

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases; to: Comment on mode of inheritance: Variants in this gene have also been reported in females with Hardikar syndrome (the phenotype that includes facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation).

In addition Polla et al 2021 (PMID: 33244165) and Riccardi et al 2021 (PMID: 34079076) report 22 females in total with de novo variants in MED12. Some physical features such as syndactyly (10/22) and anteriorly placed anus (4/22) also noted. 12/22 have severe intellectual disability.

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the predominantly male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases.
White matter disorders and cerebral calcification - childhood onset v1.200 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Red List (low evidence)
White matter disorders and cerebral calcification - childhood onset v1.200 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single individual has been described to date with white matter alternations in the context of variants in this gene.
White matter disorders and cerebral calcification - childhood onset v1.200 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - childhood onset v1.199 GTF2E2 Arina Puzriakova reviewed gene: GTF2E2: Rating: ; Mode of pathogenicity: None; Publications: 26996949, 28973399; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1316 GTF2E2 Arina Puzriakova Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive, 616943 to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
White matter disorders and cerebral calcification - childhood onset v1.199 GTF2E2 Arina Puzriakova Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive; 616943 to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.12 GTF2E2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: GTF2E2.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.12 GTF2E2 Arina Puzriakova Publications for gene: GTF2E2 were set to 26996949
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.11 GTF2E2 Arina Puzriakova Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive; 616943 to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.10 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.10 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: Four individuals from 3 different Moroccan families with the same homozygous variant (c.C559T) in the GTF2E2 gene have been identified who all presented with non-photosensitive trichothiodystrophy. Even though this likely represents a founder effect in this population, an additional patient from Asian origin has been identified with a distinct homozygous variant (c.448G>C), corroborating pertinence of GTF2E2 variants in trichothiodystrophy. Furthermore, studies on primary fibroblasts of patients harbouring the founder variant demonstrated a reduction in the cellular levels of both subunits of the transcription initiation factor TFIIE.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.10 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1315 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Tag Q3_21_MOI tag was added to gene: MED12.
Tag Q3_21_expert_review tag was added to gene: MED12.
Intellectual disability v3.1315 MED12 Eleanor Williams changed review comment from: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.; to: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+) female cases reported now with de novo variants in MED12 and an intellectual disability phenotype so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1315 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1315 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1314 MED12 Eleanor Williams Publications for gene: MED12 were set to 6711603
Intellectual disability v3.1313 MED12 Eleanor Williams edited their review of gene: MED12: Changed publications to: 33244165, 34079076, 33244166
Intellectual disability v3.1313 MED12 Eleanor Williams reviewed gene: MED12: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Skeletal dysplasia v2.134 MYO18B Arina Puzriakova Classified gene: MYO18B as Amber List (moderate evidence)
Skeletal dysplasia v2.134 MYO18B Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Skeletal dysplasia v2.134 MYO18B Arina Puzriakova Gene: myo18b has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.133 MYO18B Arina Puzriakova Publications for gene: MYO18B were set to PMID: 32637634
Skeletal dysplasia v2.132 MYO18B Arina Puzriakova Tag Q3_21_rating tag was added to gene: MYO18B.
Skeletal dysplasia v2.132 MYO18B Arina Puzriakova reviewed gene: MYO18B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25748484, 31195167, 32184166, 32637634, 33179433; Phenotypes: Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, OMIM:616549; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.59 MYO18B Arina Puzriakova Publications for gene: MYO18B were set to 27879346; 27858739; 25748484; 32637634
Congenital myopathy v2.59 MYO18B Arina Puzriakova Publications for gene: MYO18B were set to 27879346; 27858739; 25748484
Intellectual disability v3.1313 CDH15 Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3, MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v2.132 MYO18B Arina Puzriakova Phenotypes for gene: MYO18B were changed from Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, OMIM:616549
Skeletal dysplasia v2.131 ARCN1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: ARCN1.
Skeletal dysplasia v2.131 ARCN1 Arina Puzriakova Publications for gene: ARCN1 were set to PMID: 27476655
Skeletal dysplasia v2.130 ARCN1 Arina Puzriakova Classified gene: ARCN1 as Amber List (moderate evidence)
Skeletal dysplasia v2.130 ARCN1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Andžela Lazdāne. ARCN1 is associated with a relevant phenotype in OMIM (MIM# 617164) which is characterised by rhizomelic short stature. At least 6 individuals from 5 unrelated families reported in literature (PMIDs: 27476655; 31075182; 33154040), which is sufficient to rate this gene as Green at the next GMS panel update.
Skeletal dysplasia v2.130 ARCN1 Arina Puzriakova Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.129 ARCN1 Arina Puzriakova Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, OMIM:617164
Brain cancer pertinent cancer susceptibility v1.1 Catherine Snow Panel types changed to Cancer Germline 100K; GMS Cancer Germline Virtual; GMS signed-off
Panel version 1.0 has been signed off on 2021-09-29
Breast cancer pertinent cancer susceptibility v1.2 Catherine Snow Panel types changed to Cancer Germline 100K; GMS Cancer Germline Virtual; GMS signed-off
Panel version 1.1 has been signed off on 2021-09-29
Breast cancer pertinent cancer susceptibility v1.1 PTEN Catherine Snow Classified gene: PTEN as Red List (low evidence)
Breast cancer pertinent cancer susceptibility v1.1 PTEN Catherine Snow Added comment: Comment on list classification: Rating red following review by C Turnball (ICR) of predisposition panels for GMS phase 2 indications.
Breast cancer pertinent cancer susceptibility v1.1 PTEN Catherine Snow Gene: pten has been classified as Red List (Low Evidence).
Ovarian cancer pertinent cancer susceptibility v1.4 Catherine Snow Panel types changed to Cancer Germline 100K; GMS Cancer Germline Virtual; GMS signed-off
Panel version 1.3 has been signed off on 2021-09-29
Ovarian cancer pertinent cancer susceptibility v1.3 BRIP1 Catherine Snow Classified gene: BRIP1 as Green List (high evidence)
Ovarian cancer pertinent cancer susceptibility v1.3 BRIP1 Catherine Snow Gene: brip1 has been classified as Green List (High Evidence).
Ovarian cancer pertinent cancer susceptibility v1.2 BRIP1 Catherine Snow gene: BRIP1 was added
gene: BRIP1 was added to Ovarian cancer pertinent cancer susceptibility. Sources: Expert list
Mode of inheritance for gene: BRIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: BRIP1 was set to GREEN
Added comment: Rating Green, following review by C Turnball (ICR), of predisposition panels for GMS phase 2 indications.
Sources: Expert list
Ovarian cancer pertinent cancer susceptibility v1.1 PMS2 Catherine Snow Classified gene: PMS2 as Red List (low evidence)
Ovarian cancer pertinent cancer susceptibility v1.1 PMS2 Catherine Snow Added comment: Comment on list classification: Rating red, following review by C Turnball (ICR), of predisposition panels for GMS phase 2 indications.
Ovarian cancer pertinent cancer susceptibility v1.1 PMS2 Catherine Snow Gene: pms2 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.476 KDM6A Arina Puzriakova Publications for gene: KDM6A were set to 25142838; 15523604; 32048120; 25546742; 15887282; 32086639; 26411453; 22197486; 23076834; 31363182
Primary immunodeficiency or monogenic inflammatory bowel disease v2.475 KMT2A Arina Puzriakova Classified gene: KMT2A as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.475 KMT2A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is enough evidence to promote to Green at the next GMS panel update.

Immune dysfunction, including early-onset CVID and recurrent infections, have been reported in multiple individuals with Wiedemann-Steiner syndrome. Immunopathology can be a presenting feature, and as there are sufficient unrelated cases with this phenotype, this gene should be promoted to Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.475 KMT2A Arina Puzriakova Gene: kmt2a has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.474 KMT2A Arina Puzriakova Publications for gene: KMT2A were set to 32048120; 27320412; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.473 KMT2A Arina Puzriakova Tag Q3_21_rating tag was added to gene: KMT2A.
Intellectual disability v3.1313 KMT2A Arina Puzriakova Phenotypes for gene: KMT2A were changed from WSS to Wiedemann-Steiner syndrome, OMIM:605130
Fetal anomalies v1.720 KMT2A Arina Puzriakova Phenotypes for gene: KMT2A were changed from WIEDEMANN-STEINER SYNDROME to Wiedemann-Steiner syndrome, OMIM:605130
Primary immunodeficiency or monogenic inflammatory bowel disease v2.473 KMT2A Arina Puzriakova Phenotypes for gene: KMT2A were changed from Wiedemann-Steiner syndrome with Congenital immunodeficiency; Unclassified antibody deficiency; Respiratory infections, short stature, hypertelorism, hairy elbows, developmental delay, intellectual disability; Combined immunodeficiencies with associated or syndromic features to Wiedemann-Steiner syndrome, OMIM:605130
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.29 POPDC3 Arina Puzriakova Tag watchlist tag was added to gene: POPDC3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.29 POPDC3 Arina Puzriakova Mode of inheritance for gene: POPDC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.28 POPDC3 Arina Puzriakova Classified gene: POPDC3 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.28 POPDC3 Arina Puzriakova Added comment: Comment on list classification: Since the initial report no further cohorts have been released validating POPDC3 variants in limb girdle muscular dystrophy. Given this and the lack of complete segregation studies, rating as Amber awaiting further evidence.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.28 POPDC3 Arina Puzriakova Gene: popdc3 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.27 POPDC3 Arina Puzriakova reviewed gene: POPDC3: Rating: ; Mode of pathogenicity: None; Publications: 31610034; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 26, OMIM:618848; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.430 CERS1 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
However, the Q3_21_expert_review and Q3_21_phenotype tags have been added to this gene for an NHS review, because the phenotype associated with variants CERS1 includues progessive cognitive impairment and dementia.
Early onset or syndromic epilepsy v2.430 CERS1 Sarah Leigh Tag Q3_21_expert_review tag was added to gene: CERS1.
Tag Q3_21_phenotype tag was added to gene: CERS1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.27 POPDC3 Arina Puzriakova Publications for gene: POPDC3 were set to https://doi.org/10.1002/ana.25620
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.26 POPDC3 Arina Puzriakova Phenotypes for gene: POPDC3 were changed from Muscular dystrophy, limb-girdle, autosomal recessive 26 to Muscular dystrophy, limb-girdle, autosomal recessive 26, OMIM:618848
Hereditary ataxia, adult onset v2.85 GLRB Sarah Leigh reviewed gene: GLRB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v2.85 GLRB Sarah Leigh Tag Q3_21_expert_review tag was added to gene: GLRB.
Tag Q3_21_phenotype tag was added to gene: GLRB.
Intellectual disability v3.1312 EIF2AK2 Arina Puzriakova Tag missense tag was added to gene: EIF2AK2.
Inherited white matter disorders v1.139 EIF2AK2 Arina Puzriakova Publications for gene: EIF2AK2 were set to 32197074
Inherited white matter disorders v1.138 EIF2AK2 Arina Puzriakova edited their review of gene: EIF2AK2: Added comment: A further 5 families reported (PMID: 33236446) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations (including white matter abnormalities); while 6 individuals from the remaining 2 families had only isolated dystonia.; Changed publications to: 32197074, 33236446
Intellectual disability v3.1312 EIF2AK2 Arina Puzriakova Publications for gene: EIF2AK2 were set to 32197074
Intellectual disability v3.1311 EIF2AK2 Arina Puzriakova edited their review of gene: EIF2AK2: Added comment: A further 5 families reported (PMID: 33236446) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations; while 6 individuals from the remaining 2 families had only isolated dystonia.; Changed publications to: 32197074, 33236446
Inherited white matter disorders v1.138 EIF2AK2 Arina Puzriakova Tag missense tag was added to gene: EIF2AK2.
Dystonia, chorea or related movement disorder, childhood onset v1.157 EIF2AK2 Arina Puzriakova Tag missense tag was added to gene: EIF2AK2.
Dystonia, chorea or related movement disorder, childhood onset v1.157 EIF2AK2 Arina Puzriakova edited their review of gene: EIF2AK2: Added comment: A further 6 families reported (PMID:33236446; 33866603) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. Additional clinical details are limited for the family described in PMID:33866603. However, in the remaining families detailed in PMID:33236446, 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations; while the other 2 families (6 individuals) only had isolated dystonia.; Changed publications to: 32197074, 33236446, 33866603
Dystonia, chorea or related movement disorder, childhood onset v1.157 EIF2AK2 Arina Puzriakova Publications for gene: EIF2AK2 were set to 32197074
Intellectual disability v3.1311 EIF2AK2 Arina Puzriakova Phenotypes for gene: EIF2AK2 were changed from Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, OMIM:618877
Severe early-onset obesity v2.43 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Severe early-onset obesity v2.43 CPE Arina Puzriakova Added comment: Comment on list classification: There are now sufficient unrelated families (5) reported in literature presenting a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Severe early-onset obesity v2.43 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v2.42 CPE Arina Puzriakova Publications for gene: CPE were set to 26120850; 15870393; 15358678
Severe early-onset obesity v2.41 CPE Arina Puzriakova Tag Q3_21_rating tag was added to gene: CPE.
Severe early-onset obesity v2.41 CPE Arina Puzriakova edited their review of gene: CPE: Added comment: Durmaz et al. 2021 (PMID: 32936766) identified the second family with 3 affected sibs with obesity, intellectual disability and hypogonadotropic hypogonadism, and a homozygous nonsense c.405C>A (p.Y135*) variant in CPE.

Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism (GMS) v1.46 CPE Arina Puzriakova Publications for gene: CPE were set to 26120850; 32936766
Hypogonadotropic hypogonadism (GMS) v1.45 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.45 CPE Arina Puzriakova Added comment: Comment on list classification: There are now sufficient unrelated families (5) reported in literature presenting a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Hypogonadotropic hypogonadism (GMS) v1.45 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.44 CPE Arina Puzriakova edited their review of gene: CPE: Added comment: Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1310 CPE Arina Puzriakova Publications for gene: CPE were set to 26120850; 32936766
Hypogonadotropic hypogonadism (GMS) v1.44 CPE Arina Puzriakova Tag watchlist was removed from gene: CPE.
Tag Q3_21_rating tag was added to gene: CPE.
Intellectual disability v3.1309 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Intellectual disability v3.1309 CPE Arina Puzriakova Added comment: Comment on list classification: There are now sufficient unrelated families (5) reported in literature presenting a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1309 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1308 CPE Arina Puzriakova Tag watchlist was removed from gene: CPE.
Tag Q3_21_rating tag was added to gene: CPE.
Intellectual disability v3.1308 CPE Arina Puzriakova edited their review of gene: CPE: Added comment: Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.62 PIGB Arina Puzriakova Classified gene: PIGB as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.62 PIGB Arina Puzriakova Added comment: Comment on list classification: Axonal degenerative polyneuropathy and demyelinating sensorimotor polyneuropathy are observed in the more severely affected individuals with biallelic variants in this gene. There are sufficient cases with a relevant phenotype (5 individuals from 3 families) to rate as Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v1.62 PIGB Arina Puzriakova Gene: pigb has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.61 PIGB Arina Puzriakova Tag Q3_21_rating tag was added to gene: PIGB.
Retinal disorders v2.216 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Clefting v2.50 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Fetal anomalies v1.719 GREB1L Ivone Leong Publications for gene: GREB1L were set to 29261186; 29100091; 31424080; 32378186
Retinal disorders v2.216 IRX6 Eleanor Williams Tag Q3_21_rating tag was added to gene: IRX6.
Tag Q3_21_expert_review tag was added to gene: IRX6.
Retinal disorders v2.216 IRX6 Eleanor Williams edited their review of gene: IRX6: Added comment: Ideally, a region representing the IRX5/IRX6 duplication should be added to PanelApp with a monallelic mode of inheritance. There is a lack of single nucleotide variants reported in this gene with relevance to retinal disorders and and therefore adding this gene as green risks reporting irrelevant SNVs.; Changed rating: AMBER
Retinal disorders v2.216 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of gene/small variants
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Retinal disorders v2.216 IRX5 Eleanor Williams edited their review of gene: IRX5: Changed rating: AMBER
Retinal disorders v2.216 IRX5 Eleanor Williams commented on gene: IRX5: Ideally, a region representing the IRX5/IRX6 duplication should be added to PanelApp with a monallelic mode of inheritance. There is a lack of single nucleotide variants reported in this gene with relevance to retinal disorders and and therefore adding this gene as green risks reporting irrelevant SNVs alongside carrier status for Hamamy syndrome (biallelic)
Retinal disorders v2.216 IRX5 Eleanor Williams Tag Q3_21_expert_review tag was added to gene: IRX5.
Fetal anomalies v1.718 MED12 Eleanor Williams Tag Q3_21_MOI tag was added to gene: MED12.
Fetal anomalies v1.718 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Variants in this gene have also been reported in females with Hardikar syndrome and phenotype that includes facial clefting, pigmentary retinopathy, biliary anomalies, hydronephrosis, and intestinal malrotation.

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases
Fetal anomalies v1.718 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.717 MED12 Eleanor Williams Tag Q3_21_expert_review tag was added to gene: MED12.
Primary ovarian insufficiency v1.49 ZSWIM7 Ivone Leong Classified gene: ZSWIM7 as Red List (low evidence)
Primary ovarian insufficiency v1.49 ZSWIM7 Ivone Leong Added comment: Comment on list classification: New gene added by Andrey Gagunashvili (UCL Great Ormond Street Institute of Child Health). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Currently there is only 1 case (2 affected sisters) with POI associated with this gene. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Primary ovarian insufficiency v1.49 ZSWIM7 Ivone Leong Gene: zswim7 has been classified as Red List (Low Evidence).
Retinal disorders v2.216 MED12 Eleanor Williams Tag Q3_21_rating tag was added to gene: MED12.
Retinal disorders v2.216 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases.
Retinal disorders v2.216 MED12 Eleanor Williams Mode of inheritance for gene: MED12 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, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v2.215 MED12 Eleanor Williams Classified gene: MED12 as Amber List (moderate evidence)
Retinal disorders v2.215 MED12 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but with a recommendation for green rating following GMS review. 5 cases reported with a retinal phenotype and likely disease causing variants in MED12.
Retinal disorders v2.215 MED12 Eleanor Williams Gene: med12 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.214 MED12 Eleanor Williams gene: MED12 was added
gene: MED12 was added to Retinal disorders. Sources: Literature
Q3_21_expert_review tags were added to gene: MED12.
Mode of inheritance for gene: MED12 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: MED12 were set to 33244166
Phenotypes for gene: MED12 were set to Hardikar syndrome, OMIM:612726; cholestasis-pigmentary retinopathy-cleft palate syndrome, MONDO:0012997
Review for gene: MED12 was set to GREEN
Added comment: Zorntiza Stark reviewed this gene on the Clefting panel. Li et al 2021 (PMID: 33244166) report 7 females with Hardikar syndrome each of whom have had a nonsense or frameshift MED12 variant identified by exome sequencing. All five tested patients showed evidence of skewed x chromosome inactivation. 5 of the patients are reported to have a retinal phenotype (retinal rarefaction, pigmentary retinopathy, cat’s paw retinal pigmentation).

Hardikar syndrome is noted for the preserved neurodevelopment in patients unlike the other disorders associated with this gene.
Sources: Literature
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Tag Q3_21_rating was removed from gene: PCDHGC4.
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh reviewed gene: PCDHGC4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary ovarian insufficiency v1.48 YTHDC2 Ivone Leong Classified gene: YTHDC2 as Red List (low evidence)
Primary ovarian insufficiency v1.48 YTHDC2 Ivone Leong Added comment: Comment on list classification: New gene added by Andrey Gagunashvili (UCL Great Ormond Street Institute of Child Health). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There currently does not appear to be any human cases associated with this gene therefore this gene has been given a Red rating.
Primary ovarian insufficiency v1.48 YTHDC2 Ivone Leong Gene: ythdc2 has been classified as Red List (Low Evidence).
Clefting v2.50 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases.
Clefting v2.50 MED12 Eleanor Williams Mode of inheritance for gene: MED12 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, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Clefting v2.49 MED12 Eleanor Williams Tag Q3_21_expert_review tag was added to gene: MED12.
Retinal disorders v2.213 SPTLC2 Ivone Leong Classified gene: SPTLC2 as Red List (low evidence)
Retinal disorders v2.213 SPTLC2 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM and Gene2Phenotype.

PMID: 31509666 reported on 2 unrelated families (family 1 and 2) and 3 unrelated individuals (patients 1, 2 and 3) who have HSAN1 and have variants in SPTLC1 (2 families and patient 1 have the same heterozygous variant C133Y, and patient 2 and 3 have C133W, also heterozygous). Those with the C133Y variant have HSAN1 and macular telangiectasia type 2 and those with C133W variant only have HSAN1 and no eye phenotype. The authors note that patients with C133W both patients were under the age of 50 and had been treated with serine supplementation.

Affected members of family 3 was diagnosed with HSAN1C and were heterozygous for S384F in SPTLC2 and macular telangiectasia type 2.

As there is only one case, there is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Retinal disorders v2.213 SPTLC2 Ivone Leong Gene: sptlc2 has been classified as Red List (Low Evidence).
Retinal disorders v2.212 SPTLC2 Ivone Leong Publications for gene: SPTLC2 were set to PMID: 31509666
Retinal disorders v2.211 SPTLC1 Ivone Leong Tag watchlist tag was added to gene: SPTLC1.
Retinal disorders v2.211 SPTLC1 Ivone Leong Classified gene: SPTLC1 as Amber List (moderate evidence)
Retinal disorders v2.211 SPTLC1 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype.

PMID: 31509666 reported on 2 unrelated families (family 1 and 2) and 3 unrelated individuals (patients 1, 2 and 3) who have HSAN1 and have variants in SPTLC1 (2 families and patient 1 have the same heterozygous variant C133Y, and patient 2 and 3 have C133W, also heterozygous). Those with the C133Y variant have HSAN1 and macular telangiectasia type 2 and those with C133W variant only have HSAN1 and no eye phenotype. The authors note that patients with C133W both patients were under the age of 50 and had been treated with serine supplementation.

Affected members of family 3 was diagnosed with HSAN1C and were heterozygous for S384F in SPTLC2 and macular telangiectasia type 2.

While there appears to be a link between this gene and macular telangiectasia type 2, all affected families/individuals have the same variant. Therefore, there is currently enough evidence to support a gene-disease association. This gene has been given an Amber rating until more information is available.
Retinal disorders v2.211 SPTLC1 Ivone Leong Gene: sptlc1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Deleted their review
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Deleted their comment
Intellectual disability v3.1308 PCDHGC4 Sarah Leigh Classified gene: PCDHGC4 as Amber List (moderate evidence)
Intellectual disability v3.1308 PCDHGC4 Sarah Leigh Added comment: Comment on list classification: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1308 PCDHGC4 Sarah Leigh Gene: pcdhgc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1307 PCDHGC4 Sarah Leigh Deleted their comment
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Entity copied from Intellectual disability v3.1307
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh gene: PCDHGC4 was added
gene: PCDHGC4 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q3_21_rating tags were added to gene: PCDHGC4.
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to Neurodevelopmental abnormality HP:0012759
Intellectual disability v3.1307 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from neurodevelopmental syndrome to Neurodevelopmental abnormality HP:0012759
Early onset or syndromic epilepsy v2.430 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from neurodevelopmental syndrome to Neurodevelopmental abnormality HP:0012759
Intellectual disability v3.1306 KIRREL3 Aleš Maver reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33853164; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.210 SPTLC1 Ivone Leong Publications for gene: SPTLC1 were set to PMID: 31509666
Catecholaminergic polymorphic VT v2.19 TECRL Ivone Leong Tag Q3_21_rating tag was added to gene: TECRL.
Catecholaminergic polymorphic VT v2.19 TECRL Ivone Leong edited their review of gene: TECRL: Added comment: This gene is associated with a phenotype in OMIM and not Gene2Phenotype. There is now sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: GREEN
Skeletal dysplasia v2.128 LRRK1 Eleanor Williams Classified gene: LRRK1 as Amber List (moderate evidence)
Skeletal dysplasia v2.128 LRRK1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for a green rating following GMS review. More than 3 reported cases.
Skeletal dysplasia v2.128 LRRK1 Eleanor Williams Gene: lrrk1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.127 LRRK1 Eleanor Williams Tag Q3_21_rating tag was added to gene: LRRK1.
Tag Q3_21_NHS_review tag was added to gene: LRRK1.
Catecholaminergic polymorphic VT v2.19 TECRL Ivone Leong Added comment: Comment on publications: PMID: 30790670. 1 case (13 yo) with compound het variants in TECRL (R196Q, which was previously reported and a novel splice variant) was diagnosed with CPVT3. The proband's older brother suddenly died at 12 yo but DNA was unavailable for testing. Both heterozygous parents were unaffected.

PMID: 32173957. 4 families with novel homozygous/compound het TECRL variants (6 affected individuals).

PMID: 33367594. 7 additional families (10 affected individuals) with compound het/homozygous variants in TECRL.
Catecholaminergic polymorphic VT v2.19 TECRL Ivone Leong Publications for gene: TECRL were set to 27861123
Skeletal dysplasia v2.127 LRRK1 Eleanor Williams commented on gene: LRRK1
Long QT syndrome v2.23 TECRL Ivone Leong Classified gene: TECRL as Amber List (moderate evidence)
Long QT syndrome v2.23 TECRL Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber to match the gene rating suggested in my previous review.
Long QT syndrome v2.23 TECRL Ivone Leong Gene: tecrl has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.26 TRIM63 Ivone Leong Classified gene: TRIM63 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v2.26 TRIM63 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:32451364 reported 16 index cases with homozygous/compound het TRIM63 variants. 15 have HCM and 1 with restrictive cardiomyopathy. Only those with homozygous/compound het variants had disease (heterozygous family members were healthy).

This gene should be promoted to Green status at the next review as there is enough evidence to support a gene-disease association.
Hypertrophic cardiomyopathy v2.26 TRIM63 Ivone Leong Gene: trim63 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.127 LRRK1 Eleanor Williams Phenotypes for gene: LRRK1 were changed from Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198) to Osteosclerotic metaphyseal dysplasia (OSMD), OMIM: 615198; Osteosclerotic metaphyseal dysplasia, MONDO:0014080
Hypertrophic cardiomyopathy v2.25 TRIM63 Ivone Leong Tag Q3_21_rating tag was added to gene: TRIM63.
Tag Q3_21_NHS_review tag was added to gene: TRIM63.
Hypertrophic cardiomyopathy v2.25 TRIM63 Ivone Leong Phenotypes for gene: TRIM63 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, MONDO:0005045; restrictive cardiomyopathy, MONDO:0005201
Hypertrophic cardiomyopathy v2.24 TRIM63 Ivone Leong Mode of inheritance for gene: TRIM63 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v2.23 TRIM63 Ivone Leong Publications for gene: TRIM63 were set to
Hypertrophic cardiomyopathy v2.22 TRIM63 Oliver Watkinson reviewed gene: TRIM63: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 32451364; Phenotypes: hypertrophic cardiomyopathy, restrictive cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.472 PSMB9 Arina Puzriakova Publications for gene: PSMB9 were set to 26524591
Primary immunodeficiency or monogenic inflammatory bowel disease v2.471 PSMB4 Arina Puzriakova Publications for gene: PSMB4 were set to 26524591
Primary immunodeficiency or monogenic inflammatory bowel disease v2.470 PSMB9 Arina Puzriakova reviewed gene: PSMB9: Rating: ; Mode of pathogenicity: None; Publications: 33727065; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.470 PSMB4 Arina Puzriakova reviewed gene: PSMB4: Rating: ; Mode of pathogenicity: None; Publications: 34416217; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.470 PSMB9 Arina Puzriakova Phenotypes for gene: PSMB9 were changed from Autoinflammation, lipodystrophy, and dermatosis syndrome; CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome) to Proteasome-associated autoinflammatory syndrome 3, digenic, OMIM:617591; CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.469 PSMB4 Arina Puzriakova Phenotypes for gene: PSMB4 were changed from CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome) to Proteasome-associated autoinflammatory syndrome 3 and digenic forms, OMIM:617591; CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome)
Hereditary haemorrhagic telangiectasia v2.9 GDF2 Arina Puzriakova Penetrance for gene GDF2 was set from to Complete
Hereditary haemorrhagic telangiectasia v2.8 GDF2 Arina Puzriakova Publications for gene: GDF2 were set to 23972370 - 3 unrelated probands with no variants identified in ENG, ACVRL1, and SMAD4; 27081547 - a variant of unknown significance in GDF2 was detected in one of 93 unrelated individuals clinically suspected to have HHT who previously tested negative for mutations in ENG, ACVRL1 and SMAD4; 25674101 - review from the same authors as PMID:23972370
Hereditary haemorrhagic telangiectasia v2.7 GDF2 Arina Puzriakova reviewed gene: GDF2: Rating: ; Mode of pathogenicity: None; Publications: 27081547, 32573726, 32669404, 33834622, https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A6356; Phenotypes: Telangiectasia, hereditary hemorrhagic, type 5, OMIM:615506; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.209 SPTLC2 Dmitrijs Rots gene: SPTLC2 was added
gene: SPTLC2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: SPTLC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTLC2 were set to PMID: 31509666
Phenotypes for gene: SPTLC2 were set to macular telangiectasia type 2; vision loss; neuropathy
Penetrance for gene: SPTLC2 were set to unknown
Review for gene: SPTLC2 was set to GREEN
Added comment: Common feature of HSAN1 macular telangiectasia type 2 and identified in two families with primarily diagnosed macular telangiectasia type 2 in PMID: 31509666.
Sources: Literature
Retinal disorders v2.209 SPTLC1 Dmitrijs Rots gene: SPTLC1 was added
gene: SPTLC1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: SPTLC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTLC1 were set to PMID: 31509666
Phenotypes for gene: SPTLC1 were set to macular telangiectasia type 2; vision loss
Penetrance for gene: SPTLC1 were set to unknown
Review for gene: SPTLC1 was set to GREEN
Added comment: Common feature of HSAN1 macular telangiectasia type 2 and identified in two families with primarily diagnosed macular telangiectasia type 2 in PMID: 31509666.
Sources: Literature
Primary ovarian insufficiency v1.47 YTHDC2 Andrey Gagunashvili gene: YTHDC2 was added
gene: YTHDC2 was added to Primary ovarian insufficiency. Sources: Literature,Research
Mode of inheritance for gene: YTHDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YTHDC2 were set to 29033321; 29360036
Phenotypes for gene: YTHDC2 were set to Premature ovarian insufficiency; female infertility; absent puberty; primary amenorrhea
Penetrance for gene: YTHDC2 were set to Complete
Review for gene: YTHDC2 was set to RED
Added comment: Sources: Literature, Research
Primary ovarian insufficiency v1.47 ZSWIM7 Andrey Gagunashvili changed review comment from: Sources: Literature, Research; to: Sources: Literature
Primary ovarian insufficiency v1.47 ZSWIM7 Andrey Gagunashvili edited their review of gene: ZSWIM7: Changed rating: RED
Primary ovarian insufficiency v1.47 ZSWIM7 Andrey Gagunashvili gene: ZSWIM7 was added
gene: ZSWIM7 was added to Primary ovarian insufficiency. Sources: Literature,Research
Mode of inheritance for gene: ZSWIM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZSWIM7 were set to 34402903
Phenotypes for gene: ZSWIM7 were set to Primary ovarian insufficiency; absent puberty; primary amenorrhea
Penetrance for gene: ZSWIM7 were set to Complete
Mode of pathogenicity for gene: ZSWIM7 was set to Other
Review for gene: ZSWIM7 was set to AMBER
Added comment: Sources: Literature, Research
Osteogenesis imperfecta v2.37 MBTPS2 Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: MBTPS2.
Skeletal dysplasia v2.126 UNC45A Eleanor Williams commented on gene: UNC45A: Copied this gene from the Osteogenesis imperfecta panel, as all green genes on that panel should also be green on the Skeletal dysplasia panel
Skeletal dysplasia v2.126 UNC45A Eleanor Williams Entity copied from Osteogenesis imperfecta v2.37
Skeletal dysplasia v2.126 UNC45A Eleanor Williams gene: UNC45A was added
gene: UNC45A was added to Skeletal dysplasia. Sources: Expert list,Expert Review Amber
Q3_21_rating, Q3_21_NHS_review tags were added to gene: UNC45A.
Mode of inheritance for gene: UNC45A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45A were set to 29429573
Phenotypes for gene: UNC45A were set to Osteootohepatoenteric syndrome, OMIM:619377
Skeletal dysplasia v2.125 SGMS2 Eleanor Williams commented on gene: SGMS2: Copied from the Osteogenesis imperfecta panel to the Skeletal dysplasia panel.
Skeletal dysplasia v2.125 SGMS2 Eleanor Williams Entity copied from Osteogenesis imperfecta v2.37
Skeletal dysplasia v2.125 SGMS2 Eleanor Williams gene: SGMS2 was added
gene: SGMS2 was added to Skeletal dysplasia. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: SGMS2.
Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGMS2 were set to 30779713; 32028018
Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia, OMIM:126550; calvarial doughnut lesions-bone fragility syndrome, MONDO:0007470
Skeletal dysplasia v2.124 DSPP Eleanor Williams Tag Q3_21_expert_review tag was added to gene: DSPP.
Skeletal dysplasia v2.124 DSPP Eleanor Williams commented on gene: DSPP: This gene has been reviewed as RED on the Osteogenesis imperfecta panel by Zorntiza Stark with comment "Specifically NOT associated with fractures/OI.", and therefore has been tagged for further GMS review on this panel also.
Skeletal dysplasia v2.124 MESD Eleanor Williams Tag for-review was removed from gene: MESD.
Tag Q3_21_rating tag was added to gene: MESD.
Skeletal dysplasia v2.124 MESD Eleanor Williams Entity copied from Osteogenesis imperfecta v2.37
Skeletal dysplasia v2.124 MESD Eleanor Williams gene: MESD was added
gene: MESD was added to Skeletal dysplasia. Sources: Expert Review Amber,Literature
for-review tags were added to gene: MESD.
Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MESD were set to 31564437
Phenotypes for gene: MESD were set to Osteogenesis imperfecta, type XX, OMIM:618644; Osteogenesis imperfecta, type 20, MONDO:0032846
Skeletal dysplasia v2.123 MBTPS2 Eleanor Williams commented on gene: MBTPS2: Copied from the Osteogenesis imperfecta panel
Skeletal dysplasia v2.123 MBTPS2 Eleanor Williams Entity copied from Osteogenesis imperfecta v2.37
Skeletal dysplasia v2.123 MBTPS2 Eleanor Williams gene: MBTPS2 was added
gene: MBTPS2 was added to Skeletal dysplasia. Sources: Expert list,Expert Review Amber
Q3_21_rating, Q3_21_expert_review tags were added to gene: MBTPS2.
Mode of inheritance for gene: MBTPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MBTPS2 were set to 27380894
Phenotypes for gene: MBTPS2 were set to Osteogenesis imperfecta, type XIX, OMIM:301014; osteogenesis imperfecta, type 19, MONDO:0049223
Skeletal dysplasia v2.122 SUCO Eleanor Williams commented on gene: SUCO: Copied from the Osteogenesis imperfecta panel to the Skeletal Dysplasia panel. Amber rating.
Skeletal dysplasia v2.122 SUCO Eleanor Williams Entity copied from Osteogenesis imperfecta v2.37
Skeletal dysplasia v2.122 SUCO Eleanor Williams gene: SUCO was added
gene: SUCO was added to Skeletal dysplasia. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: SUCO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUCO were set to 29620724; 20440000
Phenotypes for gene: SUCO were set to Osteogenesis imperfecta, MONDO:0019019; skeletal dysplasia, HP:0002652; osteopenia
Skeletal dysplasia v2.121 COPB2 Eleanor Williams Classified gene: COPB2 as Amber List (moderate evidence)
Skeletal dysplasia v2.121 COPB2 Eleanor Williams Added comment: Comment on list classification: Gene copied from the Osteogenesis imperfecta panel. Leaving as amber for now, but there are 2 cases with fractures and 4 with osteopaenia, plus a mouse model with low bone mass, so sufficient to rate green after then next GMS review.
Skeletal dysplasia v2.121 COPB2 Eleanor Williams Gene: copb2 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.37 COPB2 Eleanor Williams Classified gene: COPB2 as Amber List (moderate evidence)
Osteogenesis imperfecta v2.37 COPB2 Eleanor Williams Added comment: Comment on list classification: Leaving as amber for now, but there are 2 cases with fractures and 4 with osteopaenia, plus a mouse model with low bone mass, so sufficient to rate green after then next GMS review.
Osteogenesis imperfecta v2.37 COPB2 Eleanor Williams Gene: copb2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.120 COPB2 Eleanor Williams Entity copied from Osteogenesis imperfecta v2.36
Skeletal dysplasia v2.120 COPB2 Eleanor Williams gene: COPB2 was added
gene: COPB2 was added to Skeletal dysplasia. Sources: NHS GMS,Expert list,Expert Review Amber
Q3_21_rating, watchlist_moi tags were added to gene: COPB2.
Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COPB2 were set to 34450031; 29036432
Phenotypes for gene: COPB2 were set to juvenile osteoporosis; Osteopenia; Osteoporosis; recurrent fractures
Intellectual disability v3.1306 PITRM1 Ivone Leong Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
Primary immunodeficiency or monogenic inflammatory bowel disease v2.468 KMT2A Dmitrijs Rots reviewed gene: KMT2A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33783954, 28623346, 27320412; Phenotypes: Hypogammaglobulinemia, intellectual disability, hypertrichosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.468 KDM6A Dmitrijs Rots changed review comment from: Immunodeficiency is a well-known and common feature of KS. Recent study shows:
"Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively"; to: Immunodeficiency is a well-known and common feature of KS. Recent study shows:
"Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively"

The gene is also included in Inborn errors of immunity classification: PMID 31953710
Thyroid cancer pertinent cancer susceptibility v1.3 CDKN1B Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'biallelic to 'monoallelic'. Literature review did not indicate presence of biallelic variants pertaining to thyroid or parathyroid tumours. The MOI for this gene is also monoallelic in OMIM and other PanelApp panels.
Thyroid cancer pertinent cancer susceptibility v1.3 CDKN1B Arina Puzriakova Mode of inheritance for gene: CDKN1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1305 ATP1A3 Zornitza Stark Deleted their comment
Osteogenesis imperfecta v2.36 COPB2 Eleanor Williams Tag watchlist_moi tag was added to gene: COPB2.
DDG2P v2.46 ALG8 Sarah Leigh Added comment: Comment on mode of inheritance: Monoallelic variants are associated with Polycystic liver disease 3 with or without kidney cysts OMIM:617874, which is not relevant to this panel. Therefore biallelic moi is relevant to this panel.
DDG2P v2.46 ALG8 Sarah Leigh Mode of inheritance for gene: ALG8 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.45 ALG8 Sarah Leigh Phenotypes for gene: ALG8 were changed from ALG8-CDG 237145 to Congenital disorder of glycosylation, type Ih OMIM:608104; ALG8-CDG MONDO:0011969
Primary immunodeficiency or monogenic inflammatory bowel disease v2.468 B2M Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic mode of inheritance is correct for Immunodeficiency 43. OMIM also has an entry for ?Amyloidosis, familial visceral, OMIM:105200 - Autosomal dominant but this phenotype is not relevant to this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.468 B2M Eleanor Williams Mode of inheritance for gene: B2M was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.156 ATXN7 Dmitrijs Rots reviewed gene: ATXN7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, childhood onset v1.156 ATXN1 Dmitrijs Rots reviewed gene: ATXN1: Rating: RED; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting were a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.429 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.429 TNPO2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting were a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.429 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.249 TNPO2 Arina Puzriakova gene: TNPO2 was added
gene: TNPO2 was added to Severe microcephaly. Sources: Literature
Q3_21_rating tags were added to gene: TNPO2.
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Review for gene: TNPO2 was set to GREEN
Added comment: Goodman et al., 2021 (PMID: 34314705) reported on 15 unrelated individuals with different variants in this gene (14 de novo, 1 mosaic in mother; 12 SNVs, 3 in-frame deletions, 1 deletion-insertion). All had GDD and all those who were assessed also had ID (9/9), ranging from mild to severe. ID also suspected but not investigated in another 3 cases. 6 had seizures starting between 1 and 2.5 years of age. 5 individuals had microcephaly (HC ranging -2.77 to -4.53 SD). Other less common features were also observed such as variable brain, gastrointestinal and ophthalmologic abnormalities.

Notably 6 individuals had additional SNVs/CNVs of uncertain significance, some of which include known ID genes (e.g. SETBP1, CUX2, ARMC9, PDE4D), but were discounted due to lack of explanation of the overall patient phenotype.

Some functional studies conducted in Drosophila demonstrated that patient-associated variants caused neurodevelopmental defects that were dosage and location (of variant within protein) dependent.
Sources: Literature
Early onset or syndromic epilepsy v2.428 TNPO2 Arina Puzriakova gene: TNPO2 was added
gene: TNPO2 was added to Genetic epilepsy syndromes. Sources: Literature
Q3_21_rating tags were added to gene: TNPO2.
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Review for gene: TNPO2 was set to GREEN
Added comment: Goodman et al., 2021 (PMID: 34314705) reported on 15 unrelated individuals with different variants in this gene (14 de novo, 1 mosaic in mother; 12 SNVs, 3 in-frame deletions, 1 deletion-insertion). All had GDD and all those who were assessed also had ID (9/9), ranging from mild to severe. ID also suspected but not investigated in another 3 cases. 6 had seizures starting between 1 and 2.5 years of age. 5 individuals had microcephaly (HC ranging -2.77 to -4.53 SD). Other less common features were also observed such as variable brain, gastrointestinal and ophthalmologic abnormalities.

Notably 6 individuals had additional SNVs/CNVs of uncertain significance, some of which include known ID genes (e.g. SETBP1, CUX2, ARMC9, PDE4D), but were discounted due to lack of explanation of the overall patient phenotype.

Some functional studies conducted in Drosophila demonstrated that patient-associated variants caused neurodevelopmental defects that were dosage and location (of variant within protein) dependent.
Sources: Literature
Intellectual disability v3.1305 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Intellectual disability v3.1305 TNPO2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are now sufficient unrelated cases with a relevant phenotype associated with various variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1305 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1304 TNPO2 Arina Puzriakova Mode of inheritance for gene: TNPO2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1303 TNPO2 Arina Puzriakova Phenotypes for gene: TNPO2 were changed from to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Intellectual disability v3.1302 TNPO2 Arina Puzriakova Publications for gene: TNPO2 were set to 26350204
Intellectual disability v3.1301 TNPO2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: TNPO2.
Intellectual disability v3.1301 TNPO2 Arina Puzriakova reviewed gene: TNPO2: Rating: ; Mode of pathogenicity: None; Publications: 34314705; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.119 LRRK1 Conor Pallatt gene: LRRK1 was added
gene: LRRK1 was added to Skeletal dysplasia. Sources: NHS GMS,Literature
Mode of inheritance for gene: LRRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRK1 were set to 27829680; 27055475; 31571209; 32119750
Phenotypes for gene: LRRK1 were set to Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198)
Penetrance for gene: LRRK1 were set to Complete
Review for gene: LRRK1 was set to GREEN
Added comment: A detailed phenotypic picture of Osteosclerotic metaphyseal dysplasia (OSMD) in patients with LRRK1 variants can be seen in table 1 of Howaldt et al (2020).

Lida et al (2016) identified homozygous deletion that is predicted to result in elongation of protein (p.E1980Afs*66) in a child with OSMD. Child was born to consanguineous parents, both heterozygous for variant.

Guo et al (2017) identified a family with OSMD. Healthy, non-consanguineous parents have two children with OSMD that are homozygous for 1bp insertion in LRRK1 that is predicted to result in a frame-shift and produce an elongated protein (p.A1991Gfs*31) without nonsense-mediated mRNA decay. A similar effect seen in Lida et al (2016).

Howaldt et al (2020) shows a patient with a homozygous splice site mutation resulting in near complete skipping of exon 3 in cDNA leading to a frameshift (p.Ala34Profs*33). The variant segregated with disorder in the family with parents being heterozygous for the variant and clinically unaffected.

Miryounesi et al (2020) identified a patient with suspected OSMD from healthy, consanguineous parents. Patient is homozygous for stop gain mutation (c.2785G > T, p.E929X) in LRRK1. Parents are heterozygous for the variant.

Homozygous nonsense variant in LRRK1 also identified in an individual recruited to the 100,000 genomes project for skeletal dysplasia, Osteosclerotic metaphyseal dysplasia is considered a good fit for phenotype.

LRRK1 gene should be included in the skeletal dysplasia panel as a green gene at the next GMS panel update.
Sources: NHS GMS, Literature
Severe microcephaly v2.248 ARCN1 Ivone Leong Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164) to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, OMIM:617164
Severe microcephaly v2.247 ARCN1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel. Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences was given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1301 LINGO4 Arina Puzriakova Classified gene: LINGO4 as Amber List (moderate evidence)
Intellectual disability v3.1301 LINGO4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There a sufficient unrelated cases with a relevant phenotype to rate as Green at the next GMS panel update.
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PMID: 33098801 - 4 individuals from 3 unrelated families harbouring private biallelic variants in this gene which co-segregated with disease. 4/4 cases presented with GDD and ID.
Intellectual disability v3.1301 LINGO4 Arina Puzriakova Gene: lingo4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1300 LINGO4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: LINGO4.
Severe microcephaly v2.247 ARCN1 Ivone Leong changed review comment from: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040; to: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040 describes another case. "3.5-yr-old Caucasian/Peruvian/Native American boy with microcephaly, severe global developmental delay, and multiple congenital abnormalities. At birth he was documented to have a small ventricular septal defect (which was closed by 3 wk), a patent foramen ovale, rhizomelic shortening of extremities on clinical examination, pectus carinatum, and underdeveloped genitalia including severe penoscrotal hypospadias and cryptorchidism." OFC at birth was just above 10th centile, at 3.5 yr OFC is below 3rd centile but no actual measurements were given. Microarrays identified a 95-kb loss at 12q23.2 including exons 1–4 of the NUP37 gene and exons 1–9 of the PARPBP gene, which were deemed nondiagnostic (neither parents had this deletion). A heterozygous variant was also found in HSPG2 (c.9893 C > T, p. Pro3298Leu). Biallelic variants in this gene is associated with skeletal disorders that did not fit the patient's phenotype and as the patient is heterozygous for a variant in HSPG2 it was deemed that this variant was not causative. WGS identified a de novo splice variant in ARCN1. mRNA studies showed that the variant caused retention of part of an intron in the transcript. The authors deemed the ARCN1 variant as the causative variant in this patient.
Severe microcephaly v2.247 ARCN1 Ivone Leong Added comment: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040
Severe microcephaly v2.247 ARCN1 Ivone Leong Publications for gene: ARCN1 were set to 27476655
Severe microcephaly v2.246 ARCN1 Ivone Leong Tag Q3_21_rating was removed from gene: ARCN1.
Tag watchlist tag was added to gene: ARCN1.
Severe microcephaly v2.246 ARCN1 Ivone Leong Classified gene: ARCN1 as Amber List (moderate evidence)
Severe microcephaly v2.246 ARCN1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel. Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.246 ARCN1 Ivone Leong Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.245 ARCN1 Ivone Leong Tag Q3_21_rating tag was added to gene: ARCN1.
Dystonia, chorea or related movement disorder, childhood onset v1.156 IMPDH2 Arina Puzriakova Publications for gene: IMPDH2 were set to 33098801
Dystonia, chorea or related movement disorder, childhood onset v1.155 IMPDH2 Arina Puzriakova Classified gene: IMPDH2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.155 IMPDH2 Arina Puzriakova Added comment: Comment on list classification: This gene is not yet associated with a relevant phenotype in OMIM or G2P, but there are sufficient unrelated cases (3) presenting with signs of dystonia to rate as Green at the next GMS review. Other cases reported with motor dysfunction, and it is plausible that this may develop into dystonia later in life.
Dystonia, chorea or related movement disorder, childhood onset v1.155 IMPDH2 Arina Puzriakova Gene: impdh2 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.154 IMPDH2 Arina Puzriakova Deleted their comment
Dystonia, chorea or related movement disorder, childhood onset v1.154 IMPDH2 Arina Puzriakova edited their review of gene: IMPDH2: Added comment: Kuukasjärvi et al., 2021 (PMID: 34305140) report on an additional large Finnish family (6 affected members) with a heterozygous truncating variant co-segregating with a dominantly inherited dystonia-tremor phenotype. Patient fibroblasts showed reduced IMPDH2 expression. IMPDH2 is the rate-limiting enzyme in the biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders.; Changed publications to: 33098801, 34305140
Dystonia, chorea or related movement disorder, childhood onset v1.154 IMPDH2 Arina Puzriakova Entity copied from Intellectual disability v3.1300
Dystonia, chorea or related movement disorder, childhood onset v1.154 IMPDH2 Arina Puzriakova gene: IMPDH2 was added
gene: IMPDH2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: IMPDH2.
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to 33098801
Phenotypes for gene: IMPDH2 were set to Neurodevelopmental disorder with dystonia
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Classified gene: IMPDH2 as Amber List (moderate evidence)
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not yet associated with a relevant phenotype in OMIM or G2P, but sufficient unrelated cases with relevant phenotype to rate Green at the next GMS review. Neurodevelopmental delay is an early feature that may be evident prior to other manifestations (plausible that other cases may develop dystonic signs later in life) and so inclusion on this panel is warranted.
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Gene: impdh2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1299 IMPDH2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: IMPDH2.
Intellectual disability v3.1299 IMPDH2 Arina Puzriakova reviewed gene: IMPDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33098801; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.427 CLCN3 Arina Puzriakova Entity copied from Intellectual disability v3.1299
Early onset or syndromic epilepsy v2.427 CLCN3 Arina Puzriakova gene: CLCN3 was added
gene: CLCN3 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: CLCN3.
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 with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Mode of pathogenicity for gene: CLCN3 was set to Other
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CLCN3.
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Classified gene: CLCN3 as Amber List (moderate evidence)
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update. Sufficient number of unrelated cases with relevant phenotype to add to the ID and epilepsy panels. Functional studies and animal model support pathogenicity. CLCN3 is also associated with a relevant phenotype in OMIM (MIM# 619512 and 619517)
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Gene: clcn3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1298 CLCN3 Arina Puzriakova 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
Intellectual disability v3.1297 CLCN3 Arina Puzriakova Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Fetal anomalies v1.717 GREB1L Rhiannon Mellis edited their review of gene: GREB1L: Added comment: A further prenatal case reported in PMID 31974414 (Vora et al 2020) - c.4881_4882del; [p.H1627fs] inherited from parent, 2 affected pregnancies with bilateral renal agenesis plus a living child with single kidney.; Changed rating: GREEN; Changed publications to: PMID: 31424080, 32378186, 31974414
Intellectual disability v3.1296 ANK2 Arina Puzriakova Classified gene: ANK2 as Amber List (moderate evidence)
Intellectual disability v3.1296 ANK2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel review - sufficient unrelated cases with relevant phenotype and de novo PTVs in this gene. Definitive gene-disease association is supported by the ClinGen ID and Autism Expert Panel.
Intellectual disability v3.1296 ANK2 Arina Puzriakova Gene: ank2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1295 ANK2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: ANK2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.467 KDM6A Arina Puzriakova Phenotypes for gene: KDM6A were changed from Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Kabuki Syndrome 2 due to KDM6A deficiency; Combined immunodeficiencies with associated or syndromic features to Kabuki syndrome 2, OMIM:300867; Recurrent infections (otitis media, pneumonia); Autoimmunity; Combined immunodeficiencies with associated or syndromic features
Primary immunodeficiency or monogenic inflammatory bowel disease v2.466 KDM6A Arina Puzriakova Publications for gene: KDM6A were set to 25142838; 15523604; 32048120; 25546742; 15887282; 32086639; 26411453; 22197486; 23076834
Primary immunodeficiency or monogenic inflammatory bowel disease v2.465 KDM6A Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: KDM6A.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.465 KDM6A Arina Puzriakova commented on gene: KDM6A
Malformations of cortical development v2.91 TP73 Arina Puzriakova Entity copied from Intellectual disability v3.1295
Malformations of cortical development v2.91 TP73 Arina Puzriakova gene: TP73 was added
gene: TP73 was added to Malformations of cortical development. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: TP73.
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, OMIM:619466
Intellectual disability v3.1295 TP73 Arina Puzriakova Publications for gene: TP73 were set to 31130284
Intellectual disability v3.1295 TP73 Arina Puzriakova Classified gene: TP73 as Amber List (moderate evidence)
Intellectual disability v3.1295 TP73 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel review - at least 7 unrelated families with distinct variants and relevant phenotypes. Supported by some functional data.

TP73 is also now associated with a relevant phenotype in OMIM (MIM# 619466) but is not yet listed in G2P.
Intellectual disability v3.1295 TP73 Arina Puzriakova Gene: tp73 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1294 TP73 Arina Puzriakova Tag Q3_21_rating tag was added to gene: TP73.
Intellectual disability v3.1294 TP73 Arina Puzriakova edited their review of gene: TP73: Changed rating: GREEN; Changed publications to: 31130284, 34077761; Changed phenotypes to: Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Intellectual disability v3.1294 TP73 Arina Puzriakova commented on gene: TP73: PMID: 34077761 (2021) - Further 7 individuals from 5 families identified with different homozygous variants in this gene. All affected individuals exhibited cortical malformations characterised by lissencephaly, central muscular hypotonia and moderate to severe cognitive dysfunction.
Intellectual disability v3.1294 TP73 Arina Puzriakova Phenotypes for gene: TP73 were changed from Intellectual disability; lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Early onset or syndromic epilepsy v2.426 AP1G1 Arina Puzriakova Entity copied from Intellectual disability v3.1293
Early onset or syndromic epilepsy v2.426 AP1G1 Arina Puzriakova gene: AP1G1 was added
gene: AP1G1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_21_rating tags were added to gene: AP1G1.
Mode of inheritance for gene: AP1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Intellectual disability v3.1293 AP1G1 Arina Puzriakova Mode of inheritance for gene AP1G1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: AP1G1.
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Classified gene: AP1G1 as Amber List (moderate evidence)
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Usmani et al., 2021 (PMID: 34102099) identified 9 families with heterozygous and 2 families with homozygous variants in this gene. All individuals (12) had GDD and ID of various severity (mild to severe), except one patient who died at 22 days. Other features include hypotonia (9/10), seizures (6/10) and spasticity (4/10). Some supportive functional data included.

There is sufficient evidence to promote this gene to Green at the next GMS panel update, with 'monoallelic' MOI. Biallelic cases would still be picked up by the Genomics England pipeline - but this may be reviewed if additional cases are discovered.
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Gene: ap1g1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1291 ATP9A Arina Puzriakova Publications for gene: ATP9A were set to
Severe microcephaly v2.245 ATP9A Arina Puzriakova Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Intellectual disability v3.1290 ATP9A Arina Puzriakova Classified gene: ATP9A as Amber List (moderate evidence)
Intellectual disability v3.1290 ATP9A Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases/clinical evidence.
Intellectual disability v3.1290 ATP9A Arina Puzriakova Gene: atp9a has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.153 CAMK4 Arina Puzriakova Entity copied from Intellectual disability v3.1289
Dystonia, chorea or related movement disorder, childhood onset v1.153 CAMK4 Arina Puzriakova gene: CAMK4 was added
gene: CAMK4 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Other,Expert Review Amber,Literature
Q3_21_rating tags were added to gene: CAMK4.
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
Mode of pathogenicity for gene: CAMK4 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Classified gene: CAMK4 as Amber List (moderate evidence)
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There are sufficient unrelated cases (3) presenting with a relevant phenotype in association with different variants in the CAMK4 gene.
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Gene: camk4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1288 CAMK4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CAMK4.
Intellectual disability v3.1288 CAMK4 Arina Puzriakova Mode of pathogenicity for gene: CAMK4 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
Early onset or syndromic epilepsy v2.425 SYNCRIP Arina Puzriakova Classified gene: SYNCRIP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.425 SYNCRIP Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as only two individuals with seizures have been reported to date (MAE type)
Early onset or syndromic epilepsy v2.425 SYNCRIP Arina Puzriakova Gene: syncrip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1287 SYNCRIP Arina Puzriakova Phenotypes for gene: SYNCRIP were changed from to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Intellectual disability v3.1286 SYNCRIP Arina Puzriakova Publications for gene: SYNCRIP were set to 27479843; 26350204
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Tag watchlist was removed from gene: SYNCRIP.
Tag Q3_21_rating tag was added to gene: SYNCRIP.
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Classified gene: SYNCRIP as Amber List (moderate evidence)
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are sufficient unrelated cases to rate as Green at the next GMS review. All individuals reported to date have presented with ID of various severity as the predominant feature.
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Gene: syncrip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1284 SYNCRIP Arina Puzriakova Mode of inheritance for gene: SYNCRIP was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.244 EIF2S3 Ivone Leong Tag Q3_21_rating tag was added to gene: EIF2S3.
Severe microcephaly v2.244 EIF2S3 Ivone Leong Classified gene: EIF2S3 as Amber List (moderate evidence)
Severe microcephaly v2.244 EIF2S3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.244 EIF2S3 Ivone Leong Gene: eif2s3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.243 EIF2S3 Ivone Leong Phenotypes for gene: EIF2S3 were changed from MEHMO syndrome, MIM# 300148 to MEHMO syndrome, OMIM:300148
Intellectual disability v3.1283 HIST1H4C Ivone Leong Tag watchlist was removed from gene: HIST1H4C.
Tag Q3_21_rating tag was added to gene: HIST1H4C.
Intellectual disability v3.1283 HIST1H4C Ivone Leong reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.242 HIST1H4C Ivone Leong Tag Q3_21_rating tag was added to gene: HIST1H4C.
Severe microcephaly v2.242 HIST1H4C Ivone Leong Classified gene: HIST1H4C as Amber List (moderate evidence)
Severe microcephaly v2.242 HIST1H4C Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (possible) but not OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.242 HIST1H4C Ivone Leong Gene: hist1h4c has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.241 HIST1H4C Ivone Leong commented on gene: HIST1H4C
Severe microcephaly v2.241 HIST1H4C Ivone Leong Tag new-gene-name tag was added to gene: HIST1H4C.
Severe microcephaly v2.241 LAGE3 Ivone Leong Tag Q3_21_rating tag was added to gene: LAGE3.
Severe microcephaly v2.241 LAGE3 Ivone Leong Classified gene: LAGE3 as Amber List (moderate evidence)
Severe microcephaly v2.241 LAGE3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (possible). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.241 LAGE3 Ivone Leong Gene: lage3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.240 LAGE3 Ivone Leong Phenotypes for gene: LAGE3 were changed from Galloway-Mowat syndrome 2, X-linked, MIM# 301006 to Galloway-Mowat syndrome 2, X-linked, OMIM:301006
Intellectual disability v3.1283 ATP1A3 Arina Puzriakova Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699; 32802951
Intellectual disability v3.1282 ATP1A3 Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: ATP1A3.
Intellectual disability v3.1282 ATP1A3 Arina Puzriakova commented on gene: ATP1A3: Gene was reassessed following a further Green review by Zornitza Stark (8 Jul 2021). Vetro et al. (PMID: 33880529) identified several individuals with variants in this gene who presented with DD/ID as the predominant feature. Therefore, ATP1A3 will be flagged for GMS expert review as inclusion on this panel may be of value in some patients but previous comments regarding association with several phenotypes should be considered.
Early onset or syndromic epilepsy v2.424 MED17 Ivone Leong Tag watchlist tag was added to gene: MED17.
Early onset or syndromic epilepsy v2.424 MED17 Ivone Leong Phenotypes for gene: MED17 were changed from Microcephaly, postnatal progressive, with seizures and brain atrophy 613668 to Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668
Early onset or syndromic epilepsy v2.423 MED17 Ivone Leong Publications for gene: MED17 were set to 26004231; 20950787
Early onset or syndromic epilepsy v2.422 MED17 Ivone Leong reviewed gene: MED17: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.239 MED17 Ivone Leong Classified gene: MED17 as Amber List (moderate evidence)
Severe microcephaly v2.239 MED17 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene as been given an Amber rating as 2 out of 3 cases (PMID:20950787 is caused by founder effect) have severe microcephaly. Until further evidence is available this gene will remain as Amber.
Severe microcephaly v2.239 MED17 Ivone Leong Gene: med17 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.238 MED17 Ivone Leong Tag watchlist tag was added to gene: MED17.
Severe microcephaly v2.238 MED17 Ivone Leong Phenotypes for gene: MED17 were changed from Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668 to Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668
Severe microcephaly v2.237 MED17 Ivone Leong Publications for gene: MED17 were set to 20950787; 30345598; 26004231
Intellectual disability v3.1282 CPE Dmitrijs Rots reviewed gene: CPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 34383079; Phenotypes: Obesity, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1282 RFX3 Arina Puzriakova Phenotypes for gene: RFX3 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability v3.1282 RFX7 Arina Puzriakova Phenotypes for gene: RFX7 were changed from Intellectual disability, MONDO:0001071, autism spectrum disorder, MONDO:0005258, attention deficit-hyperactivity disorder, MONDO:0007743 to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability v3.1281 RFX4 Arina Puzriakova Phenotypes for gene: RFX4 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258
Intellectual disability v3.1280 RFX7 Arina Puzriakova Classified gene: RFX7 as Amber List (moderate evidence)
Intellectual disability v3.1280 RFX7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 14 unrelated individuals were identified with different variants in the RFX7 gene (13 de novo, 1 unknown). Presenting phenotypes were predominantly of ID/GDD (13/14) and dysmorphism (12/14).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1280 RFX7 Arina Puzriakova Gene: rfx7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1279 RFX4 Arina Puzriakova Classified gene: RFX4 as Amber List (moderate evidence)
Intellectual disability v3.1279 RFX4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 6 individuals from 4 unrelated families were identified with different variants in the RFX4 gene (3 de novo, 1 inherited). Presenting phenotypes include ID/GDD (6/6) and ASD (5/6).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1279 RFX4 Arina Puzriakova Gene: rfx4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1278 RFX7 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RFX7.
Intellectual disability v3.1278 RFX4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RFX4.
Intellectual disability v3.1278 RFX3 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RFX3.
Intellectual disability v3.1278 RFX3 Arina Puzriakova Classified gene: RFX3 as Amber List (moderate evidence)
Intellectual disability v3.1278 RFX3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 18 individuals from 15 unrelated families were identified with different heterozygous variants in the RFX3 gene (14 de novo, 1 inherited). Presenting phenotypes include ID/GDD (14/18), ASD (13/18) and ADHD (10/18).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1278 RFX3 Arina Puzriakova Gene: rfx3 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.36 TAPT1 Eleanor Williams Classified gene: TAPT1 as Green List (high evidence)
Osteogenesis imperfecta v2.36 TAPT1 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green; 2 cases reported, supportive zebrafish data and green review by NHS expert.
Osteogenesis imperfecta v2.36 TAPT1 Eleanor Williams Gene: tapt1 has been classified as Green List (High Evidence).
Osteogenesis imperfecta v2.35 TAPT1 Eleanor Williams commented on gene: TAPT1: Only 2 cases reported but PMID: 26365339 - Symoens et al 2015 - also report that knock-down of zebrafish tapt1b resulted in severe malformations of the craniofacial skeleton and delayed ossification.

PMID: 17151244 - Howell et al 2007 - also reports a skeletal phenotype in a mouse with a homozygous mutation in Tapt1, primarily posterior-to-anterior transformations of the vertebral column midsection.
Severe microcephaly v2.236 NSD2 Ivone Leong Classified gene: NSD2 as Amber List (moderate evidence)
Severe microcephaly v2.236 NSD2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases associated with this gene; however, the severity of microcephaly in these cases do not satisfy our criteria for severe microcephaly. Therefore, this gene has been given an Amber rating.
Severe microcephaly v2.236 NSD2 Ivone Leong Gene: nsd2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.235 NSD2 Ivone Leong Publications for gene: NSD2 were set to 30345613; 31171569
Severe microcephaly v2.234 NSD2 Ivone Leong Phenotypes for gene: NSD2 were changed from microcephaly; intellectual disability to microcephaly, MONDO:0001149
Osteogenesis imperfecta v2.35 DSPP Eleanor Williams Tag Q3_21_expert_review tag was added to gene: DSPP.
Osteogenesis imperfecta v2.35 DSPP Eleanor Williams commented on gene: DSPP: Conflicting reviews so tagging for GMS review.
Severe microcephaly v2.233 NUP107 Ivone Leong Phenotypes for gene: NUP107 were changed from Galloway-Mowat syndrome 7, MIM# 618348 to Galloway-Mowat syndrome 7, OMIM:618348
Severe microcephaly v2.232 NUP107 Ivone Leong Classified gene: NUP107 as Amber List (moderate evidence)
Severe microcephaly v2.232 NUP107 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (possible). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.232 NUP107 Ivone Leong Gene: nup107 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.231 NUP107 Ivone Leong Tag Q3_21_rating tag was added to gene: NUP107.
Osteogenesis imperfecta v2.35 SGMS2 Eleanor Williams Classified gene: SGMS2 as Amber List (moderate evidence)
Osteogenesis imperfecta v2.35 SGMS2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 8 cases reported with 3 different variants.
Osteogenesis imperfecta v2.35 SGMS2 Eleanor Williams Gene: sgms2 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.34 SGMS2 Eleanor Williams Tag Q3_21_rating tag was added to gene: SGMS2.
Osteogenesis imperfecta v2.34 SGMS2 Eleanor Williams Phenotypes for gene: SGMS2 were changed from Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia MIM#126550 to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia, OMIM:126550; calvarial doughnut lesions-bone fragility syndrome, MONDO:0007470
Osteogenesis imperfecta v2.33 SGMS2 Eleanor Williams reviewed gene: SGMS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30779713, 32028018; Phenotypes: Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia, OMIM:126550, calvarial doughnut lesions-bone fragility syndrome, MONDO:0007470; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.231 PCDH12 Ivone Leong Classified gene: PCDH12 as Amber List (moderate evidence)
Severe microcephaly v2.231 PCDH12 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.231 PCDH12 Ivone Leong Gene: pcdh12 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.230 PCDH12 Ivone Leong Tag Q3_21_rating tag was added to gene: PCDH12.
Severe microcephaly v2.230 PCDH12 Ivone Leong Phenotypes for gene: PCDH12 were changed from Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280 to Diencephalic-mesencephalic junction dysplasia syndrome 1, OMIM:251280
Osteogenesis imperfecta v2.33 COPB2 Eleanor Williams Added comment: Comment on mode of inheritance: Left as monoallelic for now as only 1 biallelic case reported.
Osteogenesis imperfecta v2.33 COPB2 Eleanor Williams Mode of inheritance for gene: COPB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Osteogenesis imperfecta v2.32 SUCO Eleanor Williams Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta; skeletal dysplasia; osteopenia to Osteogenesis imperfecta, MONDO:0019019; skeletal dysplasia, HP:0002652; osteopenia
Osteogenesis imperfecta v2.31 SUCO Eleanor Williams Phenotypes for gene: SUCO were changed from Osteogenesis imperfecta to Osteogenesis imperfecta; skeletal dysplasia; osteopenia
Osteogenesis imperfecta v2.30 SUCO Eleanor Williams Classified gene: SUCO as Amber List (moderate evidence)
Osteogenesis imperfecta v2.30 SUCO Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 1 case plus supportive mouse model.
Osteogenesis imperfecta v2.30 SUCO Eleanor Williams Gene: suco has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.29 SUCO Eleanor Williams reviewed gene: SUCO: Rating: AMBER; Mode of pathogenicity: None; Publications: 29620724, 20440000; Phenotypes: skeletal dysplasia, osteopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1277 EIF2AK2 Dmitrijs Rots reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare anaemia v1.26 RPS27 Zornitza Stark reviewed gene: RPS27: Rating: RED; Mode of pathogenicity: None; Publications: 25424902; Phenotypes: Diamond-Blackfan anemia 17, MIM# 617409; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.229 COPB2 Eleanor Williams gene: COPB2 was added
gene: COPB2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: COPB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to 29036432
Phenotypes for gene: COPB2 were set to Microcephaly, HP:0000252
Review for gene: COPB2 was set to RED
Added comment: PMID: 29036432 - DiStasio et al 2017 - report of severe microcephaly (developing to be below -4.0 SD) and severe intellectual disability in the two siblings with a COPB2 homozygous variant.

The siblings were later investigated for low bone mass in PMID: 34450031 - Marom et al 2021 (in which heterozygous variants in COPB2 in 4 other families with probands with osteoporosis and developmental delay were identified, but no microcephaly reported).
Sources: Literature
Intellectual disability v3.1277 COPB2 Eleanor Williams Classified gene: COPB2 as Amber List (moderate evidence)
Intellectual disability v3.1277 COPB2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber with a recommendation for green rating following GMS review.
Intellectual disability v3.1277 COPB2 Eleanor Williams Gene: copb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1276 COPB2 Eleanor Williams Tag Q3_21_rating tag was added to gene: COPB2.
Intellectual disability v3.1276 COPB2 Eleanor Williams changed review comment from: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass
Sources: Literature; to: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass

PMID: 29036432 - original report of microcephaly in the two siblings with the COPB2 homozygous variant.
Osteogenesis imperfecta v2.29 COPB2 Eleanor Williams changed review comment from: As Zornitza Stark reports, PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass; to: As Zornitza Stark reports, PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2 +/-mice exhibit low bone mass.

PMID: 29036432 - original report of microcephaly in the two siblings with the COPB2 homozygous variant.
Osteogenesis imperfecta v2.29 COPB2 Eleanor Williams Publications for gene: COPB2 were set to 34450031
Intellectual disability v3.1276 COPB2 Eleanor Williams Added comment: Comment on mode of inheritance: 4 families with heterozygous variants and 1 with biallelic (more severe phenotype)
Intellectual disability v3.1276 COPB2 Eleanor Williams Mode of inheritance for gene: COPB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1275 COPB2 Eleanor Williams gene: COPB2 was added
gene: COPB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COPB2 were set to 34450031
Phenotypes for gene: COPB2 were set to osteoporosis; developmental delay
Review for gene: COPB2 was set to GREEN
Added comment: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass
Sources: Literature
Osteogenesis imperfecta v2.28 COPB2 Eleanor Williams Phenotypes for gene: COPB2 were changed from juvenile osteoporosis to juvenile osteoporosis; Osteopenia; Osteoporosis; recurrent fractures
Osteogenesis imperfecta v2.27 COPB2 Eleanor Williams Publications for gene: COPB2 were set to Marom et al 2018 ASBMR: COPB2 Loss of Function Leads to Disrupted Collagen Trafficking and Juvenile Osteoporosis
Osteogenesis imperfecta v2.26 COPB2 Eleanor Williams Tag Q3_21_rating tag was added to gene: COPB2.
Osteogenesis imperfecta v2.26 COPB2 Eleanor Williams edited their review of gene: COPB2: Added comment: As Zornitza Stark reports, PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass; Changed rating: GREEN; Changed publications to: 34450031; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Osteogenesis imperfecta v2.26 MESD Eleanor Williams commented on gene: MESD: Further green review from NHS clinician, but already tagged for green rating in next GMS review.
Osteogenesis imperfecta v2.26 FAM46A Eleanor Williams commented on gene: FAM46A: Further green review by Meena Balasubramanian, so keeping green rating.
Osteogenesis imperfecta v2.26 FAM46A Eleanor Williams Phenotypes for gene: FAM46A were changed from Osteogenesis imperfecta, type XVIII, OMIM:617952 to Osteogenesis imperfecta, type XVIII, OMIM:617952; osteogenesis imperfecta, type 18, MONDO:0044329
Osteogenesis imperfecta v2.25 MBTPS2 Eleanor Williams Classified gene: MBTPS2 as Amber List (moderate evidence)
Osteogenesis imperfecta v2.25 MBTPS2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. Only 2 cases reported in literature so waiting for further GMS feedback on the rating of this gene.
Osteogenesis imperfecta v2.25 MBTPS2 Eleanor Williams Gene: mbtps2 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.24 MBTPS2 Eleanor Williams changed review comment from: Associated with Osteogenesis imperfecta, type XIX #301014 (AR) in OMIM.

PMID: 27380894 - Lindert et al 2016 - report two independent OI pedigrees (Thai and German) without symptoms of any dermatological condition previously associated with variants in this gene(ichthyosis follicularis, atrichia, and photophobia (IFAP); BRESEK/BRESHECK syndrome; and keratosis follicularis spinulosa decalvans (KFSD)). In both families missense mutations were identified which was in or near the S2P NPDG motif vital for metal ion coordination. All those affected were male. Mutant S2P protein was found to be stable but cleavage or activation of S2P substrates OASIS and ATF6, respectively, was impaired, consistent with reduced proband collagen secretion.

A search of PubMed find no further cases.; to: Associated with Osteogenesis imperfecta, type XIX #301014 (AR) in OMIM.

PMID: 27380894 - Lindert et al 2016 - report two independent OI pedigrees (Thai and German) without symptoms of any dermatological condition previously associated with variants in this gene(ichthyosis follicularis, atrichia, and photophobia (IFAP); BRESEK/BRESHECK syndrome; and keratosis follicularis spinulosa decalvans (KFSD)). In both families missense mutations were identified which was in or near the S2P NPDG motif vital for metal ion coordination. All those affected were male. Mutant S2P protein was found to be stable but cleavage or activation of S2P substrates OASIS and ATF6, respectively, was impaired, consistent with reduced proband collagen secretion.

A search of PubMed finds no further cases.
Osteogenesis imperfecta v2.24 MBTPS2 Eleanor Williams Phenotypes for gene: MBTPS2 were changed from Osteogenesis imperfecta, type XIX, MIM# 301014 to Osteogenesis imperfecta, type XIX, OMIM:301014; osteogenesis imperfecta, type 19, MONDO:0049223
Osteogenesis imperfecta v2.23 MBTPS2 Eleanor Williams Tag Q3_21_rating tag was added to gene: MBTPS2.
Tag Q3_21_expert_review tag was added to gene: MBTPS2.
Osteogenesis imperfecta v2.23 MBTPS2 Eleanor Williams reviewed gene: MBTPS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27380894; Phenotypes: Osteogenesis imperfecta, type XIX, OMIM:301014; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.7 HID1 Arina Puzriakova Entity copied from Intellectual disability v3.1274
Pituitary hormone deficiency v2.7 HID1 Arina Puzriakova gene: HID1 was added
gene: HID1 was added to Pituitary hormone deficiency. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: HID1.
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Early onset or syndromic epilepsy v2.422 HID1 Arina Puzriakova Entity copied from Intellectual disability v3.1274
Early onset or syndromic epilepsy v2.422 HID1 Arina Puzriakova gene: HID1 was added
gene: HID1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: HID1.
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Intellectual disability v3.1274 HID1 Arina Puzriakova Tag Q3_21_rating tag was added to HID1.
Intellectual disability v3.1273 HID1 Arina Puzriakova Classified gene: HID1 as Amber List (moderate evidence)
Intellectual disability v3.1273 HID1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1273 HID1 Arina Puzriakova Gene: hid1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1272 HID1 Arina Puzriakova reviewed gene: HID1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33999436; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.717 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Fetal anomalies v1.717 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to None
Dystonia, chorea or related movement disorder, childhood onset v1.152 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Dystonia, chorea or related movement disorder, childhood onset v1.152 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from None to Other
Intellectual disability v3.1272 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Intellectual disability v3.1272 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to None
Early onset or syndromic epilepsy v2.421 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Early onset or syndromic epilepsy v2.421 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from None to Other
Clefting v2.49 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Clefting v2.49 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to Other
Dystonia, chorea or related movement disorder, childhood onset v1.151 GRIN1 Sarah Leigh edited their review of gene: GRIN1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen, although there is a confirmed association with epileptic encephalopathy in Gen2Phen. At least 20 variants have been associated with Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254 and three have been associated with Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820.; Changed rating: GREEN
Intellectual disability v3.1271 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; Mental retardation, autosomal dominant 8, 614254; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Early onset or syndromic epilepsy v2.420 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Mental retardation, autosomal dominant 8; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; early onset epileptic encephalopathies; involuntary movements; severe developmental delay; intellectual disability; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Fetal anomalies v1.716 GRIN1 Sarah Leigh edited their review of gene: GRIN1: Added comment: The MOI monoallelic is listed for this panel, as the phenotype was initially listed as epileptic encephalopathy and only one biallelic case has been reported with this phenotype. However, other fetal phenotypes are associated with both monoallelic and biallelic GRIN1 variants in Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254 and Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820.; Changed rating: GREEN
Fetal anomalies v1.716 GRIN1 Sarah Leigh changed review comment from: Comment on mode of inheritance: The Q3_21_MOI tag has been added to this gene as the MOI should be changed to - BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: The Q3_21_MOI tag has been added to this gene as the MOI should be changed to - BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Fetal anomalies v1.716 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Malformations of cortical development v2.90 GRIN1 Sarah Leigh Added comment: Comment on mode of inheritance: Although the MOI could be listed as "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, this was not done on this panel, as the phenotypes of malformation of cortical development have not been reported with biallelic variants.
Malformations of cortical development v2.90 GRIN1 Sarah Leigh Mode of inheritance for gene: GRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.44 GRIN1 Sarah Leigh changed review comment from: Comment on mode of inheritance: The MOI could be changed to "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, however, this was not done on this panel, as the phenotype that is confirmed on Gen2Phen is epileptic encephalopathy, and only one biallelic case has been reported with this phenotype.; to: Comment on mode of inheritance: The MOI could be changed to "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, however, this was not done on this panel, as the phenotype that is confirmed on Gen2Phen is epileptic encephalopathy (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=1357), and only one biallelic case has been reported with this phenotype.
DDG2P v2.44 GRIN1 Sarah Leigh Deleted their comment
DDG2P v2.44 GRIN1 Sarah Leigh Added comment: Comment on phenotypes: EPILEPTIC ENCEPHALOPATHY
DDG2P v2.44 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655
DDG2P v2.43 GRIN1 Sarah Leigh Added comment: Comment on mode of inheritance: The MOI could be changed to "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, however, this was not done on this panel, as the phenotype that is confirmed on Gen2Phen is epileptic encephalopathy, and only one biallelic case has been reported with this phenotype.
DDG2P v2.43 GRIN1 Sarah Leigh Mode of inheritance for gene: GRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.715 GRIN1 Sarah Leigh Added comment: Comment on mode of inheritance: The Q3_21_MOI tag has been added to this gene as the MOI should be changed to - BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Fetal anomalies v1.715 GRIN1 Sarah Leigh Mode of inheritance for gene: GRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.714 GRIN1 Sarah Leigh Tag Q3_21_MOI tag was added to gene: GRIN1.
Malformations of cortical development v2.89 GRIN1 Sarah Leigh edited their review of gene: GRIN1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen, although there is a confirmed association with epileptic encephalopathy in Gen2Phen. Nine de novo GRIN1 variants in eleven cases of bilateral polymicrogyria have been reported by Fry et al (PMID: 29365063), analysis of available samples from parents confirmed the de novo occurance of these GRIN1 variants.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.89 GRIN1 Sarah Leigh Tag Q3_21_rating tag was added to gene: GRIN1.
Malformations of cortical development v2.89 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, OMIM:614254 to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655
Malformations of cortical development v2.88 GRIN1 Sarah Leigh Publications for gene: GRIN1 were set to 29365063
Dystonia, chorea or related movement disorder, childhood onset v1.151 GRIN1 Sarah Leigh Publications for gene: GRIN1 were set to 29365063; 27164704; 27164704; 28051072
Dystonia, chorea or related movement disorder, childhood onset v1.150 GRIN1 Sarah Leigh Tag Q3_21_rating tag was added to gene: GRIN1.
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RAD21.
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). At least 3 unrelated individuals reported in literature with different heterozygous KMT2D variants and holoprosencephaly, which may be observed with or without overt features of CdLS. Sufficient to rate this gene as Green at the next GMS panel update.
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.22 RAD21 Arina Puzriakova Added comment: Comment on publications: PMID: 32696056 (2020) - fourth unrelated individual reported presenting holoprosencephaly associated with a heterozygous RAD21 LoF variant
Holoprosencephaly v2.22 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 31334757
Holoprosencephaly v2.21 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Holoprosencephaly; Septo-optic dysplasia to Cornelia de Lange syndrome 4, OMIM:614701; Holoprosencephaly with or without CdLS features; Septo-optic dysplasia
Fetal hydrops v1.35 KMT2D Arina Puzriakova Classified gene: KMT2D as Green List (high evidence)
Fetal hydrops v1.35 KMT2D Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There are sufficient unrelated cases with prenatal hydrops and variants in this gene to rate as Green on this panel. KMT2D is also already Green on the GMS Fetal anomalies (R21) panel.
Fetal hydrops v1.35 KMT2D Arina Puzriakova Gene: kmt2d has been classified as Green List (High Evidence).
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Tag Q3_21_rating tag was added to gene: KMT2D.
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Classified gene: KMT2D as Amber List (moderate evidence)
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). At least 3 unrelated individuals reported in literature with different heterozygous KMT2D variants and holoprosencephaly, which may be observed in the absence of overtly obvious features of Kabuki syndrome. Sufficient to rate this gene as Green at the next GMS panel update.
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Gene: kmt2d has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.228 OSGEP Ivone Leong Tag Q3_21_rating tag was added to gene: OSGEP.
Severe microcephaly v2.228 OSGEP Ivone Leong Classified gene: OSGEP as Amber List (moderate evidence)
Severe microcephaly v2.228 OSGEP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.228 OSGEP Ivone Leong Gene: osgep has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.227 OSGEP Ivone Leong Phenotypes for gene: OSGEP were changed from Galloway-Mowat syndrome 3, MIM# 617729 to Galloway-Mowat syndrome 3, OMIM:617729
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.53 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 147920; 147920 to Kabuki syndrome 1, OMIM:147920
Intellectual disability v3.1270 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome to Kabuki syndrome 1, OMIM:147920
Severe microcephaly v2.226 VRK1 Ivone Leong Tag Q3_21_rating tag was added to gene: VRK1.
Severe microcephaly v2.226 VRK1 Ivone Leong Classified gene: VRK1 as Amber List (moderate evidence)
Severe microcephaly v2.226 VRK1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.226 VRK1 Ivone Leong Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.225 VRK1 Ivone Leong Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A MIM#607596 to Pontocerebellar hypoplasia type 1A, OMIM:607596
Malformations of cortical development v2.87 GRIN1 Sarah Leigh Classified gene: GRIN1 as Amber List (moderate evidence)
Malformations of cortical development v2.87 GRIN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.87 GRIN1 Sarah Leigh Gene: grin1 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.19 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920 to Kabuki syndrome 1, OMIM:147920
Dystonia, chorea or related movement disorder, childhood onset v1.150 GRIN1 Sarah Leigh Classified gene: GRIN1 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.150 GRIN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Dystonia, chorea or related movement disorder, childhood onset v1.150 GRIN1 Sarah Leigh Gene: grin1 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.149 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820 to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, OMIM:616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Early onset or syndromic epilepsy v2.419 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, 616973; seizures to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Clefting v2.48 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, 616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855